Adverse effects of montelukast in children

Adverse effects of montelukast in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Adverse effects of montelukast in children Abdullah saeed Al-Shamrani, Saleh Alharbi, Sumayyah Kobeisy, Suzan Alkhater, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1955880/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Montelukast is a leukotriene receptor antagonist (LTRA) commonly prescribed for asthma, allergic rhinitis and sleep-related breathing disorders. Recently, some studies have reported several adverse events, such as neuropsychiatric disorders and sleep disturbances, among children. Objective: To obtain more insight into the safety profile of montelukast for children with asthma, allergic rhinitis and sleep-related breathing disorders. Method and results: We retrospectively studied all adverse drug reactions to montelukast among 385 children 6 months or older in five tertiary centers over a two-year period. A total of 89.6% were asthmatic, 50% had allergic rhinitis and 13.6% had sleep-related breathing disorders; Singulair was the most common type of montelukast used (67.9%). This study reported a high prevalence of adverse effects among 123 patients (31.9%), predominantly in those aged 4-9 years (52.8%), followed by adolescent children (24.4%) and toddlers (22.8%). Two adverse effects were reported in 9.8% of the children, while three or more were reported in 5.5%. Sleep disturbance was the most commonadverse effect, affecting 15.1% of participants (overlap was common; 5.5% of children experienced sleep difficulties, 4.4% experienced sleep interruption and decreased sleep, and 1.82% experienced nightmares), followed by agitation (10.4%), pain (9.4%) and hyperactivity (6.8%). No serious adverse effects were reported. Eleven percent of families faced difficulties in purchasing montelukast, and only 57% of families had insurance. Misconceptions were common (9.8% reported it to be a steroid, while 30.6% believed it to be a bronchodilator). Although 81% of the families believed it was an effective and preventive medication, 5.3% stopped the drug due to concern about side effects, especially agitation (3%) and nightmares (0.6%). Conclusion: These data demonstrate that montelukast is effective, but the associated adverse neuropsychiatric drug reactions are more prevalent than those reported in the literature. In particular, sleep disturbance, agitation, pain and hyperactivity were observed. Pediatricians should be aware of such adverse effects. Misconceptions about montelukast are still common, and parental counseling and urgent epidemiological studies are needed to quantify the risk for management plans. Montelukast singular neuropsychiatry side effect adverse effect Introduction Montelukast is a leukotriene receptor antagonist (LTRA) that is one of the most common medications used for asthma and other medical conditions. LTRAs function by inhibiting inflammatory mediators of bronchoconstriction, and they are prescribed primarily as adjuvant medication to inhaled corticosteroids for patients with step 3 or higher asthma, although they might be prescribed as an alternative to inhaled corticosteroids for mild asthma. 1 In 2009, the US Food and Drug Administration (FDA) warned clinicians about the use of montelukast, which included certain important observations that may involve neuropsychiatric changes. 2 This study was intended to evaluate all potential side effects that have been reported or addressed by searching the MEDLINE database and focusing on neuropsychiatric attributes after starting montelukast, such as sleep disturbance, anxiety, oppositional, depression and any sort of suicidal attempt. 3 – 4 During this decade, numerous studies were released discussing the neuropsychiatric effects of leukotrienes, but the relationship was not direct and remained controversial. 5 – 8 Due to the high prevalence of asthma among children and the serious side effects of montelukast, we decided to investigate whether this popular medication, which is commonly used under limited conditions for pediatric patients, is associated with any neuropsychiatric event in children in five main cities in Saudi Arabia. 7 – 10 Asthma is a common childhood condition, and its prevalence has increased in the last two decades from 8 to 23%. 11,12 In the Kingdom of Saudi Arabia, the highest prevalence is reported in Hafoof (33%), and the lowest is reported in the southern region of the kingdom (Abha) (7%). 13 Unfortunately, the majority of asthma cases in the Kingdom of Saudi Arabia are uncontrolled, as reported by Dr. Jahdali et al using Asthma Control Test (ACT). 14 A similar study was conducted by Dr. Aslan et al., which showed that 50% of asthma cases among children were uncontrolled in a tertiary center in Riyadh. 15 Asthma is an often heterogeneous disease with a wide range of presentations from mild cough to severe exacerbation with different asthma phenotypes. 16 , 50 Asthma cases are often divided into two main groups: a younger age group and an older age group . Such classification helps health care providers diagnose and manage the patients’ conditions. In patients older than 5 years of age, it is easy to diagnose asthma, as it is straightforward based on clinical presentation. asthma medical history suggesting asthma includes intermittent cough that is often worse in winter, at night or after exercise. The cough in asthma is often dry except during exacerbation and then becomes wet and is associated with wheezing, shortness of breath, and chest tightness. Such patients respond well to asthma therapy, including bronchodilators or corticosteroids. There are different types of montelukast that are used for this group as add-ons to inhaled steroids, and they are often chewable tablets (4,5 or 10 mg) 16 , 17 , 18 . However, it is a real challenge for health care providers to diagnose asthma in patients younger than 5 years, as patients of this age are unable to undergo spirometry may have similar conditions that share the same symptoms of cough, wheezing and shortness of breath. Furthermore, there are different asthma phenotypes and different presentations, which are often summarized as follows: - a residual cough after a flu-like illness; - coughing late at night or early in the morning, which could be the only presentation of asthma; - recurrent or persistent wheezing; and - bronchopneumonia, which is rare. - Currently, the majority of asthma cases worldwide are still uncontrolled, even in Saudi Arabia, per different reports; fortunately, there has been some improvement according to recent publications. 19 – 22 Montelukast plays an important role in the management of asthma, nasal allergies and sleep-related breathing disturbances, and the most common types of montelukast are 4 mg granules or chewable tablets. 17 Allergic rhinitis and sinusitis are frequent causes of nocturnal coughing and are most often misdiagnosed as asthma. They share triggers with asthma, and there are two main types of presentation: Type 1 (non-inflammatory /watery) is the predominant type, and the child presents with clear nasal discharge, sneezing and nasal itching; and Type 2 (inflammatory) is the less common type, and the child presents with a blocked nose and signs of nasal obstruction. 23 , 24 , 66 Allergic rhinitis should also be suspected if the presentation is associated with other clinical features of allergic rhinitis, such as sneezing, nasal blockage, allergic salute, or allergic shiners, or if the response to asthma medications is poor. Commonly used medications include intranasal corticosteroids and oral antihistamines. 23 Intranasal antihistamines may be necessary to improve the treatment of nonallergic rhinitis with eosinophilia(NARES) or vasomotor rhinitis. 24 , 25 Longitudinal studies have confirmed that both allergic rhinitis and positive allergic skin tests are risk factors for asthma. 26 Montelukast is often used as an adjuvant to inhaled steroids for asthma with proven efficacy, 27 and allergic rhinitis is often associated with asthma and called united airway disease. 28 Chronic rhinosinusitis with and without nasal polyps may aggravate some symptoms, particularly coughing, which may be attributed to severe asthma. 29 – 30 Sleep-related breathing disorders are characterized by prolonged partial upper airway obstruction and/or intermittent complete obstructive apnea that disrupts normal ventilation during sleep and normal sleep patterns. 31 Classification based on polysomnography results as proposed by Dayyat, E. et al. stated that it is essential to differentiate OSA from other disorders as the treatment and complications are different. 32 OSA occurs in children of all ages, and the prevalence varies depending on the populations studied and on the stringency of the diagnostic criteria. The prevalence is 1 − 5% among children, with the peak prevalence occurring between the ages of 2 − 8 years and the peak of symptoms often occurring in the middle of the second year, which could be related to the peak growth of lymphoid tissue. 33 – 35 While the prevalence of habitual snoring is estimated to be approximately 15%, although it has been reported to be as high as 30% in the pediatric age group, the ratio of the prevalence of habitual snoring and OSA varies from 4:1 to 6:1. 36 OSA occurs equally among boys and girls during the prepubertal stage. 34 , 37 – 40 OSA has been reported to cause significant school problems among children, such as short attention span, aggressive behavior, poor academic performance, excessive daytime sleepiness, behavioral disorders, and multiple other problems, including cardiac growth and metabolic consequences. 