Montelukast in the Treatment of Asthma and Allergic Rhinitis

Therapy in Practice

Montelukast in the treatment of asthma and allergic rhinitis

Helen Neighbour1 & Andrew McIvor*1

Practice Points Montelukast is used in the treatment of both asthma and allergic rhinitis. Montelukast is included in asthma guidelines as an adjunctive anti-inflammatory therapy. Montelukast should not be used as first-line treatment for allergic rhinitis. Montelukast is well tolerated and side effects are generally mild. summary Asthma and allergic rhinitis are common diseases that impact a large number of people worldwide. Safe and effective treatments are needed to reduce the morbidity and, in asthma, the mortality associated with them. In this article, we review the use of a leukotriene receptor antagonist, montelukast, in the treatment of these conditions. This article provides an overview of the pharmacology of montelukast and the guidline recommendations for its use in asthma and allergic rhinitis.

Leukotriene: basic pharmacology of cysteinyl leukotrienes have been shown to & approved indications be elevated in patients with symptomatic aller- Leukotrienes are lipid mediators produced by gic rhinitis (AR) [2]. Montelukast is a selective inflammatory cells such as mast cells and baso- leukotriene receptor antagonist that inhibits the phils during the early phase, and eosinophils cysteinyl leukotriene receptor 1. Cystinyl leu- and macrophages during the late phase [1] . The kotriene receptor 1 is found on inflammatory cysteineinyl leukotrienes include leukotriene C4, cells, smooth muscle cells and endothelium in

D4 and E4. They play a role in the pathogenesis the respiratory mucosa of both the upper and of allergic inflammation in the upper and lower the lower airway. airways. They are derived from arachidonic acid Montelukast is used in the treatment of both via the 5-lipoxygenase pathway. Their role in asthma and AR. It is indicated for the prophy- the pathogenesis of asthma derives from their laxis and chronic treatment of asthma in patients effects on smooth muscle tone, mucous secre- 2 years and older [3]. In adults, montelukast can tion, microvascular permeability and chemo- be used to treat asthma if the patient remains tactic effects. They also promote dendritic cell symptomatic after intermittent short-acting maturation, which in turn promotes the genera- b-agonists and cannot or will not use an inhaled tion of further allergic stimulation. The levels corticosteroid (ICS). It is also indicated for the

1Firestone Institute for Respiratory Health, T2127, St Joseph’s Healthcare, McMaster University, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada *Author for correspondence: Tel.: +1 905 522 1155 ext 34330; Fax: +1 905 521 6183; [email protected] part of

