Rhinitis is an inflammation of the nasal mucosa, accompanied by symptoms such as rhinorrhea, sneezing, itching, nasal obstruction and postnasal drip. Allergic rhinitis, an immunoglobulin E-mediated inflammatory response caused by exposure to allergens, accounts for more than half of all rhinitis cases and is seen in 10% to 50% of the world’s population.
Asthma is a chronic inflammatory disorder of the lower airway, and its prevalence ranges between 1% and 18%. Allergic rhinitis and asthma were considered as separate diseases of the upper and lower respiratory tract, respectively. However, recent research has shown that allergic respiratory diseases are not limited to areas, such as the nasal cavity or bronchi, but are present throughout the respiratory system; They appear as a wide range of clinical disorders, including rhinitis and asthma, which are closely related to each other epidemiologically, clinically and pathophysiologically.
The development of one disease may precede the other, and the 2 diseases are induced by the same triggering factors. In this way, they can manifest symptoms simultaneously. Based on this concept, international treatment guidelines recommend that physicians verify the presence of asthma in patients with allergic rhinitis, and vice versa, in order to adequately apply an integrated therapeutic approach for the 2 diseases.
Many mediators, cytokines, and growth factors produced by various cells are involved in the chronic inflammation seen in rhinitis and asthma. Cysteinyl leukotrienes are one of the mediators responsible for diseases of the upper respiratory tract (rhinitis) and lower respiratory tract (asthma). These mediators contribute to the manifestations of asthma, including airway edema, smooth muscle contraction, and infiltration of inflammatory cells.
Montelukast effectively relieves asthma symptoms and improves lung function through inhibition of the cysteinyl leukotriene receptor. It also reduces daytime and nighttime (i.e., late-phase) nasal symptoms in patients with rhinitis.
Histamine is an important mediator of allergic rhinitis through the stimulation of H1 receptors in the upper airway. Levocetirizine is a non-sedating oral antihistamine that is widely used to relieve the symptoms of the early phase of allergic rhinitis, including sneezing, nasal itching, and rhinorrhea.
In theory, the effectiveness of treating nasal symptoms may be improved with a combination of levocetirizine and montelukast. The objective of the present study was to compare the efficacy and safety of a fixed-dose combination (FDC) of montelukast (10 mg/day) and levocetirizine (5 mg/day) vs. montelukast monotherapy (5 mg/day) in subjects with perennial allergic rhinitis and mild to moderate asthma.
> Study design
This analysis was a multicenter, double-blind, randomized, phase III study conducted at 22 centers in the Republic of Korea from October 2014 to July 2015.
Participants received placebo medication the week before the start of the study and then the aforementioned treatment regimens. It was indicated to complete a daily card on rhinitis symptoms for 5 weeks.
Daytime nasal symptoms included rhinorrhea, obstruction, sneezing, and itching, each scored from 0 to 3 (0 = none; 1 = mild; 2 = moderate; and 3 = severe). Nocturnal nasal symptoms included awake nasal obstruction (0 = none; 1 = mild; 2 = moderate; 3 = severe), difficulty falling asleep (0 = none; 1 = little; 2 = moderate; 3 = severe), and night waking (0 = not at all; 1 = once; 2 = more than once; 3 = awake all night). For the overall evaluation of allergic rhinitis, the scoring system was used: 0 = very improved, 1 = much improved, 2 = slightly improved, 3 = no change, 4 = slightly worse, 5 = much worse, and 6 = much worse. .
Forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC were measured by spirometry. The use of rescue medication was prohibited for at least 6 hours before measurement. Additionally, subjects completed the Asthma Control Test (PCA) questionnaire. Rescue medication (120 mg salbutamol aerosol) was administered as needed. Subjects recorded on their diary cards the number of times they used rescue medication.
| Results |
> Patient disposition and baseline characteristics
Of the 333 subjects examined, 228 were randomized to treatment, and 209 completed the study. The average age was 43.32 (15.02) years, with two thirds being female (66.67%). The mean duration of asthma was 72.30 (86.77) months, the majority with mild asthma (84.29%). There were no statistically significant differences in baseline characteristics, except that the frequency of rescue medication used during the placebo run-in period was significantly higher in the montelukast/levocetirizine group than in the montelukast group.