41 – 43 Inhaled steroids and montelukast are effective medical therapies for mild forms of OSA. 44 – 50 Materials And Methods We retrospectively evaluated all potential adverse drug reactions (ADRs) to montelukast among children aged 6 m–17 years. This study was conducted in six tertiary centers in the Kingdom of Saudi Arabia [Prince Sultan Military Medical City (PSMMC) in Riyadh, Qassim University, Imam Abdulrahman Bin Faisal University in Dammam, Dr. Suleiman Fakeeh Hospital, King Abdul-Aziz University Hospital in Jeddah and Maternity and Children Hospital in Abha, Saudi Arabia] among children with a physician-confirmed diagnosis of asthma, allergic rhinitis or OSA until May 2022. The sample size was calculated using Epitools ( https://epitools.ausvet.com.au/oneproportion ). A sample of 385 children treated with montelukast was the minimum sample to have 80% power to ascertain a prevalence of adverse effects with a 95% confidence interval and a precision of 5%. An electronic questionnaire was used for the majority of patients, and the other patients were evaluated with a direct questionnaire or through the clinic; the focus was on children with symptoms suggestive of asthma, nasal allergies or sleep-related breathing disorders. The use of montelukast alone or as adjunct therapy to inhaled corticosteroids and/or long-acting bronchial agonists currently or in the past was also recorded. Children with known CNS disorders, associated comorbidities, or those who did not receive montelukast were excluded. The occurrence of montelukast-related adverse drug effects was assessed by questioning using three approaches. First, parents were asked about the three potential indications for montelukast, the types of montelukast and potential adverse effects and their knowledge of montelukast. However, for those children with sleep-related breathing disorders, we double checked if the symptoms worsened after being prescribed montelukast, as the disease itself can cause similar adverse effects to montelukast. The statistical analysis was performed using SPSS for Windows, version 21.0 (SPSS Inc., Chicago, IL, USA). The data are reported as frequencies and proportions. A nonparametric test was employed for variables with nonnormal distribution. Independent sample t tests were used to compare data between participants of different ages. Chi-square tests were used to compare categorical groups. P < 0.05 with a 95% confidence interval was considered statistically significant. Result A total of 385 patients were included in this study (boys, 64.4% and girls, 35.6%). Toddlers aged 1–3 years, children aged 4–9 years and adolescents aged over 10 years were the most affected (30.8%, 44.3%, and 23.4%, respectively). Boys were the most affected (62% asthma, 66% allergic rhinitis and 71% sleep-related breathing disorders). The most common indication for prescribing montelukast was asthma, with 89.6% (46.6% isolated and 43% associated), followed by allergic rhinitis at 50% (7% isolated) and asthma and allergic rhinitis at 28.1%; the least common indication was sleep-related breathing disorders alone at 13.6% (0.8% isolated) ( Table 1 ). Singulair was the most common type of montelukast (67.9%), followed by Airfast (20.2%), and 9.3% of the parents did not know the brand name. The most common concentration prescribed was 4 mg powder (33.9%), followed by 4 mg chewable tablets (31.9%) and 5 mg chewable tablets (26.7%); 1.8% patients used the 10 mg tablets, and 5.7% did not know the concentration. Families were satisfied with montelukast (78% agreed that it is a good preventive medication, 86% preferred to use it, and 81% believed that it is an effective medication). Only 5.3% stopped montelukast due to concerns about side effects. A total of 31.9% of the patients reported at least one adverse effect. The most common was observed among school children aged 4–9 years (52.8%), followed by adolescent children (24.4%) and toddlers (22.8%). The distribution of ADRs was as follows (Table 2) : sleep problems (15.1%), agitation (10.4%), pain (9.3%), hyperactivity (6.8%), short attention span (3.1%), aggression (2.1%) and headache (1.82%). There were different types of sleep problems, including sleep difficulties (5.5%), decreased sleep (4.4%), interrupted sleep (4.4%) and nightmares (1.82%). A total of 9.8% of patients reported two complaints, and 5.5% reported three or more complaints. Twenty percent of the parents were worried about the side effects of montelukast; furthermore, 11% faced difficulties in purchasing the medication, and only 57% had insurance. Regarding misconceptions, 9.8% believed montelukast was a steroid, while 30.6% believed it was a bronchodilator. The duration of montelukast usage ranged from one month to 108 months, with a mean of 8 months; the youngest patient was 6 months old, and the oldest was 17 years old. Regarding pain, predominantly abdominal pain (6.32%), chest and muscle pain (2.1%), and hyperactivity with short attention span or agitation (3.6%) were reported. No serious adverse effects, required hospitalizations or deaths were reported in this study. Recovery was reported for most patients when they discontinued the medication. Discussion Montelukast is a cysteinyl leukotriene receptor (D4 and E4) antagonist that is commonly used as prophylactic treatment for asthma and in the treatment of allergic rhinitis and sleep-related breathing disorders. 1 Since 2008, there has been an increasing number of reports on potential adverse drug reactions to montelukast, including irritability, aggressiveness, and sleep disturbances, usually occurring after 1 week of commencing therapy and occurring in up to 10% of children. 7 – 8 , 51 – 54 , 56 , 57 The World Health Organization (WHO) pharmacovigilance database reported multiple adverse effects, including depression, headache, aggression, suicidal ideation, anxiety, insomnia, abnormal behavior, nightmares, shortness of breath, abdominal pain, nausea, rash, dizziness, myalgia and muscle spasm. 52 The FDA advised caution when montelukast and other LTRAs are prescribed due to the potential adverse neuropsychiatric events (such as depression and suicidality) as a precaution. 52 – 53 , 58 On the other hand, a large nested case‒control study with 1920 asthmatic patients matched for age, sex, and geographic region did not detect a significant positive association between montelukast and neuropsychiatric events among children. 53 However, a more recent nested case‒control study reported an odds ratio of nearly 2 for new-onset neuropsychiatric events in children prescribed montelukast in the year before the event. 45 A retrospective study of reported adverse drug reactions in the Netherlands and worldwide data from the WHO indicated that nightmares were frequently reported after commencing montelukast in the first week of treatment, 52 with a reported odds ratio of 78.04 (95% CI 70.0–87.1) among children. Glockler-Lauf et al. reported that adverse effects occur within a week of starting montelukast, and children exposed to this drug tend to have a quick recovery of sleep disturbance upon cessation. 54 Given the high reported incidences of such adverse effects among both adults and children in the USA, Canada, and Europe, 7 – 8 , 45 , 52 – 54 60 , 61 (Table 3 ) summarizes reported adverse effects of montelukast among children. It is essential to know the prevalence and pattern of the adverse effects of montelukast among children with asthma, allergic rhinitis and OSA in Saudi Arabia. In this study, we found that almost one-third of the patients reported adverse effects that could be serious enough to disturb their lifestyle. Neuropsychiatric events were predominant, and the causative mechanism for montelukast is still not known. 54 Agitation (10.4%) was the single predominant adverse neuropsychiatric effect, which was slightly different from the aggression previously reported by Harman et al. 52 or anxiety as reported by Glockler-Lauf et al. 45 This report stresses the high prevalence (15.1%) of sleep disturbance among children using montelukast, including sleep difficulties (5.5%), interrupted sleep (4.4%), insomnia (4.4%), and nightmares (2.8%); three patients reported increased sleep duration (0.8%), and 5.5% reported more than three adverse sleep complaints. Previous studies have reported different types of sleep disturbance and depression effects associated with montelukast. 4 , 6 , 8 , 45 , 51 Nightmares were the main sleep-related cause to discontinue montelukast. 63 This report highlights different sleep disorders compared to what has been reported in the literature. The prevalence of pain (9.3%) was higher than that in a previous report (abdominal pain, 6.3%, chest and muscle pain, 2.1%); however, this high number could be exaggerated due to functional abdominal pain and growing pain, which are common in this age group. 6 , 62 Hyperactivity was reported in 6.8% of participants, while attention deficit was reported in 1.8%, which is similar to previous studies. 4 , 6 , 8 , 59 While Po-Yu Huang et al reported that montelukast Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients. 59 Hyperactivity or attention deficit hyperactivity disorder (ADHD) could be the presentation of sleep disturbance. Since a minority of the patients experienced sleep disturbance, it is difficult to reach a conclusion. 32 , 37 , 43 . Headaches were experienced by 1.82% of participants and were reported most frequently in the Dutch database (ROR, 2.26; 95% CI: 1.61–3.19). 52 Fatigue was reported in 1.5% of participants, and other adverse effects were reported in less than 1% (skin rash, vomiting, visual disturbance, itching and learning difficulties). No participants in this study showed any suicidal behavior, and no deaths occurred, as was cautioned by the US FDA in 2008. 9 Approximately 80% of the parents believed that montelukast is a good preventive and effective medication; however, the Pearson’s chi-square result was 4.455. Our result is similar to that in a Dutch study conducted in 2016, in which few families were aware of the side effects of montelukast, although this study emphasizes the limited knowledge of parents about this medication. 64 Eleven percent of participants’ families faced difficulties in purchasing the medication, and only 57% had insurance. Misconceptions were common (9.8% believed it was a steroid, while 30.6% believed it was a bronchodilator). 