relief of symptoms of seasonal AR in patients they are seen more often, asthma is not assessed 15 years and older when other treatments are nor management addressed in these visits unless not effective or tolerated. they are presenting with an asthma worsening Montelukast is administered as a tablet or exacerbation. of 10 mg in adults 15 years or older, 5 mg in Most physicians adhere to national or inter- children aged 6–14 years, 4 mg in children national guidelines with respect to management aged 2–5 years. It is available as quick-dissolve of many chronic diseases, however, guidelines granules for administration to young children. are based on efficacy of randomized controlled The pharmacokinetic profile allows for it to be trials (RCTs), which may not reflect day-to-day administered once a day. practice [7]. Patients may often have concerns about long-term therapy and prefer the symp- What is asthma? tomatic relief offered by antihistamines in AR Asthma may be considered as a chronic inflam- and short‑acting b-agonists in asthma. Patients matory disease of the airways in which the air- may also have significant concerns or mispercep- flow obstruction returns to, or towards, normal tions about potential side effects from commonly with anti-inflammatory treatment [4]. To avoid prescribed medications (i.e., ICS). A plethora the side effects of oral administration, ICS are of different ICS dosage regimens and devices accepted as the gold standard of anti-inflamma- compound these concerns. tory treatment. When patients remain uncon- Montelukast being a simple, once-daily trolled despite adherence to ICS, we suggest NSAID with efficacy in both AR and asthma may switching to foundation therapy with a combi- explain the effectiveness of oral antileukotrienes nation inhaler, including the addition of a long- in office management of asthma and AR. acting b-agonist (LABA) to the ICS in a single ICS/LABA inhaler [4,5,101] . Guidelines promote Asthma & asthma with AR applying this concept in a stepwise approach to Clinical evidence: summary of recent gain current control and reduce future risk of clinical data & postmarketing data exacerbations. Adding montelukast or salmeterol to ICS: a RCT In asthma most patients remain To assess the effect of montelukast versus sal- uncontrolled meterol when added to the ICS, fluticasone It is easy for both physicians and patients to be propionate, on asthma exacerbation in patients complacent with day-to-day asthma manage- whose symptoms are inadequately controlled ment. Surveys in Canada consistently show that with fluticasone alone, a 52-week, two-period, more than half of asthma patients remain uncon- double-blind, randomized controlled multi- trolled and this has not changed significantly center trial, during which patients whose symp- over the last decade [6]. toms remained uncontrolled by ICS were ran- One recent study of 350 primary care physi- domized to add montelukast or salmeterol, was cian in Canada confirmed that 60% of nearly conducted. 1490 asthma patients were random- 11,000 current patients were uncontrolled by ized. The primary end point was the percentage one or more parameters of the Canadian Asthma of patients with at least one asthma exacerbation Control Questionnaire (ACQ) at routine office during the 1-year follow-up. A total of 20.1% of visits [6]. This was shown to be associated with the patients in the group receiving montelukast the patients being six-times more likely to have and fluticasone had an asthma exacerbation, an unscheduled physician visit, 3.5-times more compared with 19.1% in the group receiving likely to end up in the emergency room and salmeterol and fluticasone [8]. twice as likely to be admitted to hospital with asthma compared with an asthmatic who was Montelukast in a real-life asthma study currently controlled [6]. Two parallel, multicenter, pragmatic trials to Although there is mounting interest in adopt- evaluate the real-world effectiveness of a leuko ing new models of chronic disease management triene-receptor antagonist (LTRA) as com- for asthma, outside of specialist practice it is pared with either an ICS for first-line asthma- unusual for asthmatics to be regularly followed controller therapy or a LABA as add-on ther- specifically for their asthma or AR. Although apy in patients already receiving ICS therapy.

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Eligible primary care patients were between 12 Place in therapy and 80 years of age and had impaired asthma- Asthma guideline recommendations related quality of life (Mini Asthma Quality Montelukast is a widely prescribed LTRA, orally of Life Questionnaire score ≤6) or inadequate administered anti-inflammatory therapy for asthma control (ACQ score ≥1). They randomly asthma. It is included in the Global Initiative assigned patients to 2 years of open-label ther- for Asthma guidelines as an adjunctive anti- apy, under the care of their usual physician, with inflammatory therapy for all severities of asthma a LTRA (148 patients) or an ICS (158 patients) requiring anti-inflammatory treatment in addi- in the first-line controller therapy trial and a tion to other therapy, instead of or as well as LTRA (170 patients) or a LABA (182 patients) ICS or ICS/LABA combination inhalers [4,5,101]. added to an ICS in the add-on therapy trial. The relative cost of anti-inflammatory therapy Study results at 2 months suggest that the LTRA in persistent asthma has been assessed. It has was equivalent to an ICS as first-line control- been determined that using a combination of ler therapy and to LABA as add-on therapy for fluticasone–salmeterol is more cost effective than diverse primary care patients. Equivalence was using montelukast alone as initial maintenance not proved at 2 years [9]. therapy for persistent asthma in patients treated

