Efficacy and safety of montelukast in adults with asthma and allergic rhinitis

Open ArchivePublished:April 24, 2006DOI:https://doi.org/10.1016/j.rmed.2006.02.026

      Summary

      Several clinical studies have confirmed the effectiveness of montelukast 10mg orally in adults with both asthma and allergic rhinitis. The objective of this phase IV study was to investigate the efficacy and safety of montelukast 10mg in adults with both asthma and allergic rhinitis in a real-life setting. Data from 5855 patients (mean age: 42.8±15.4 years) were collected and analyzed following treatment for 4−6 weeks. Efficacy was analyzed by comparing baseline values of: general, day- and night-time improvement in asthma symptoms, need for rescue medication or inhaled corticosteroids (ICSs), general and specific improvement in allergic rhinitis symptoms, reduction in rhinitis medication use, and general and specific quality of life (QoL) improvement with values collected at the end of the observation period of 4–6 weeks. Following treatment with 10mg montelukast 86.5% (n=4547) of patients reported a strong or marked improvement in day-time asthma symptoms and 88.5% (n=4367) reported improvement in night-time symptoms. A similarly high proportion of patients had a strong or marked improvement in all symptoms of allergic rhinitis (i.e. sneezing/itching (84%), rhinorrhea (81.7%), nasal congestion (79.3%), watery eyes (78.4%) and red or burning eyes (77.7%). The use of asthma and rhinitis medication was also reduced. 92.3% (n=5685) of all patients intended to continue montelukast therapy. Overall QoL was “very good” or “good” in 85.2% of patients (n=4991) and a “strong” or “marked” improvement in each of the four domains of sleep, work, everyday life and physical activity. Montelukast was well tolerated. Adverse drug reactions occurred in 14 out of 6158 patients. None of the adverse events was serious. Accordingly, montelukast 10mg is a safe and effective treatment for patients with both asthma and allergic rhinitis.

      Keywords

      Introduction

      The prevalence of asthma and allergic rhinitis has risen markedly worldwide in recent years.
      Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, atopic eczema: ISACC
      The international study of asthma and allergies in childhood (ISAAC) steering committee.
      Asthma is estimated to affect ∼4–11% of the general population, while allergic rhinitis is estimated to affect between 10% and 30% of the general population.
      • Von Mutius E.
      The rising trends in asthma and allergic disease.
      • Nathan R.
      • Meltzer E.
      • Selner J.
      • Storms W.
      Prevalence of allergic rhinitis in the United States.
      Comorbidity of asthma and rhinitis has been well documented, suggesting a link between upper and lower airway disease and the hypothesis that asthma and rhinitis represent a systemic disease (i.e. one airway one disease).
      • Bousquet J.
      • Vignola A.
      • Demoly P.
      Links between rhinitis and asthma.
      • Vignola A.
      • Chanez P.
      • Bousquet J.
      The relationship between asthma and allergic rhinitis: exploring the basis for a common pathophysiology.
      • Young Y.
      • Chang K.
      The development of asthma in patients with allergic rhinitis.
      The finding of nasal inflammation in asthma and bronchial inflammation and hyperresponsiveness in rhinitis further supports this hypothesis.
      • Bousquet J.
      • Vignola A.
      • Demoly P.
      Links between rhinitis and asthma.
      • Vignola A.
      • Chanez P.
      • Bousquet J.
      The relationship between asthma and allergic rhinitis: exploring the basis for a common pathophysiology.
      • Young Y.
      • Chang K.
      The development of asthma in patients with allergic rhinitis.
      The majority of patients with asthma also suffers from allergic rhinitis. It has been reported that up to 80% of patients with asthma also have rhinitis,
      • Leynaert B.
      • Bousquet J.
      • Neukirch C.
      • Liard R.
      • Neukirch F.
      Perennial rhinitis: an independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey.
      while a significant number of patients with rhinitis also have asthma.
      • Leynaert B.
      • Bousquet J.
      • Neukirch C.
      • Liard R.
      • Neukirch F.
      Perennial rhinitis: an independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey.
      • Sibbald B.
      • Rink E.
      Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history.
      In patients with asthma and allergic rhinitis healthcare costs are significantly increased while quality of life (QoL) is significantly worse.
      • Yawn B.
      • Yunginger J.
      • Wollan P.
      • Reed C.
      • Silverstein M.
      • Harris A.
      Allergic rhinitis in rochester, minnesota residents with asthma: frequency and impact on health care charges.
      • Leynaert B.
      • Neukirch F.
      Quality of life in allergic rhinitis and asthma. A population-based study of young adults.
      • Price D.
      • Zhang Q.
      • Kocevar V.
      • Yin D.
      • Thomas M.
      Effect of a concomitant diagnosis of allergic rhinitis on asthma-related health care use by adults.
      In addition, patients with rhinitis have an increased risk of developing asthma.
      • Wright A.
      • Holberg C.
      • Martinez F.
      • Halonen M.
      • Morgan W.
      • Taussig L.
      Epidemiology of physician-diagnosed allergic rhinitis in childhood.
      • Settipane G.
      • Hagy G.
      • Settipane R.
      Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students.
      The Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines categorize patients’ allergic rhinitis as either “intermittent” or “persistent” with regards to duration.
      • Bousquet J.
      • van Cauwerberge P.
      • Khattaev N.
      Allergic rhinitis and its impact on asthma (ARIA).
      The severity of allergic rhinitis is subdivided into “mild” or “moderate-severe”, depending on symptoms and QoL.
      • Bousquet J.
      • van Cauwerberge P.
      • Khattaev N.
      Allergic rhinitis and its impact on asthma (ARIA).
      These guidelines suggest to use combined strategies for the treatment of upper and lower airways. They propose a stepwise approach according to symptom severity and treatment response. Leukotriene antagonists, such as montelukast, were included in these guidelines as a treatment option for allergic rhinitis
      • Bousquet J.
      • van Cauwerberge P.
      • Khattaev N.
      Allergic rhinitis and its impact on asthma (ARIA).
      despite the fact that clinical studies about their efficacy were limited at the time of publication.
      Since cysteinyl leukotrienes participate in the pathophysiology of both asthma and allergic rhinitis
      • Dahlen S.
      Cysteinyl leukotrienes as common mediators of asthma and allergic disease.
      it has been suggested that blocking the cysteinyl leukotriene receptor might be beneficial to patients with asthma and allergic rhinitis.
      • Dahlen S.
      Cysteinyl leukotrienes as common mediators of asthma and allergic disease.
      Accordingly, a recent study has shown that montelukast can improve symptoms of seasonal allergic rhinitis and asthma in patients with both diseases.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      The aim of the present article was to evaluate the efficacy and safety of add-on montelukast (10mg orally) to existing controller medication in the treatment of patients with asthma and allergic rhinitis.