65 The duration of usage ranged from one month to 108 months, with a mean of 8 months; the youngest patient was 6 months old, and the oldest was 17 years old. This study emphasizes the importance of explaining the potential adverse effects to parents when prescribing montelukast for children. Risk management plans should be explained carefully. Pediatric health care providers should be aware of the risk of neuropsychiatric events and sleep disturbance associated with montelukast use and should advise the patient to observe, monitor and report any potential adverse effects. Conclusion This article offers a comprehensive overview of the safety of montelukast in clinical practice. This study confirms the concern of a high prevalence of adverse neuropsychiatric effects among patients receiving montelukast, especially agitation, sleep disturbance, pain, and hyperactivity. Families and physicians should be aware of the potential adverse effects of montelukast when it is prescribed; fortunately, no serious side effects have been reported. Misconceptions about montelukast are still common; therefore, education of the families is necessary. Further epidemiological studies are urgently needed to quantify the risk for management. Abbreviations LTRA, leukotriene receptor antagonist; ADRs, adverse drug reactions; ICSR, individual case safety report; ROR, reporting odds ratio; WHO, World Health Organization; ADHD, attention deficit hyperactivity disorder; CI, confidence interval. DAE: Drug adverse effect, NEC: Neurological disorders not elsewhere classified. Declarations Author Contributions Study conception and design: AS, AY, SA, and AM; Data acquisition: HA, AY, and SA; Data analysis: AS, SK, and AY; Data interpretation: AS and SK; Manuscript drafting and revision: TA and AH Disclosure The authors have no conflicts of interest, and the work was not supported or funded by any drug company. Acknowledgment Authors would like to thank the American journal experts for editing this manuscript. Financial support and sponsorship This manuscript did not receive any financial and logistic support. Conflicts of interest The authors declare that there is no conflict of interest regarding the publication of this article Ethics approval Signed informed consent for participation and publication of medical details was obtained from the parents of this child. Confidentiality of patient’s data was ensured at all stages. Ethics approval was obtained from the IRB Prince Sultan Medical city. (IRB-2020-0416). References Balzano G, Fuschillo S, Gaudiosi C. 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Owens; Lippincott Williams & Wilkins Owens, J. A., & Dalzell, V. (2005). Use of the “BEARS” sleep screening tool in a pediatric residents’ continuity clinic: a pilot study. Sleep Medicine 2004; 6(1): 63–69. The Global Initiative for Asthma (GINA) 2022 main report. Available at https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf Ernst P, Ernst G. Neuropsychiatric adverse effects of montelukast in children. Eur Respir J. 2017;50: 1701020 Haarman MG, van Hunsel F, de Vries TW. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect. 2017;5(5). e00341. Ali MM, O'Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case control study. Pharmacoepidemiol Drug Saf. 2015;24(4):435-45. Cereza G, Garcia Dolade N, Laporte JR. Nightmares induced by montelukast in children and adults. Eur Respir J. 2012;40(6):1574–5. Dariusz M Lebensztejn , Anna Bobrus-Chociej , Monika Kłusek, et al . Hepatotoxicity caused by montelukast in a paediatric patient. Prz Gastroenterol. 2014;9(2):121-3. doi: 10.5114/pg.2014.42509. Ji Soo Park, Yoo Jung Cho, Je-Yeon Yun, Hye Jin Lee, Jinho Yu, Hyeon-Jong Yang, Dong in Suh. Leukotriene-receptor antagonist and risk of neuropsychiatric events in children, adolescents, and young adults: a self-controlled case series. J Eur Respir J 2022; in press (https://doi.org/10.1183/13993003.02467-2021). https://www.drugs.com/sfx/montelukast-side-effects.html. Last updated on Mar 18, 2022. M.-S. Marchand, A.-P. Jonville-Be´raa, E. Autret-Leca et al. Psychiatric disorders associated with montelukast: Data from the National Pharmacovigilance Database. Archives de Pe´diatrie 2013; 20:269-273. Po-Yu Huang. Yao -Hsu Yang Ying Hua Huang and Hu Chang Kuo. et al. Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients: A nationwide population-based matched cohort study. Journal of formosan medical association 120(2021): 1369-1376. https://doi.org/10.1016/j.jfma.2020.10.018. Ekhart, C., Vries, T. de, & Hunsel, F. van. (2020). Psychiatric adverse drug reactions in the paediatric population. Archives of Disease in Childhood, archdischild–2019–317933. doi:10.1136/archdischild-2019-317933 Adriel Gerard , Shantie Harkisoon. Singulair-induced anaphylaxis? J Fam Pract. 2009 Mar;58(3):133-4. Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional Disorders: Children and Adolescents. Gastroenterology. 2016 Feb 15 ; [ PubMed ] Sarah Watson, Elenor Kaminsky, Henric Taavola, Marian Attalla and Qun‑Ying Yu. Montelukast and Nightmares: Further Characterisation Using Data from VigiBase. Drug Safety (2022) 45:675–684 https://doi.org/10.1007/s40264-022-01183-2 Dutch Farmacotherapeutic Compass. (2016). Available at: https://www.farmacotherapeutischkompas.nl Kam Lun Ellis Hon, Ting Fan Leung, and Alexander KC Leung. Clinical effectiveness and safety of montelukast in asthma. What are the conclusions from clinical trials and meta-analyses? Drug Des Devel Ther. 2014; 8: 839–850.doi: 10.2147/DDDT.S39100 Liva, G. A., Karatzanis, A. D., & Prokopakis, E. P. (2021). Review of Rhinitis: Classification, Types, Pathophysiology. Journal of Clinical Medicine, 10(14), 3183. doi:10.3390/jcm10143183 tables Table 1: Prevalence of diseases in Montelukast patient Disease Number Percent Sleep disorder of breathing 3 0.8% Allergic rhinitis 27 7.0% Allergic rhinitis and sleep disorder of breathing 10 2.6% Asthma 180 46.6% Asthma, sleep disorder of breathing 10 2.6% Asthma and AR 108 28.1% asthma, AR, Sleep disorder of breathing 29 7.6% Asthma, AR, and other 18 4.7% 385 100 Table-2: Adverse effect of montelukast in children Montelukast side effect Number Percent Agitation 40 10.4% Sleep problems 1- Decrease sleep 2- Interrupted sleep 3- Increase sleep 4- Sleep difficulties 5- Night mare 6- Decrease and interrupted sleep 7- Decrease and difficult sleep 8- ≥3 sleep complaint 58 17 17 3 21 7 11 7 21 15.1% 4.4% 4.4% 0.8% 5.5% 1.82% 2.9% 1.82% 5.55% Hyperactivity Hyperactivity and low attention Hyperactivity and agitation 26 7 7 6.8% 1.82% 1.82% Pain - Abdominal pain - Chest pain - Muscle pain - Chest and abdomen 36 24 8 8 5 9.35% 6.23% 2.1% 2.1% 1.3% Low attention 12 3.1% Aggression 8 2.1 % Headache 7 1.82% Fatigue 6 1.5% Skin rash 4 1% Vomiting 3 0.8% Itching 3 0.8% Visual disturbance 3 0.8% Learning difficulty 1 0.3 Table 3: Summary of reported montelukast side effect in children Study Sample size Adverse effect 1 A. Aldea Perona et al. 4 2015 14,670 patients Psychiatric disorders 36%, sleep disturbance 36%, nervous system disorder 25% Suicide, Anxiety, sleep disorder of breathing, changes in physical activity, cognitive and attention disorders and disturbances, communication disorders and disturbances, deliria (Including Confusion), depressed mood disorders and disturbances, disturbances in thinking and perception, impulse control disorders NEC, Mood disorders and disturbances NEC, personality disorders and disturbances in behavior, psychiatric and behavioral symptoms NEC. Psychiatric disorders NEC, Schizophrenia and other psychotic disorders, sleep disorders and disturbances 2 Pilar Caudevilla Lafuente et al 6 2021 348 patients Insomnia (n = 7), hyperactivity (n = 4), nightmares (n = 3), abdominal pain (n = 2) and paranesthesia in extremities (n = 2) 3 Susanna M. Wallerstedt et al. 8 2009 Swedish ADR database SWEDIS (1998–2007) 48 DAE Nightmares ( n = 15), unspecified anxiety ( n = 11), aggressiveness ( n = 11), sleep disorders ( n = 10), insomnia ( n = 3), irritability ( n = 3), hallucination ( n = 3), hyperactivity ( n = 3), and personality disorder ( n = 2). 4 George Philip et al. 9 2009 9,287 patients Reports of suicidality in clinical trials of montelukast 5 Pierre Ernst, and Geneviève Ernst 51 2017 106 patients Irritability ( n = 9), aggressiveness ( n = 8) and sleep disturbances ( n = 7) 6 Dariusz M Lebensztejn et al 55 2014 Case report Hepatotoxicity 7 M.-S. Marchand et al. 58 2012. National Pharmacovigilance Database 56 Psychiatric disorders (20%of all DAE) sleep disorders, behavioral disorders, and depression. 8 Po-Yu Huang et al. 59 2020 12,806 patients Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients: A nationwide population-based matched cohort study 9 Corine Ekhart et al. 60 2020 918 15% pediatric Night mare, abnormal behavior, insomnia, aggression, depression, restlessness 10 Adriel Gerard and Shantie Harkisoon 61 2009 case report Anaphylaxis Sarah Watson et al 63 2022 1118 reports of nightmares VigiBase, World Health Organization’s About half of the reports were classified as serious. 11 Alshamrani et al. 2022 385patients Sleep disorder of breathing (decrease sleep, sleep interruption, difficult sleep, night mares, increased sleep) hyperactivity, low attention, nervousness, aggressiveness, headache, visual disturbance, skin rash, chest pain, abdominal pain, myalgia, fatigue, vomiting, and itching. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1955880","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":137473676,"identity":"d8283fcd-c53e-4322-bc00-dbaf72fe2c27","order_by":0,"name":"Abdullah saeed Al-Shamrani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYDCCA0D8AEwCQUKFjRxY8AEhLQlwLWfSjMGCCURrYWw7nNgA1otHB9/tA4wfEv7ckdedffjZg4dth9Pnhx1+CLTFTk63AbsWyXMJzBKJbc8Mt51LMzdIOJeeu/F2mgFQS7Kx2QHsWgzOMDBIJDYcZtx2hsFMIqHMOnfj7ASQlgOJ23BrYf6R8Oew/bYz7N8kEtiY0w1np38gpIUNqPJw4rYzPEBb2pwT5KVz8NsieYaxzSKx7XAyUEuZBDCQDTdI5xQcSDDA7Re+M8yHb3z4c9gW6LBtkj8qbOTlZ6dv/vChwk4OlxZgXDSgORWs0gCXcmxAvoGgklEwCkbBKBhhAAAuDGuXWOdwgwAAAABJRU5ErkJggg==","orcid":"","institution":"PSMMC: Prince Sultan Military Medical City","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Abdullah","middleName":"saeed","lastName":"Al-Shamrani","suffix":""},{"id":137473677,"identity":"9d94aed8-29e2-45d4-b916-e1e871f5cbf2","order_by":1,"name":"Saleh Alharbi","email":"","orcid":"","institution":": Dr Soliman Fakeeh Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saleh","middleName":"","lastName":"Alharbi","suffix":""},{"id":137473678,"identity":"4d0e043e-5da8-4014-9cbf-9829bcdae006","order_by":2,"name":"Sumayyah Kobeisy","email":"","orcid":"","institution":"Dr Soliman Fakeeh Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sumayyah","middleName":"","lastName":"Kobeisy","suffix":""},{"id":137473679,"identity":"d098da20-808b-44bf-bd05-6602a8e090c2","order_by":3,"name":"Suzan Alkhater","email":"","orcid":"https://orcid.org/0000-0001-7315-6581","institution":"Imam Abdulrahman Bin Faisal University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suzan","middleName":"","lastName":"Alkhater","suffix":""},{"id":137473680,"identity":"86c2453a-f4c7-42f9-8089-782cc8e0ff04","order_by":4,"name":"Haleimah Alalkami","email":"","orcid":"","institution":"Maternity