with a short-acting b2-agonist only [11] . For chil- RADAR trial: montelukast in asthma & AR dren with mild-to-moderate persistent asthma, To evaluate the effectiveness of montelukast low-dose fluticasone had lower cost and higher as add-on therapy for patients diagnosed with effectiveness compared with montelukast [12] . asthma and concurrent AR that remain uncontrolled while on ICS monotherapy or ICS/ AR LABA with any product and at any dosage in Clinical evidence: summary of recent a ‘real-world’ setting. An 8 week, multicenter, clinical data & postmarketing data open-label, observational study was conducted. AR is an allergen-induced, upper-airway inflam- Patients were ≥15 years old, and, while treated matory disease characterized by hyperactive air- with an ICS or ICS/LABA had AR and uncon- way mucosa resulting in symptoms of rhinor- trolled asthma symptoms by at least two criteria rhea, sneezing, nasal pruritus, and congestion, as per the Canadian Asthma Consensus Guide- with associated symptoms of red, itchy, watery lines. The primary outcome measure was the eyes, itching of the palate and throat, and cough. percentage of patients with controlled asthma AR is widely recognized as being the most com- symptoms after 8 weeks of treatment with mon allergic disorder, but detailed estimates of montelukast 10 mg once a day added to ICS or its actual prevalence are lacking. Canadian prev- ICS/LABA therapy. alence studies suggest the life-time prevalence A total of 319 patients were enrolled in the of AR to be between 39 and 52% [13] . AR has a 8-week assessment. At baseline, all patients significant economic burden as it is common in had uncontrolled asthma symptoms based on young working adults and can cause poor sleep, the Canadian Asthma Consensus Guidelines; interruption of daily activities and can increase at the 8-week assessment, 229 (76.1%) patients the severity of associated asthma. achieved asthma control. According to the ACQ When compared with placebo, montelu- (ACQ score ≤0.75), 164 (54.7%) achieved well- kast improves disease-specific quality of life of controlled asthma at week 8. The mean ACQ patients with persistent AR [14] . score decreased from 2.03 (SD: 0.80) to 0.92 A 32-week randomized, placebo-controlled (SD: 0.80; p < 0.001) for all patients, represent- crossover study in patients with persistent AR ing a clinically significant improvement. A sta- but no associated respiratory disease, compared tistically and clinically significant reduction in antihistamine treatment alone or in combina- the overall Mini Rhinoconjunctivitis Quality of tion with montelukast. The results showed that Life Questionnaire score was also achieved with montelukast alone or in combination with an a mean decrease of -1.45 (SD: 1.35) from 2.57 antihistamine gave a gradual increase in nasal (SD: 1.20) to 1.12 (SD: 1.00; p < 0.001). Patient symptom improvement within 6 weeks of treat- and physician satisfaction with montelukast ment in patients with persistent AR [15] . Similar add-on therapy were also significantly increased results have been shown in patients with seasonal when compared with baseline treatment [10] . AR [16] .

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Nitric oxide (NO) is a mediator with the montelukast were more likely to need additional potential to cause inflammation, and NO imbal- AR medications and other medical services. It ance appears to be important in the pathogenesis can be inferred from this study that montelukast of AR. NO is synthesized from l-arginine by NO is inferior to second-generation antihistamines as synthase. Arginase competes with NO synthase first-line therapy for AR[26] . for arginine. Therefore, increased serum arginase A systematic review and meta-analysis of activity could potentially limit NO production. the use of montelukast in AR has shown that Montelukast reduced serum arginase levels in montelukast reduces nasal symptom scores patients with seasonal AR and this may be a when compared with placebo. Montelukast is novel mechanism of action of montelukast that not as effective as topical nasal steroids or anti is worthy of further study [17]. histamines and should be regarded as second- Corticosteroids have wide-ranging anti- line therapy. If montelukast is used in the treat- inflammatory and immunosuppressive effects ment of AR it should be in combination with an and often are seen as the ‘gold standard’ com- antihistamine [27]. parator in trials of novel therapies for allergic Montelukast has also been compared with disease. Compared to montelukast, fluticasone subcutaneous immunotherapy (SCIT). It has proprionate has been shown to significantly been shown that SCIT is more effective than improve daytime and nighttime seasonal AR montelukast in the treatment of seasonal AR symptoms [18]. It has been shown that adding [28] in patients with birch pollen-induced mod- montelukast to nasal steroid therapy does not erate asthma and rhinitis, the addition of SCIT improve nasal symptom scores in patients with provides a greater clinical benefit than that of seasonal AR [19] or perennial AR [20]. However, montelukast [29]. montelukast is administered systemically and Increased levels of leukotrienes have been has the potential to have effects remote from found in the nasal secretions of patients with the nose. Compared with topical nasal steroids viral infections of the upper airways [30]. There- and topical antihistamine, montelukast had the fore, it was hypothesized that treatment with greatest effect on ocular itching and throat and montelukast may reduce the incidence of respi- palate itching [21] . However this effect was not ratory tract infection. A randomized control trial seen in asthmatics administered montelukast of montelukast for 12 weeks in children aged in a placebo-controlled trial, although the need 1–5 years without a history of reactive airways