      Patients and methods

       Study design

      This multicentre, phase IV study with 3018 physicians was designed to investigate the efficacy of 10mg montelukast in adults with asthma and allergic rhinitis. Current therapy for each patient was recorded for ∼4–6 weeks of treatment between February 1st, 2004 and July 31st, 2004.

       Patients

      Patients were required to suffer from physician diagnosed asthma and allergic rhinitis. The minimum age of inclusion was 16 years. Montelukast was either used as a monotherapy or in addition to another anti-asthmatic therapy which was judged to be inadequate prior to the administration of the leukotriene receptor antagonist.

       Baseline parameters

      At visit 1 patients demographic data (gender and age), disease diagnosis and severity were recorded. Asthma severity was categorized according to recent guidelines as “intermittent”, “mild” or “moderate” and rhinitis was subdivided into “intermittent” or “persistent”. Asthma daytime symptoms (cough, wheezing, chest tightness and shortness of breath) and night-time symptoms (cough, shortness of breath and nocturnal awakenings), the need for rescue medication and inhaled corticosteroids (ICSs) were recorded together with symptoms of allergic rhinitis (sneezing/itching, runny nose, nasal congestion, watery eyes and red/burning eyes). Any recent medication and its perceived effectiveness to treat symptoms of rhinitis were also recorded. In addition, patients’ overall QoL was assessed as “good”, “satisfactory” or “reduced” and also more specifically according to the four domains of “difficulty sleeping”, “difficulty with work”, “difficulty with everyday life” and “limitation to daily activities”.

       Efficacy parameters

      At the end of the observation period (4–6 weeks) the following efficacy parameters were collected: general improvement in asthma symptoms, improvement of day- and night-time asthma symptoms, need for rescue medication, need for ICSs, general and specific improvement in allergic rhinitis symptoms, reduction in medication to treat the symptoms of allergic rhinitis, and general and specific QoL improvement. General improvements were categorized as “very good”, “good”, “satisfactory”, “sufficient” or “not sufficient”. Specific improvements in symptoms or QoL domains were categorized as “strong”, “marked”, “moderate” or “none”.

       Safety parameters

      Undesirable effects (UE) and adverse drug effects (ADE) were recorded during the treatment period with montelukast 10mg.