and Children Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haleimah","middleName":"","lastName":"Alalkami","suffix":""},{"id":137473681,"identity":"8374b72c-c7a5-4532-9f69-ef10c6fdb089","order_by":5,"name":"Turki Alahmadi","email":"","orcid":"","institution":"King Abdulaziz University Faculty of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Turki","middleName":"","lastName":"Alahmadi","suffix":""},{"id":137473682,"identity":"56c756d0-41b3-4f56-aae2-d4a800dd8fbb","order_by":6,"name":"Aisha Almutairi","email":"","orcid":"","institution":"Qassim University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aisha","middleName":"","lastName":"Almutairi","suffix":""},{"id":137473683,"identity":"3c05988f-4686-4fe8-b52d-a8d04db8a784","order_by":7,"name":"Adel Alharbi","email":"","orcid":"","institution":"PSMMC: Prince Sultan Military Medical City","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adel","middleName":"","lastName":"Alharbi","suffix":""},{"id":137473684,"identity":"15761173-0564-4e55-8ce7-476108d59104","order_by":8,"name":"Abdullah Yousef","email":"","orcid":"","institution":"Imam Abdulrahman Bin Faisal University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Abdullah","middleName":"","lastName":"Yousef","suffix":""}],"badges":[],"createdAt":"2022-08-12 10:37:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1955880/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1955880/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":27427967,"identity":"217a1c06-9836-4989-b0f4-358ab5723e91","added_by":"auto","created_at":"2022-10-06 15:22:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":290238,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1955880/v1/d2279f7b-0b52-47b5-9a98-5ad162d18834.pdf"}],"financialInterests":"","formattedTitle":"Adverse effects of montelukast in children","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMontelukast is a leukotriene receptor antagonist (LTRA) that is one of the most common medications used for asthma and other medical conditions. LTRAs function by inhibiting inflammatory mediators of bronchoconstriction, and they are prescribed primarily as adjuvant medication to inhaled corticosteroids for patients with step 3 or higher asthma, although they might be prescribed as an alternative to inhaled corticosteroids for mild asthma.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In 2009, the US Food and Drug Administration (FDA) warned clinicians about the use of montelukast, which included certain important observations that may involve neuropsychiatric changes.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e This study was intended to evaluate all potential side effects that have been reported or addressed by searching the MEDLINE database and focusing on neuropsychiatric attributes after starting montelukast, such as sleep disturbance, anxiety, oppositional, depression and any sort of suicidal attempt.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e During this decade, numerous studies were released discussing the neuropsychiatric effects of leukotrienes, but the relationship was not direct and remained controversial.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Due to the high prevalence of asthma among children and the serious side effects of montelukast, we decided to investigate whether this popular medication, which is commonly used under limited conditions for pediatric patients, is associated with any neuropsychiatric event in children in five main cities in Saudi Arabia.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Asthma is a common childhood condition, and its prevalence has increased in the last two decades from 8 to 23%.\u003csup\u003e11,12\u003c/sup\u003e In the Kingdom of Saudi Arabia, the highest prevalence is reported in Hafoof (33%), and the lowest is reported in the southern region of the kingdom (Abha) (7%).\u003csup\u003e13\u003c/sup\u003e Unfortunately, the majority of asthma cases in the Kingdom of Saudi Arabia are uncontrolled, as reported by Dr. Jahdali et al using Asthma Control Test (ACT).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e A similar study was conducted by Dr. Aslan et al., which showed that 50% of asthma cases among children were uncontrolled in a tertiary center in Riyadh.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Asthma is an often heterogeneous disease with a wide range of presentations from mild cough to severe exacerbation with different asthma phenotypes.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e Asthma cases are often divided into two main groups: \u003cem\u003ea younger age group and an older age group\u003c/em\u003e. Such classification helps health care providers diagnose and manage the patients\u0026rsquo; conditions. In patients older than 5 years of age, it is easy to diagnose asthma, as it is straightforward based on clinical presentation. asthma medical history suggesting asthma includes intermittent cough that is often worse in winter, at night or after exercise. The cough in asthma is often dry except during exacerbation and then becomes wet and is associated with wheezing, shortness of breath, and chest tightness. Such patients respond well to asthma therapy, including bronchodilators or corticosteroids. There are different types of montelukast that are used for this group as add-ons to inhaled steroids, and they are often chewable tablets (4,5 or 10 mg) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. However, it is a real challenge for health care providers to diagnose asthma in patients younger than 5 years, as patients of this age are unable to undergo spirometry may have similar conditions that share the same symptoms of cough, wheezing and shortness of breath. Furthermore, there are different asthma phenotypes and different presentations, which are often summarized as follows:\u003c/p\u003e\n\u003cp\u003e- a residual cough after a flu-like illness;\u003c/p\u003e\n\u003cp\u003e- coughing late at night or early in the morning, which could be the only presentation of asthma;\u003c/p\u003e\n\u003cp\u003e- recurrent or persistent wheezing; and\u003c/p\u003e\n\u003cp\u003e- bronchopneumonia, which is rare.\u003c/p\u003e\n\u003cp\u003e- Currently, the majority of asthma cases worldwide are still uncontrolled, even in Saudi Arabia, per different reports; fortunately, there has been some improvement according to recent publications.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Montelukast plays an important role in the management of asthma, nasal allergies and sleep-related breathing disturbances, and the most common types of montelukast are 4 mg granules or chewable tablets.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Allergic rhinitis and sinusitis are frequent causes of nocturnal coughing and are most often misdiagnosed as asthma. They share triggers with asthma, and there are two main types of presentation: Type 1 (non-inflammatory /watery) is the predominant type, and the child presents with clear nasal discharge, sneezing and nasal itching; and Type 2 (inflammatory) is the less common type, and the child presents with a blocked nose and signs of nasal obstruction.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e Allergic rhinitis should also be suspected if the presentation is associated with other clinical features of allergic rhinitis, such as sneezing, nasal blockage, allergic salute, or allergic shiners, or if the response to asthma medications is poor. Commonly used medications include intranasal corticosteroids and oral antihistamines.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Intranasal antihistamines may be necessary to improve the treatment of nonallergic rhinitis with eosinophilia(NARES) or vasomotor rhinitis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Longitudinal studies have confirmed that both allergic rhinitis and positive allergic skin tests are risk factors for asthma.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Montelukast is often used as an adjuvant to inhaled steroids for asthma with proven efficacy,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and allergic rhinitis is often associated with asthma and called united airway disease.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Chronic rhinosinusitis with and without nasal polyps may aggravate some symptoms, particularly coughing, which may be attributed to severe asthma. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Sleep-related breathing disorders are characterized by prolonged partial upper airway obstruction and/or intermittent complete obstructive apnea that disrupts normal ventilation during sleep and normal sleep patterns.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Classification based on polysomnography results as proposed by Dayyat, E. et al. stated that it is essential to differentiate OSA from other disorders as the treatment and complications are different.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e OSA occurs in children of all ages, and the prevalence varies depending on the populations studied and on the stringency of the diagnostic criteria. The prevalence is 1\u0026thinsp;\u0026minus;\u0026thinsp;5% among children, with the peak prevalence occurring between the ages of 2\u0026thinsp;\u0026minus;\u0026thinsp;8 years and the peak of symptoms often occurring in the middle of the second year, which could be related to the peak growth of lymphoid tissue.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e While the prevalence of habitual snoring is estimated to be approximately 15%, although it has been reported to be as high as 30% in the pediatric age group, the ratio of the prevalence of habitual snoring and OSA varies from 4:1 to 6:1.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e OSA occurs equally among boys and girls during the prepubertal stage. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e OSA has been reported to cause significant school problems among children, such as short attention span, aggressive behavior, poor academic performance, excessive daytime sleepiness, behavioral disorders, and multiple other problems, including cardiac growth and metabolic consequences. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Inhaled steroids and montelukast are effective medical therapies for mild forms of OSA. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Materials And Methods ","content":"\u003cp\u003eWe retrospectively evaluated all potential adverse drug reactions (ADRs) to montelukast among children aged 6 m\u0026ndash;17 years. This study was conducted in six tertiary centers in the Kingdom of Saudi Arabia [Prince Sultan Military Medical City (PSMMC) in Riyadh, Qassim University, Imam Abdulrahman Bin Faisal University in Dammam, Dr. Suleiman Fakeeh Hospital, King Abdul-Aziz University Hospital in Jeddah and Maternity and Children Hospital in Abha, Saudi Arabia] among children with a physician-confirmed diagnosis of asthma, allergic rhinitis or OSA until May 2022. The sample size was calculated using Epitools (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://epitools.ausvet.com.au/oneproportion\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"Underline\"\u003e).\u003c/span\u003e A sample of 385 children treated with montelukast was the minimum sample to have 80% power to ascertain a prevalence of adverse effects with a 95% confidence interval and a precision of 5%. An electronic questionnaire was used for the majority of patients, and the other patients were evaluated with a direct questionnaire or through the clinic; the focus was on children with symptoms suggestive of asthma, nasal allergies or sleep-related breathing disorders. The use of montelukast alone or as adjunct therapy to inhaled corticosteroids and/or long-acting bronchial agonists currently or in the past was also recorded. Children with known CNS disorders, associated comorbidities, or those who did not receive montelukast were excluded. The occurrence of montelukast-related adverse drug effects was assessed by questioning using three approaches. First, parents were asked about the three potential indications for montelukast, the types of montelukast and potential adverse effects and their knowledge of montelukast. However, for those children with sleep-related breathing disorders, we double checked if the symptoms worsened after being prescribed montelukast, as the disease itself can cause similar adverse effects to montelukast. The statistical analysis was performed using SPSS for Windows, version 21.0 (SPSS Inc., Chicago, IL, USA). The data are reported as frequencies and proportions. A nonparametric test was employed for variables with nonnormal distribution. Independent sample t tests were used to compare data between participants of different ages. Chi-square tests were used to compare categorical groups. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 with a 95% confidence interval was considered statistically significant.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eA total of 385 patients were included in this study (boys, 64.4% and girls, 35.6%). Toddlers aged 1\u0026ndash;3 years, children aged 4\u0026ndash;9 years and adolescents aged over 10 years were the most affected (30.8%, 44.3%, and 23.4%, respectively). Boys were the most affected (62% asthma, 66% allergic rhinitis and 71% sleep-related breathing disorders). The most common indication for prescribing montelukast was asthma, with 89.6% (46.6% isolated and 43% associated), followed by allergic rhinitis at 50% (7% isolated) and asthma and allergic rhinitis at 28.1%; the least common indication was sleep-related breathing disorders alone at 13.6% (0.8% isolated) \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e Singulair was the most common type of montelukast (67.9%), followed by Airfast (20.2%), and 9.3% of the parents did not know the brand name. The most common concentration prescribed was 4 mg powder (33.9%), followed by 4 mg chewable tablets (31.9%) and 5 mg chewable tablets (26.7%); 1.8% patients used the 10 mg tablets, and 5.7% did not know the concentration. Families were satisfied with montelukast (78% agreed that it is a good preventive medication, 86% preferred to use it, and 81% believed that it is an effective medication). Only 5.3% stopped montelukast due to concerns about side effects. A total of 31.9% of the patients reported at least one adverse effect. The most common was observed among school children aged 4\u0026ndash;9 years (52.8%), followed by adolescent children (24.4%) and toddlers (22.8%). The distribution of ADRs was as follows \u003cem\u003e(Table\u0026nbsp;2)\u003c/em\u003e: sleep problems (15.1%), agitation (10.4%), pain (9.3%), hyperactivity (6.8%), short attention span (3.1%), aggression (2.1%) and headache (1.82%). There were different types of sleep problems, including sleep difficulties (5.5%), decreased sleep (4.4%), interrupted sleep (4.4%) and nightmares (1.82%). A total of 9.8% of patients reported two complaints, and 5.5% reported three or more complaints. Twenty percent of the parents were worried about the side effects of montelukast; furthermore, 11% faced difficulties in purchasing the medication, and only 57% had insurance. Regarding misconceptions, 9.8% believed montelukast was a steroid, while 30.6% believed it was a bronchodilator. The duration of montelukast usage ranged from one month to 108 months, with a mean of 8 months; the youngest patient was 6 months old, and the oldest was 17 years old. Regarding pain, predominantly abdominal pain (6.32%), chest and muscle pain (2.1%), and hyperactivity with short attention span or agitation (3.6%) were reported. No serious adverse effects, required hospitalizations or deaths were reported in this study. Recovery was reported for most patients when they discontinued the medication.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMontelukast is a cysteinyl leukotriene receptor (D4 and E4) antagonist that is commonly used as prophylactic treatment for asthma and in the treatment of allergic rhinitis and sleep-related breathing disorders.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Since 2008, there has been an increasing number of reports on potential adverse drug reactions to montelukast, including irritability, aggressiveness, and sleep disturbances, usually occurring after 1 week of commencing therapy and occurring in up to 10% of children.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e The World Health Organization (WHO) pharmacovigilance database reported multiple adverse effects, including depression, headache, aggression, suicidal ideation, anxiety, insomnia, abnormal behavior, nightmares, shortness of breath, abdominal pain, nausea, rash, dizziness, myalgia and muscle spasm. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e The FDA advised caution when montelukast and other LTRAs are prescribed due to the potential adverse neuropsychiatric events (such as depression and suicidality) as a precaution. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e On the other hand, a large nested case‒control study with 1920 asthmatic patients matched for age, sex, and geographic region did not detect a significant positive association between montelukast and neuropsychiatric events among children.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHowever, a more recent nested case‒control study reported an odds ratio of nearly 2 for new-onset neuropsychiatric events in children prescribed montelukast in the year before the event.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective study of reported adverse drug reactions in the Netherlands and worldwide data from the WHO indicated that nightmares were frequently reported after commencing montelukast in the first week of treatment,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e with a reported odds ratio of 78.04 (95% CI 70.0\u0026ndash;87.1) among children. Glockler-Lauf et al. reported that adverse effects occur within a week of starting montelukast, and children exposed to this drug tend to have a quick recovery of sleep disturbance upon cessation.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Given the high reported incidences of such adverse effects among both adults and children in the USA, Canada, and Europe, \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e \u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e summarizes reported adverse effects of montelukast among children. It is essential to know the prevalence and pattern of the adverse effects of montelukast among children with asthma, allergic rhinitis and OSA in Saudi Arabia. In this study, we found that almost one-third of the patients reported adverse effects that could be serious enough to disturb their lifestyle. Neuropsychiatric events were predominant, and the causative mechanism for montelukast is still not known. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Agitation (10.4%) was the single predominant adverse neuropsychiatric effect, which was slightly different from the aggression previously reported by Harman et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e or anxiety as reported by Glockler-Lauf et al. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e This report stresses the high prevalence (15.1%) of sleep disturbance among children using montelukast, including sleep difficulties (5.5%), interrupted sleep (4.4%), insomnia (4.4%), and nightmares (2.8%); three patients reported increased sleep duration (0.8%), and 5.5% reported more than three adverse sleep complaints. Previous studies have reported different types of sleep disturbance and depression effects associated with montelukast. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e Nightmares were the main sleep-related cause to discontinue montelukast. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e This report highlights different sleep disorders compared to what has been reported in the literature. The prevalence of pain (9.3%) was higher than that in a previous report (abdominal pain, 6.3%, chest and muscle pain, 2.1%); however, this high number could be exaggerated due to functional abdominal pain and growing pain, which are common in this age group.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e Hyperactivity was reported in 6.8% of participants, while attention deficit was reported in 1.8%, which is similar to previous studies. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e While Po-Yu Huang et al reported that montelukast Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e Hyperactivity or attention deficit hyperactivity disorder (ADHD) could be the presentation of sleep disturbance. Since a minority of the patients experienced sleep disturbance, it is difficult to reach a conclusion. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Headaches were experienced by 1.82% of participants and were reported most frequently in the Dutch database (ROR, 2.26; 95% CI: 1.61\u0026ndash;3.19).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e Fatigue was reported in 1.5% of participants, and other adverse effects were reported in less than 1% (skin rash, vomiting, visual disturbance, itching and learning difficulties). No participants in this study showed any suicidal behavior, and no deaths occurred, as was cautioned by the US FDA in 2008. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Approximately 80% of the parents believed that montelukast is a good preventive and effective medication; however, the Pearson\u0026rsquo;s chi-square result was 4.455. Our result is similar to that in a Dutch study conducted in 2016, in which few families were aware of the side effects of montelukast, although this study emphasizes the limited knowledge of parents about this medication.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e Eleven percent of participants\u0026rsquo; families faced difficulties in purchasing the medication, and only 57% had insurance. Misconceptions were common (9.8% believed it was a steroid, while 30.6% believed it was a bronchodilator).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e The duration of usage ranged from one month to 108 months, with a mean of 8 months; the youngest patient was 6 months old, and the oldest was 17 years old. This study emphasizes the importance of explaining the potential adverse effects to parents when prescribing montelukast for children. Risk management plans should be explained carefully. Pediatric health care providers should be aware of the risk of neuropsychiatric events and sleep disturbance associated with montelukast use and should advise the patient to observe, monitor and report any potential adverse effects.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis article offers a comprehensive overview of the safety of montelukast in clinical practice.\u003c/p\u003e \u003cp\u003eThis study confirms the concern of a high prevalence of adverse neuropsychiatric effects among patients receiving montelukast, especially agitation, sleep disturbance, pain, and hyperactivity. Families and physicians should be aware of the potential adverse effects of montelukast when it is prescribed; fortunately, no serious side effects have been reported. Misconceptions about montelukast are still common; therefore, education of the families is necessary. Further epidemiological studies are urgently needed to quantify the risk for management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLTRA, leukotriene receptor antagonist; ADRs, adverse drug reactions; ICSR, individual case safety report; ROR, reporting odds ratio; WHO, World Health Organization; ADHD, attention deficit hyperactivity disorder; CI, confidence interval. DAE: Drug adverse effect, NEC: Neurological disorders not elsewhere classified.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception and design: AS, AY, SA, and AM; Data acquisition: HA, AY, and SA; Data analysis: AS, SK, and AY; Data interpretation: AS and SK; Manuscript drafting and revision: TA and AH\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest, and the work was not supported or funded by any drug company.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors would like to thank the American journal experts for editing this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support and sponsorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript did not receive any financial and logistic support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest regarding the publication of this article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSigned informed consent for participation and publication of medical details was obtained from the parents of this child. Confidentiality of patient\u0026rsquo;s data was ensured at all stages. Ethics approval was obtained from the IRB Prince Sultan Medical city. (IRB-2020-0416).\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eBalzano G, Fuschillo S, Gaudiosi C. Leukotriene receptor antagonists in the treatment of asthma: an update. Allergy 2002; 57:16-9.\u003c/li\u003e\n\u003cli\u003eUS Food and Drug Administration. Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR). https://wayback.archive-it.org/7993/20170111080414/http://www. fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165 489.htm; August 28, 2009. Accessed March 6, 2019.\u003c/li\u003e\n\u003cli\u003eGioacchino Calapai\u003csup\u003e \u003c/sup\u003e, Marco Casciaro, Marco Miroddi, Fabrizio Calapai, Michele Navarra, Sebastiano Gangemi. Montelukast-induced adverse drug reactions: a review of case reports in the literature Pharmacology. 2014;94(1-2): 60-70.doi: 10.1159/000366164. Epub 2014 Sep 2.\u003c/li\u003e\n\u003cli\u003eAldea Perona A, Garcia Siz M, Sanz AE. Psychiatric Disorders and Montelukast in Children: A Disproportionality Analysis of the VigiBase. Drug Saf 2016; 39:69-78. \u003c/li\u003e\n\u003cli\u003eAli MM, O\u0026rsquo;Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case\u0026ndash;control study. Pharma co epidemiol Drug Saf. 2015; 24:435-45. \u003c/li\u003e\n\u003cli\u003ePilar Caudevilla Lafuente\u003csup\u003e \u003c/sup\u003e, Juan P Garc\u0026iacute;a \u0026Iacute;\u0026ntilde;iguez\u003csup\u003e \u003c/sup\u003e, Carlos Mart\u0026iacute;n de Vicente\u003csup\u003e \u003c/sup\u003e. Adverse drug reactions of montelukast: from theory to practice. [Case report] Arch Argent Pediatr. 2021 Aug;119(4): e357-e359. doi: 10.5546/aap. 2021.e357.\u003c/li\u003e\n\u003cli\u003eSchumock GT, Stayner LT, Valuck RJ, Joo MJ, Gibbons RD, Lee TA. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol 2012; 130:368-75.\u003c/li\u003e\n\u003cli\u003eWallerstedt SM, Brunlof G, Sundstrom A, Eriksson AL. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf 2009; 18: 858-64. \u003c/li\u003e\n\u003cli\u003ePhilip G, Hustad CM, Malice M-P, Noonan G, Ezekowitz A, Reiss TF, et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol 2009; 124:699-706.e8.\u003c/li\u003e\n\u003cli\u003eBenard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J 2017; 50:1700148.\u003c/li\u003e\n\u003cli\u003eAl Frayh AR, Shakoor Z, ElRab MG, Hasnain SM. Increased prevalence of asthma in Saudi Arabia. Annals of Allergy, Asthma \u0026amp; Immunology. 2001 Mar 1; 86(3):292\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eAl Frayh AR, al Nahdi M, Bener AR, Jawadi TQ. Epidemiology of asthma and allergic rhinitis in two coastal regions of Saudi Arabia. Allerg Immunol (Paris) 1989; 21:389‐93.\u003c/li\u003e\n\u003cli\u003eAlahmadi TS, Alharbi AS. 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Improper inhaler technique is associated with poor asthma control and frequent emergency department visits. Allergy Asthma Clin Immunol 2013; 9(1):8. \u003c/li\u003e\n\u003cli\u003eHamdan AJ, Wali S, Salem G, Al-Hameed F, Almotair A, Zeitouni M, et al. Asthma control and predictive factors among adults in Saudi Arabia: Results from the Epidemiological Study on the Management of Asthma in Asthmatic Middle East Adult Population study. Annals of thoracic medicine. 2019 Apr;14(2):148. \u003c/li\u003e\n\u003cli\u003eAl-Muhsen S, Horanieh N, Dulgom S, Al Aseri Z, Vazquez-Tello A, Halwani R, et al. Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children. Annals of thoracic medicine. 2015 A; 10(2):123.\u003c/li\u003e\n\u003cli\u003eGreiwe JC, Bernstein JA. Combination therapy in allergic rhinitis: What works and what does not work. Am J Rhinol Allergy. 2016; 30(6):391\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eBernstein JA. MP29-02: a breakthrough for the treatment of allergic rhinitis. Expert Opin Pharmacother. 2013; 14(15):2101\u0026ndash;13\u003c/li\u003e\n\u003cli\u003eMartinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, Group Health Medical Associates. Asthma and wheezing in the first six years of life. New England Journal of Medicine. 1995 Jan 19; 332(3):133-8.\u003c/li\u003e\n\u003cli\u003eShapiro G, Rachelefsky GS. Introduction and definition of sinusitis. J Allergy Clin Immunol. 1992; 90:417\u0026ndash;418.\u003c/li\u003e\n\u003cli\u003eYilmaz, Ozge; Altintas, Derya; Rondon, Carmen; Cingi, Cemal; Oghan, Fatih. Effectiveness of montelukast in pediatric patients with allergic rhinitis. Int J Pediatr Otorhinolaryngol, 2013; 77, (12):1922-4.\u003c/li\u003e\n\u003cli\u003eAthina Papadopoulou. Rhinitis and Asthma in Children: Comorbidity or United Airway Disease? Current Pediatric Reviews, 2014; 10(4):275-81.\u003c/li\u003e\n\u003cli\u003eDi Cara G, Carelli A, Latini A, Panfili E, Bizzarri I, Ciprandi G, et al. Severity of allergic rhinitis and asthma development in children. World Allergy Organization Journal. 2015; 8(1):1.\u003c/li\u003e\n\u003cli\u003eShapiro G, Boulay ME. Asthma-related comorbidities. Expert Rev Respir Med. 2011; 5:377\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003ePediatrics Syndrome Section on Pediatric Pulmonology and Subcommittee on Obstructive Sleep Apnea Obstructive Sleep Apnea Syndrome Clinical Practice Guideline: Diagnosis and Management of Childhood Paediatric 2002; 109; 704-12.\u003c/li\u003e\n\u003cli\u003eEhab Dayyat, Leila Kheirandish-Gozal, and David Gozal, Childhood Obstructive Sleep Apnea: One or Two Distinct Disease Entities? Sleep Med Clin. 2007; 2(3): 433\u0026ndash;44. \u003c/li\u003e\n\u003cli\u003eCapdevila, O. S., Kheirandish-Gozal, L., Dayyat, E., \u0026amp; Gozal, D. Pediatric Obstructive Sleep Apnea: Complications, Management, and Long-term Outcomes. Proceedings of the American Thoracic Society 2008; 5(2): 274\u0026ndash;282. \u003c/li\u003e\n\u003cli\u003eMarcus CL, Brooks LJ, Draper KA, et al; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012; 130(3):714\u0026ndash;55.\u003c/li\u003e\n\u003cli\u003eS. Savini, A. Ciorba, C. Bianchini, F. Stomeoiv. Corazzi, C. Vicini, S. Pelucci. Assessment of obstructive sleep apnoea (OSA) in children: an update ACTA. OTORHINOLARYNGOLOGICA ITALICA 2019; 39:289-297.\u003c/li\u003e\n\u003cli\u003eFerreira AM, Clemente V, Gozal D, et al. Snoring in Portuguese primary school children. Pediatrics 2000; 106 (5): 64.