for inhaled b2-agonists was significantly lower disease failed to show any benefit in prevent- during montelukast treatment [22]. An environ- ing the development of upper respiratory tract mental challenge chamber study in ragweed-sen- infections [31]. This result is not surprising, as sitized patients has shown that antihistamines the increased levels of leukotrienes are likely to have a more rapid onset of action than montelu- be secondary to the presence of the virus, rather kast [23]. Montelukast alone improves perennial than indicating a susceptibility to infection. AR symptoms when compared with placebo [24]. Montelukast has a role to play in maintenance Health economics is becoming an increasingly treatment of AR; however, its effects are not as important consideration. AR is one of the top ten great as those of antihistamines and substantially reasons for a primary care visit (a review of insur- less than topical corticosteroids. Montelukast ance data in the USA has shown that newly diag- should be considered a second-line treatment nosed AR patients who are given montelukast and should be used in combination with an as first-line therapy have higher medical costs antihistamine. and resource utilization in the year following treatment initiation than those prescribed first- Place in therapy line branded second-generation antihistamines Allergy guideline recommendations [fexofenadine, desloratidine and cetirizine]) The Allergic Rhinitis and its Impact on Asthma [25,26]. This finding was not related to demo- guidelines 2010 have recommendations for the graphics, available disease severity or comor- use of montelukast in the treatment of rhinitis bidity confounders. Asthmatic subjects were with or without asthma [32]. In patients without specifically excluded from the analysis. Some of asthma, oral leukotriene receptor antagonists the effect may be related to the higher medica- are recommended in adults and children with tion cost of montelukast, but patients prescribed seasonal AR and in preschool children with

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perennial AR. In adults with perennial allergic in adverse reactions versus placebo. Side-effects rhinitis oral leukotriene receptor antagonists commonly reported included headache, otitis are not recommended. In patients with AR media, upper respiratory tract infection and and asthma, inhaled glucocorticosteroids, are pharyngitis [33]. recommended over oral leukotriene receptor A review of eight studies has shown that antagonists as a single controlling medication adverse events occurred at a similar frequency in for asthma. In patients with AR and asthma who patients taking either montelukast or placebo [34]. prefer not to use or cannot use inhaled gluco- Postmarketing surveillance systems, usually corticosteroids or in children whose parents do assessing side effects, are not as fully developed not agree to use inhaled glucocorticosteroids, as our knowledge and understanding of RCTs oral leukotriene receptor antagonists for the to prove drug efficacy. Neuropsychiatric adverse treatment of asthma are recommended. events, including agitation, aggressive behavior, depression and insomnia have been reported in Patient selection association with LTRAs. There have been con- In patients with AR it can be a useful addition cerns about an association between montelukast to therapy in those sensitized to both seasonal and suicidality, and in 2008 the US FDA stated and perennial allergens. It should not be used as that it was investigating this suspected association monotherapy, and should not be considered as a further [102] . Following the FDA announcement first-line therapy. It has a particular usefulness there was a sevenfold increase in the number of in patients who have upper airways disease, in montelukast-related cases reported to the Adverse particular nasal polyps, with coexistent asthma. Event Reporting System database in the USA [103] . It also has a particular role in patients with There have also been sporadic reports of the intro- aspirin-sensitive disease. duction of montelukast being associated with the development of Churg–Strauss syndrome, but Dosage & administration in both asthma this has usually been associated with the reduction & AR of systemic corticosteroids that may have led to The recommended dose in adults 15 years and worsening of the underlying vasculitis rather than older is 10 mg to be taken once daily in the eve- montelukast being a direct cause of the condition. ning. The dose for pediatric patients 6–14 years is a 5 mg chewable tablet to be taken in the Conclusion evening, or one packet of 4 mg granules to be Table 1 summarizes the current evidence for the taken in the evening. No dose adjustment is use of montelukast in the treatment of asthma needed in the elderly or those with renal insuf- and AR. ficiency. Additionally, no dose modification is There have been two relevant Cochrane needed in mild-to-moderate liver failure; its reviews [35,36]. A review of the evidence for the use use has not been studied in severe liver failure. of leukotriene receptor antagonists for nonspecific The only absolute contraindication to the use of cough in children concluded that there was not montelukast is hypersensitivity to the drug or enough evidence to supports its use [35]. In adults any ingredient in the formulation. The patient with asthma that is inadequately controlled on should be educated about the preventive nature low doses of inhaled steroids and showing sig- of montelukast, and advised to take it even when nificant reversibility with b2-agonists, LABAs are their asthma is well-controlled, they should also superior to leukotriene receptor antagonists in be advised that it should not be used to treat reducing oral steroid-treated exacerbations [36]. acute attacks. Montelukast has not been stud- Oral therapy with an antileukotriene, Mon- ied in pregnant and lactating women and that it telukast, has widespread application for the real- should only be used if clearly needed. life, day-to-day, anti-inflammatory management of asthma and AR. We have identified some of Tolerability & adverse events the current literature on montelukast, which, In general, montelukast is well tolerated, side in conjunction with national and international effects are mild and generally do not require dis- guidelines in both asthma and AR, should help continuation of the drug. In a study specifically assist healthcare professionals perhaps re-exam- looking at safety and adverse effects, there was ine the role of montelukast in their asthma and generally no clinical or laboratory differences allergy practice.