       Statistical analysis

      The methods of descriptive statistics were employed to analyze results from this post-marketing surveillance study and all analyses were performed using SAS (Statistical Analysis System version 8.2 for Windows). Case reports were considered evaluable for efficacy (efficacy group) if the following criteria were met: documented therapy with montelukast (case report form filled out); data recorded for visit 2; patient aged at least 16 years; beginning of monitored study medication not earlier than February 1st, 2004. Case reports were considered evaluable for drug safety (drug safety group) when the following criteria were met: documented therapy with montelukast 10mg. Undesirable effects were calculated on the “preferred term” level.

      Results

       Study population

      In total, 6158 patients were identified by 3018 physicians. In all, 303 of these patients were not included into the study due to prior treatment with montelukast (n=140), age<16 years (n=175) or missing data at visit 2 (n=4). Patients (5855) (n=2487 male; n=3299 female) with a mean age of 42.8±15.4 years met all inclusion criteria and were included in this post-marketing surveillance study (Table 1). The average duration of observation was 5.5 weeks.
      Table 1Patient baseline characteristics.
      Characteristicn (%)
      Gender
      Male2487 (42.5)
      Female3299 (56.3)
      No data69 (1.2)
      Age (years)
      Mean±standard deviation42.8±15.40
      Range16–96
      Asthma severity
      Intermittent1728 (29.5)
      Mild1695 (29.0)
      Moderate2369 (40.5)
      No data63 (1.1)
      Asthma symptoms in last weeks
      Day-time symptoms5256 (89.8)
      Night-time symptoms4930 (84.2)
      Allergic rhinitis
      Persistent2754 (47.0)
      Intermittent3032 (51.8)
      No data69 (1.2)
      Current rhinitis symptoms5774 (98.6)
      The majority of patients (40.5%) had moderate asthma with both day- and night-time symptoms in the last weeks prior to enrolment (Table 1). Cough was the most frequently reported day- and night-time symptom; more than half of the patients (58%) had nocturnal awakenings due to asthma (Table 2). There was a fairly even spread of patients with intermittent and persistent allergic rhinitis (51.8% and 47.0%, respectively); almost all patients reported symptoms of allergic rhinitis in the weeks prior to enrolment (Table 1), namely sneezing/itching, rhinorrhea, nasal congestion, watery eyes and/or red/burning eyes. In 70% of all patients overall QoL was reduced due to symptoms of asthma and rhinitis; most patients reported difficulty sleeping, work-related problems, impairments during everyday life and a limitation in daily activities due to asthma and/or rhinitis (Table 2 and Fig. 1). Well over half (58%) of the patients reported a moderate limitation in each of the four QoL domains while 16.8% of patients reported severe impairment in sleeping, 10.9% had severe work-related difficulties and 10.8% and 22.1% of patients reported severe limitations in their every day lives and physical activity, respectively (Fig. 1).
      Table 2Pre-study symptoms and quality of life (QoL).
      Characteristicn (%)
      Day-time asthma symptoms
      Cough4381 (75)
      Wheezing2598 (44)
      Chest tightness2485 (42)
      Shortness of breath2166 (37)
      Night-time asthma symptoms
      Cough3823 (65)
      Shortness of breath2062 (35)
      Nocturnal awakening3378 (58)
      Allergic rhinitis symptoms
      Sneezing/itching5521 (94)
      Running nose5218 (89)
      Congested nose4646 (79)
      Watery eyes5052 (86)
      Red/burning eyes4507 (77)
      Overall QoL assessment
      Good196 (3)
      Satisfactory1518 (26)
      Reduced4089 (70)
      Individual QoL assessment
      Difficulty sleeping5509 (94)
      Difficulty with job5262 (90)
      Difficulty with everyday life5639 (96)
      Limitations to daily activities5610 (96)
      Figure thumbnail gr1
      Figure 1Pre-study degree of quality of life limitation.

       Efficacy results

       Asthma symptoms

      Following treatment with 10mg montelukast there was an overall improvement in asthma symptoms in the majority of patients, where 36.6% (n=2143) rated this improvement as “very good”, and 45.2% (n=2648) as “good” (Fig. 2). Day-time symptoms improved “strongly” or “markedly” in 86.5% (n=4547) of patients and 88.5% (n=4367) reported an improvement in night-time symptoms (Fig. 2). This was accompanied by a reduction in the requirement for other asthma medications such as ß2-agonists and ICSs. The number of patients who needed additional asthma medication decreased by 19.9% (n=1,163) for ß2-agonist use and by 14.8% (n=865) for ICS use; in addition, the mean number of puffs per day of ß2-agonists was reduced from 4.0 to 1.9 and from 2.5 to 1.6 for ICSs.
      Figure thumbnail gr2
      Figure 2Improvement in asthma. Sat: satisfactory; Suff: sufficient.