\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics in 5\u0026ndash;7-yearold hyperactive children. Pediatrics 2003; 111:554\u0026ndash;563. \u003c/li\u003e\n\u003cli\u003eUrschitz MS, Guenther A, Eitner S, et al. Risk factors and natural history of habitual snoring. Chest ;2004; 126:790\u0026ndash;800 \u003c/li\u003e\n\u003cli\u003eErsu R, Arman AR, Save D, et al. Prevalence of snoring and symptoms of sleep-disordered breathing in primary school children in Istanbul. Chest; 2004; 126:19\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eRosen CL, Larkin EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr. 2003; 142 (4):38.\u003c/li\u003e\n\u003cli\u003eGozal D. Sleep-disordered breathing and school performance in children. Pediatrics 1998; 102:616\u0026ndash;620.\u003c/li\u003e\n\u003cli\u003eUrschitz MS, Eitner S, Guenther A, Eggebrecht E, Wolff J, Urschitz- Duprat PM, Schlaud M, Poets CF. Habitual snoring, intermittent hypoxia, and impaired behavior in primary school children. Pediatrics 2004; 114:1041\u0026ndash;1048.\u003c/li\u003e\n\u003cli\u003eAbdullah Al-Shamrani, Adel S. Alharbi. Diagnosis and management of childhood sleep-disordered breathing Clinical approach. Saudi Med J 2020; Vol. 41 (9): doi: 10.15537/smj.2020.9.25262\u003c/li\u003e\n\u003cli\u003eChadha NK, Zhang L, Mendoza-Sassi RA, C\u0026eacute;sar JA. Using nasal steroids to treat nasal obstruction caused by adenoid hypertrophy: does it work? Otolaryngol Head Neck Surg 2009; 140: 139-147.\u003c/li\u003e\n\u003cli\u003eGlockler-Lauf SD, Finkelstein Y, Zhu J, Feldman LY, To T. Montelukast and neuropsychiatric events in children with asthma: A nested case-control study. J Pediatr 2019; 209: 176-182\u003c/li\u003e\n\u003cli\u003eKheirandish L, Goldbart AD, Gozal D. Intranasal steroids and oral leukotriene modifier therapy in residual sleep-disordered breathing after tonsillectomy and adenoidectomy in children. Pediatrics 2006; 117: 61-66.\u003c/li\u003e\n\u003cli\u003eAnne K Ellis, Mena Soliman, and Helen Neighbour et al. The Allergic Rhinitis \u0026ndash; Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies. Ellis et al. Allergy, Asthma \u0026amp; Clinical Immunology 2015; 11:16.\u003c/li\u003e\n\u003cli\u003eA Clinical Guide to Pediatric Sleep: Diagnosis and Management of Sleep Problems\u0026rdquo; \u003cem\u003ethird edition\u003c/em\u003e by Jodi A. Mindell and Judith A. Owens; Lippincott Williams \u0026amp; Wilkins\u003c/li\u003e\n\u003cli\u003eOwens, J. A., \u0026amp; Dalzell, V. (2005). Use of the \u0026ldquo;BEARS\u0026rdquo; sleep screening tool in a pediatric residents\u0026rsquo; continuity clinic: a pilot study. Sleep Medicine 2004; 6(1): 63\u0026ndash;69. \u003c/li\u003e\n\u003cli\u003eThe Global Initiative for Asthma (GINA) 2022 main report. Available at https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf\u003c/li\u003e\n\u003cli\u003eErnst P, Ernst G. Neuropsychiatric adverse effects of montelukast in children. Eur Respir J. 2017;50: 1701020\u003c/li\u003e\n\u003cli\u003eHaarman MG, van Hunsel F, de Vries TW. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect. 2017;5(5). e00341.\u003c/li\u003e\n\u003cli\u003eAli MM, O\u0026apos;Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case control study. Pharmacoepidemiol Drug Saf. 2015;24(4):435-45.\u003c/li\u003e\n\u003cli\u003eCereza G, Garcia Dolade N, Laporte JR. Nightmares induced by montelukast in children and adults. Eur Respir J. 2012;40(6):1574\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eDariusz M Lebensztejn\u003csup\u003e \u003c/sup\u003e, Anna Bobrus-Chociej\u003csup\u003e \u003c/sup\u003e, Monika Kłusek, \u003cem\u003eet al\u003c/em\u003e. Hepatotoxicity caused by montelukast in a paediatric patient. Prz Gastroenterol. 2014;9(2):121-3. doi: 10.5114/pg.2014.42509. \u003c/li\u003e\n\u003cli\u003eJi Soo Park, Yoo Jung Cho, Je-Yeon Yun, Hye Jin Lee, Jinho Yu, Hyeon-Jong Yang, Dong in Suh. Leukotriene-receptor antagonist and risk of neuropsychiatric events in children, adolescents, and young adults: a self-controlled case series. J Eur Respir J 2022; in press (https://doi.org/10.1183/13993003.02467-2021).\u003c/li\u003e\n\u003cli\u003ehttps://www.drugs.com/sfx/montelukast-side-effects.html. Last updated on Mar 18, 2022.\u003c/li\u003e\n\u003cli\u003eM.-S. Marchand, A.-P. Jonville-Be\u0026acute;raa, E. Autret-Leca et al. Psychiatric disorders associated with montelukast: Data from the National Pharmacovigilance Database. Archives de Pe\u0026acute;diatrie 2013; 20:269-273.\u003c/li\u003e\n\u003cli\u003ePo-Yu Huang. Yao -Hsu Yang Ying Hua Huang and Hu Chang Kuo. et al. Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients: A nationwide population-based matched cohort study. Journal of formosan medical association 120(2021): 1369-1376. https://doi.org/10.1016/j.jfma.2020.10.018. \u003c/li\u003e\n\u003cli\u003eEkhart, C., Vries, T. de, \u0026amp; Hunsel, F. van. (2020). \u003cem\u003ePsychiatric adverse drug reactions in the paediatric population. Archives of Disease in Childhood, archdischild\u0026ndash;2019\u0026ndash;317933.\u003c/em\u003e doi:10.1136/archdischild-2019-317933 \u003c/li\u003e\n\u003cli\u003eAdriel Gerard\u003csup\u003e \u003c/sup\u003e, Shantie Harkisoon. Singulair-induced anaphylaxis? J Fam Pract. 2009 Mar;58(3):133-4.\u003c/li\u003e\n\u003cli\u003eHyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional Disorders: Children and Adolescents. Gastroenterology. 2016 Feb 15\u003cu\u003e; [\u003c/u\u003ePubMed\u003cu\u003e]\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eSarah Watson, Elenor Kaminsky, Henric Taavola, Marian Attalla and Qun‑Ying Yu. Montelukast and Nightmares: Further Characterisation Using Data from VigiBase. Drug Safety (2022) 45:675\u0026ndash;684 https://doi.org/10.1007/s40264-022-01183-2\u003c/li\u003e\n\u003cli\u003eDutch Farmacotherapeutic Compass. (2016). Available at: https://www.farmacotherapeutischkompas.nl \u003c/li\u003e\n\u003cli\u003eKam Lun Ellis Hon, Ting Fan Leung, and Alexander KC Leung. Clinical effectiveness and safety of montelukast in asthma. What are the conclusions from clinical trials and meta-analyses? Drug Des Devel Ther. 2014; 8: 839\u0026ndash;850.doi: 10.2147/DDDT.S39100\u003c/li\u003e\n\u003cli\u003eLiva, G. A., Karatzanis, A. D., \u0026amp; Prokopakis, E. P. (2021). \u003cem\u003eReview of Rhinitis: Classification, Types, Pathophysiology. Journal of Clinical Medicine, 10(14), 3183.\u003c/em\u003e doi:10.3390/jcm10143183\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Prevalence of diseases in Montelukast patient\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eSleep disorder of breathing \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e0.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAllergic rhinitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e\u0026nbsp;27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e7.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAllergic rhinitis and sleep disorder of breathing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e2.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e46.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAsthma, sleep disorder of breathing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e2.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAsthma and AR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e28.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003easthma, AR, Sleep disorder of breathing \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e7.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.73262032085562%\"\u003e\n \u003cp\u003eAsthma, AR, and other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e4.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"49.73262032085562%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25.668449197860962%\"\u003e\n \u003cp\u003e385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.59893048128342%\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable-2: Adverse effect of montelukast in children\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eMontelukast side effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003ePercent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eAgitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e10.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eSleep problems\u003c/p\u003e\n \u003cp\u003e1-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Decrease sleep\u003c/p\u003e\n \u003cp\u003e2-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Interrupted sleep\u003c/p\u003e\n \u003cp\u003e3-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Increase sleep\u003c/p\u003e\n \u003cp\u003e4-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Sleep difficulties\u003c/p\u003e\n \u003cp\u003e5-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Night mare\u003c/p\u003e\n \u003cp\u003e6-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Decrease and interrupted sleep\u003c/p\u003e\n \u003cp\u003e7-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Decrease and difficult sleep\u003c/p\u003e\n \u003cp\u003e8-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026ge;3 sleep complaint\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e\u0026nbsp;58\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e15.1%\u003c/p\u003e\n \u003cp\u003e4.4%\u003c/p\u003e\n \u003cp\u003e4.4%\u003c/p\u003e\n \u003cp\u003e0.8%\u003c/p\u003e\n \u003cp\u003e5.5%\u003c/p\u003e\n \u003cp\u003e1.82%\u003c/p\u003e\n \u003cp\u003e2.9%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.82%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.55%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eHyperactivity\u003c/p\u003e\n \u003cp\u003eHyperactivity and low attention\u003c/p\u003e\n \u003cp\u003eHyperactivity and agitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e6.8%\u003c/p\u003e\n \u003cp\u003e1.82%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.82%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Abdominal pain\u003c/p\u003e\n \u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Chest pain\u003c/p\u003e\n \u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Muscle pain\u003c/p\u003e\n \u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Chest and abdomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e\u0026nbsp;9.35%\u003c/p\u003e\n \u003cp\u003e6.23%\u003c/p\u003e\n \u003cp\u003e2.1%\u003c/p\u003e\n \u003cp\u003e2.1%\u003c/p\u003e\n \u003cp\u003e1.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eLow attention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e3.