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Table 1. Important studies of montelukast in the treatment of asthma and allergic rhinitis. Study (year) Comparison Conclusion Ref. Asthma Bjermer et al. (2003) Montelukast and fluticasone The addition of montelukast when symptoms are uncontrolled could [8] compared with salmeterol and provide equivalent control to salmeterol fluticasone Price et al. (2011) Comparison of montelukast and At 2 months montelukast was equivalent to inhaled steroid as first-line [9] inhaled steroid and addition of therapy and to LABA as add-on. Equivalence was not proved at 2 years either montelukast or LABA as add‑on therapy Keith et al. (2009) Open-label observational study of Montelukast is effective for managing asthma and allergic rhinitis [10] patients with uncontrolled asthma symptoms in patients who were previously uncontrolled with ICS or ICS/LABA Allergic rhinitis Ciebiada et al. (2008) Montelukast with or without Combining montelukast with an antihistamine significantly improved [37] antihistamine quality of life compared with each agent alone Patel et al. (2005) Montelukast versus placebo Montelukast significantly reduced perennial allergic rhinitis symptoms [24] during 6 weeks of treatment Martin et al. (2006) Fluticasone versus montlukast Fluticasone significantly reduced daytime and night-time seasonal [18] allergic rhinitis symptoms ICS: Inhaled corticosteroid; LABA: Long-acting b-agonist.

Ongoing properly designed effectiveness Financial & competing interests disclosure and postmarketing surveillance trials are sorely H Neighbour has participated in CME presentations organ- needed in primary care, including both objective ized by Merck and GlaxoSmithKline. A McIvor has efficacy outcomes, and incorporating patient- received honoraria for providing medical education and reported outcomes. The information should attending advisory meetings for pharmaceutical companies be integrated into practice guidelines to not involved in the management of asthma including: only improve patient symptoms, but to assist in AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKlein, improving outcomes by gaining and maintain- Merch, Novartis and Takeda. The authors have no other ing control and reducing future risk of exacerba- relevant affiliations or financial involvement with any tions. It is possible that montelukast may reduce organization or entity with a financial interest in or finan- regrowth of nasal polyps following surgery; this cial conflict with the subject matter or materials discussed is an area that requires further study. There also in the manuscript apart from those disclosed. needs to be more research into the effectiveness No writing assistance was utilized in the production of of using montelukast to treat preschool wheeze. this manuscript.

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