       Allergic rhinitis symptoms

      Adding montelukast 10mg to current asthma medication led to an overall improvement in allergic rhinitis symptoms in 86.5% of patients; 37.7% (n=2210) rated this improvement as “very good” and 45.8% (n=2684) as “good” (Fig. 3). Most patients reported a “strong” or “marked” improvement in all symptoms of allergic rhinitis; 77.7% (n=3502) reported a “strong” or “marked” improvement in red/burning eyes, 78.4% (n=3961) had a “strong” or “marked” improvement in watery eyes, and 79.3% (n=3682) reported similar improvement in nasal congestion, while 81.7% (n=4266) had a “strongly” or “markedly” improved rhinorrhea and 84% (n=4637) similarly improved sneezing/itching (Fig. 3). This was accompanied by a reduction in rhinitis medication in 88.1% (n=4228) of all patients (n=5855). The strongest decrease was observed for nasal steroids with 77.1% (n=1566 of a total of 2031 patients). The use of α-sympaticomimetics was reduced in 75.9% of patients (n=576 of a total of 759 patients), the use of eye drops in 69% of patients (n=1616 of a total of 2311 patients), anti-histamines in 69% of patients (n=2499 of a total of 3621 patients) and other rhinitis medications in 67.1% of patients (n=336 of a total of 501 patients).
      Figure thumbnail gr3
      Figure 3Improvement in rhinitis. Sat: satisfactory; Suff: sufficient.

       Quality of life

      There was a “very good” or “good” improvement in 85.2% of patients (n=4991) in overall QoL and a “strong”/“marked” improvement in each of the four domains of sleep, work, everyday life and physical activity in 86.3% (n=4752), 81.6% (n=4293), 84.4% (n=4764) and 82.1% (n=4605) of patients, respectively (Fig. 4).
      Figure thumbnail gr4
      Figure 4Improvement in quality of life (QoL). Sat: satisfactory; Suff: sufficient.

       Other efficacy results

      Almost all patients (92.3%, n=5685) planned to continue montelukast therapy after the end of the observation period, while only 7.2% of patients (n=442) discontinued montelukast. In 2.6% (n=160) further treatment was not required due to either almost completely resolved symptoms or due to the fact that the hay fever season had ended. A similarly large percentage (2.3%, n=142) discontinued therapy due to insufficient efficacy and 0.2% (n=10) due to adverse events. 2.1% (n=130) reported other or no reason for discontinuation.

       Safety results

      Montelukast was well tolerated in this large phase IV study. In 14 of 6158 patients (0.23%) 21 drug-related adverse events were reported. Most frequently headache, gastrointestinal infections and sleepiness were observed as single symptoms. None of the adverse events was serious.