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eAggression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e2.1 %\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e1.82%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e1.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eSkin rash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e0.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eItching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e0.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eVisual disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e0.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"208\"\u003e\n \u003cp\u003eLearning difficulty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"116\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"90\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Summary of reported montelukast side effect in children\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse effect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eA. Aldea Perona et al.\u003csup\u003e4\u0026nbsp;\u003c/sup\u003e 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e14,670 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003ePsychiatric disorders 36%, sleep disturbance 36%, nervous system disorder 25%\u003c/p\u003e\n \u003cp\u003eSuicide, Anxiety, sleep disorder of breathing, changes in physical activity, cognitive and attention disorders and disturbances, communication disorders and disturbances, deliria (Including Confusion), depressed mood disorders and disturbances, disturbances in thinking and perception, impulse control disorders NEC, Mood disorders and disturbances NEC, personality disorders and disturbances in behavior, psychiatric and behavioral symptoms NEC. Psychiatric disorders NEC, Schizophrenia and other psychotic disorders, sleep disorders and disturbances\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003e\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Caudevilla+Lafuente+P\u0026cauthor_id=34309318\"\u003ePilar Caudevilla Lafuente\u003c/a\u003e et al\u0026nbsp;\u003csup\u003e6\u0026nbsp;\u003c/sup\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e348 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eInsomnia (n = 7), hyperactivity (n = 4), nightmares (n = 3), abdominal pain (n = 2) and paranesthesia in extremities (n = 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eSusanna M. Wallerstedt et al.\u003csup\u003e8\u0026nbsp;\u003c/sup\u003e 2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003eSwedish ADR database SWEDIS (1998\u0026ndash;2007)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003e48 DAE\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Nightmares (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15), unspecified anxiety (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), aggressiveness (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), sleep\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;disorders (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10), insomnia (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3), irritability (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3), hallucination (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3),\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ehyperactivity (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3), and personality disorder (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2).\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eGeorge Philip et al.\u003csup\u003e9\u0026nbsp;\u003c/sup\u003e 2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e9,287 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eReports of suicidality in clinical trials of montelukast\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003e\u0026nbsp; Pierre Ernst, and Genevi\u0026egrave;ve Ernst\u003csup\u003e51\u0026nbsp;\u003c/sup\u003e 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e\u0026nbsp;106 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;Irritability (\u003cem\u003en\u003c/em\u003e = 9), aggressiveness (\u003cem\u003en\u003c/em\u003e = 8) and sleep disturbances (\u003cem\u003en\u003c/em\u003e = 7)\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003e\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Lebensztejn+DM\u0026cauthor_id=25061494\"\u003eDariusz M Lebensztejn\u003c/a\u003e et al\u0026nbsp;\u003csup\u003e55\u0026nbsp;\u003c/sup\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003eCase report\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eHepatotoxicity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eM.-S. Marchand et al.\u003csup\u003e58\u0026nbsp;\u003c/sup\u003e 2012.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003eNational Pharmacovigilance Database\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003e\u003cstrong\u003e56\u0026nbsp;\u003c/strong\u003ePsychiatric disorders\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(20%of all DAE)\u003c/p\u003e\n \u003cp\u003esleep disorders, behavioral disorders, and depression.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003ePo-Yu Huang et al.\u0026nbsp;\u003csup\u003e59 \u003cstrong\u003e2020\u0026nbsp;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e12,806 patients\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eMontelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients: A nationwide population-based matched cohort study\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eCorine Ekhart et al.\u0026nbsp;\u003csup\u003e60\u0026nbsp;\u003c/sup\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e918\u003c/p\u003e\n \u003cp\u003e15% pediatric\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eNight mare, abnormal behavior, insomnia, aggression, depression, restlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;Adriel Gerard and Shantie Harkisoon\u0026nbsp;\u003csup\u003e61\u0026nbsp;\u003c/sup\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;case report\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;Anaphylaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eSarah Watson et al \u003csup\u003e63 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/sup\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e1118 reports of nightmares VigiBase, World Health Organization\u0026rsquo;s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eAbout half of the reports were classified as serious.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.830369357045144%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.01504787961696%\"\u003e\n \u003cp\u003eAlshamrani et al. 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.00547195622435%\"\u003e\n \u003cp\u003e385patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"61.149110807113544%\"\u003e\n \u003cp\u003eSleep disorder of breathing (decrease sleep, sleep interruption, difficult sleep,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003enight mares, increased sleep) hyperactivity, low attention, nervousness, aggressiveness, headache, visual disturbance, skin rash, chest pain, abdominal pain, myalgia, fatigue, vomiting, and itching.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Montelukast, singular, neuropsychiatry, side effect, adverse effect","lastPublishedDoi":"10.21203/rs.3.rs-1955880/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1955880/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMontelukast is a leukotriene receptor antagonist (LTRA) commonly prescribed for asthma, allergic rhinitis and sleep-related breathing disorders. Recently, some studies have reported several adverse events, such as neuropsychiatric disorders and sleep disturbances, among children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo obtain more insight into the safety profile of montelukast for children with asthma, allergic rhinitis and sleep-related breathing disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod and results:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively studied all adverse drug reactions to montelukast among 385 children 6 months or older in five tertiary centers over a two-year period. A total of 89.6% were asthmatic, 50% had allergic rhinitis and 13.6% had sleep-related breathing disorders; Singulair was the most common type of montelukast used (67.9%). This study reported a high prevalence of adverse effects among 123 patients (31.9%), predominantly in those aged 4-9 years (52.8%), followed by adolescent children (24.4%) and toddlers (22.8%). Two adverse effects were reported in 9.8% of the children, while three or more were reported in 5.5%. Sleep disturbance was the most commonadverse effect, affecting 15.1% of participants (overlap was common; 5.5% of children experienced sleep difficulties, 4.4% experienced sleep interruption and decreased sleep, and 1.82% experienced nightmares), followed by agitation (10.4%), pain (9.4%) and hyperactivity (6.8%). No serious adverse effects were reported. Eleven percent of families faced difficulties in purchasing montelukast, and only 57% of families had insurance. Misconceptions were common (9.8% reported it to be a steroid, while 30.6% believed it to be a bronchodilator). Although 81% of the families believed it was an effective and preventive medication, 5.3% stopped the drug due to concern about side effects, especially agitation (3%) and nightmares (0.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese data demonstrate that montelukast is effective, but the associated adverse neuropsychiatric drug reactions are more prevalent than those reported in the literature. In particular, sleep disturbance, agitation, pain and hyperactivity were observed. Pediatricians should be aware of such adverse effects. Misconceptions about montelukast are still common, and parental counseling and urgent epidemiological studies are needed to quantify the risk for management plans.\u003c/p\u003e","manuscriptTitle":"Adverse effects of montelukast in children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-20 23:14:40","doi":"10.21203/rs.3.rs-1955880/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"436ac2b1-bfc9-4132-9e52-063bc0363e36","owner":[],"postedDate":"September 20th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-06T15:22:19+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-20 23:14:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1955880","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1955880","identity":"rs-1955880","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}