      Discussion

      Asthma and allergic rhinitis have been linked clinically for many years. This has recently been acknowledged in the “one airway one disease” concept which underlines the hypothesis that both diseases share a common pathophysiology, characterized by inflammation of the respiratory mucosa by the same pro-inflammatory cells (e.g. eosinophils, Th2 lymphocytes and mast cells) and mediators (e.g. cytokines, histamine and leukotrienes).
      • Bousquet J.
      • Vignola A.
      • Demoly P.
      Links between rhinitis and asthma.
      • Vignola A.
      • Chanez P.
      • Bousquet J.
      The relationship between asthma and allergic rhinitis: exploring the basis for a common pathophysiology.
      • Casale T.
      • Lazarus S.
      Immunobiology of asthma and rhinitis: pathogenic factors and therapeutic options.
      Patients with asthma and rhinitis are twice as likely to require emergency care for asthma, and need more asthma-related hospitalizations and GP visits leading to higher asthma drug costs. In addition, patients with allergic asthma and rhinitis are significantly more likely to experience asthma attacks compared to patients with asthma alone.
      • Price D.
      • Zhang Q.
      • Kocevar V.
      • Yin D.
      • Thomas M.
      Effect of a concomitant diagnosis of allergic rhinitis on asthma-related health care use by adults.
      • Bousquet J.
      • Gaugris S.
      • Sazonov Kocevar V.
      • et al.
      Increased risk of asthma attacks and emergency visits among asthma patients with allergic rhinitis: a subgroup analysis of the improving asthma control trial.
      Based on these findings it has been suggested that both conditions should be ideally treated together.
      • Bousquet J.
      • van Cauwerberge P.
      • Khattaev N.
      Allergic rhinitis and its impact on asthma (ARIA).
      Montelukast, a leukotriene receptor antagonist, has been shown to improve both asthma and allergic rhinitis symptoms
      • Dahlen S.
      Cysteinyl leukotrienes as common mediators of asthma and allergic disease.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      • Price D.
      • Swern A.
      • Tozzi C.
      • Philip G.
      • Polos P.
      Additional benefit of montelukast for asthma in patients with both asthma and allergic rhinitis: analysis from the COMPACT trial.
      and therefore has the potential to conveniently treat patients with asthma and rhinitis.
      • Barnes N.
      • Thomas M.
      • Price D.
      • Tate H.
      The national montelukast survey.
      • Chervinsky P.
      • Philip G.
      • Malice M.
      • et al.
      Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies.
      In this phase IV study treatment with montelukast 10mg for 4–6 weeks (added to existing controller medication) was effective and well tolerated in patients with mild-to-moderate asthma and allergic rhinitis. There was a “strong” or “marked” improvement in both day- and night-time asthma symptoms as well as the symptoms of allergic rhinitis. These improvements were associated with a reduction in both asthma and rhinitis medication. Similar results have been previously reported from studies in which montelukast was added to existing therapies.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      • Price D.
      • Swern A.
      • Tozzi C.
      • Philip G.
      • Polos P.
      Additional benefit of montelukast for asthma in patients with both asthma and allergic rhinitis: analysis from the COMPACT trial.
      Accordingly, a subgroup analysis from the Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) study
      • Price D.
      • Swern A.
      • Tozzi C.
      • Philip G.
      • Polos P.
      Additional benefit of montelukast for asthma in patients with both asthma and allergic rhinitis: analysis from the COMPACT trial.
      suggested that the mean increase in pulmonary function in patients with persistent asthma and a physician-based diagnosis of allergic rhinitis was greater when montelukast was added to a previous regimen of 800μg of budesonide/day versus doubling the dose of budesonide to 1600μg/day.
      • Price D.
      • Swern A.
      • Tozzi C.
      • Philip G.
      • Polos P.
      Additional benefit of montelukast for asthma in patients with both asthma and allergic rhinitis: analysis from the COMPACT trial.
      Adding montelukast to existing maintenance therapy also significantly improved the symptoms of seasonal allergic rhinitis in patients with concomitant active asthma.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      Furthermore, the addition of montelukast significantly (P<0.001) reduced daily rhinitis symptom scores, day-time nasal symptoms, nasal congestion, rhinorrhea and sneezing, night-time symptoms, especially nasal congesting upon awakening and day-time eye symptoms.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      Both patients and physicians also reported significant improvements in the global evaluation of allergic rhinitis (P0.001) and asthma (P0.05). Similar to our findings patients who took montelukast needed significantly less rescue medication which is likely to impact on healthcare resource use
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      as has been suggested by a study from Italy in children under 14 years of age where montelukast decreased the total use and costs of asthma rescues/acute and allergy medication over a 2-year period.

      Sturkenboom MC, Picelli G, Scarmarcia B, et al. Change in use of asthma and allergy drugs after start of montelukast or other controllers in Italian children with asthma and allergic rhinitis. The World Allergy Congress, Munich, Germany 26 June–1 July, 2005.

      The results of these studies which are now expanded with our post-marketing surveillance study, add further proof to the effectiveness of montelukast not only in a clinical setting, but also in a real-life setting.
      Both asthma and allergic rhinitis can impair QoL which is further reduced in patients with both diseases.
      • Leynaert B.
      • Neukirch F.
      Quality of life in allergic rhinitis and asthma. A population-based study of young adults.
      Patients treated in an open label setting with montelukast 10mg orally reported a “strong”/“marked” improvement in their QoL most notably in the domains of sleep, work, everyday life and physical activity. Similar results have been obtained from controlled trials
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      which also showed that montelukast treatment improved rhinoconjunctivitis QoL overall score in patients with both asthma and allergic rhinitis. Significant (P<0.05 each) improvements were noted in the QoL domains of nasal symptoms, eye symptoms, activity, sleep, emotions and practical problems.
      • Philip G.
      • Nayak A.
      • Berger W.
      • et al.
      The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
      In conclusion, based on previous findings asthma and allergic rhinitis often occur together and common treatment strategies have been recently suggested for both diseases. Our findings from a very large number of patients suggest that previous results from smaller, randomized controlled trials can be translated into a real-life setting, where montelukast is a safe and effective systemic treatment of both upper and lower airways in patients with both asthma and allergic rhinitis.

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