> Efficacy evaluation
Allergic rhinitis: The montelukast/levocetirizine group achieved a statistically significant improvement from baseline in mean daytime nasal symptoms score (PMSND) over the 2-week treatment period compared to the montelukast group. It also exhibited a statistically significant improvement in sneezing compared to the montelukast alone group, although rhinorrhea, pruritus, and nasal obstruction improved marginally. The combined group scores also revealed greater improvement in PMSND, excluding nasal obstruction. However, there were no statistically significant differences between the treatment groups in terms of mean nocturnal nasal symptoms score (PMSNN) and mean composite symptom score (PCMS).
Asthma: The change in FEV 1 from baseline to the end of the study for the montelukast/levocetirizine group was similar to the result for the montelukast group. The change in FVC, FEV 1 /FVC, and PCA scores from baseline was also similar between the 2 groups. The total and mean daily frequency of rescue medication use were significantly higher for the montelukast/levocetirizine group than for the montelukast group.
> Security assessment
No significant differences were found in treatment-emergent adverse events (TEAEs), adverse drug reactions, or serious adverse events between the treatment groups.
| Discussion |
The main objective of the study was to show the efficacy of a FDC of montelukast and levocetirizine in allergic rhinitis in patients with asthma. The montelukast/levocetirizine group exhibited a statistically significant improvement in PMSND, compared to the montelukast group. Additionally, it exhibited numerical improvement in all allergic rhinitis efficacy endpoints, including each PMSND symptom score, and in the sneezing and PMSND score, excluding nasal obstruction.
Meltzer et al. reported that coadministration of montelukast and loratadine significantly improved daytime nasal symptom scores, with a safety profile comparable to that of placebo or each agent alone. They concluded that this combination provides clinical benefits against the prevalence of respiratory diseases, because comorbidities are common in asthma and allergic rhinitis. Furthermore, Ciebiada et al. reported that the combination of montelukast and desloratadine or levocetirizine is more effective than monotherapy for persistent allergic rhinitis.
Asthma is prevalent in 10% to 40% of patients with allergic rhinitis, and approximately 80% of patients with asthma have allergic rhinitis. Furthermore, the severity of rhinitis is associated with the severity of coexisting asthma. Specifically, rhinitis not only worsens the prognosis of asthma, but also reduces the patient’s quality of life. Rhinitis in asthma can also contribute to more frequent asthma exacerbations and relapses, as well as hospitalization.
In the present study, changes in lung function parameters and baseline PCA scores were similar between the montelukast/levocetirizine group and the montelukast group. However, the total and mean daily frequency of rescue medication use during the treatment period was higher in the montelukast/levocetirizine group. These differences between groups were attributed to baseline characteristics rather than treatment effects.
During the run-in period, the mean daily frequency of rescue medication use was significantly higher in the montelukast/levocetirizine group than in the montelukast group. This difference could have affected the results. Subjects with a tendency to use rescue medication during the pre-period were more likely to continue using it in the treatment period.
A potential limitation of the present study is the short duration of asthma symptom assessment (4 weeks). In general, the recommended duration of evaluation in clinical trials for control medication is at least 6 months.
| Conclusions |
This study shows that, although both montelukast and levocetirizine are widely used therapeutic agents, greater improvement in allergic rhinitis symptoms occurs with a FDC of montelukast and levocetirizine than with montelukast alone.
The combination therapy was well tolerated and demonstrated an acceptable safety profile, similar to that observed with montelukast. Therefore, the FDC of montelukast and levocetirizine is fully expected to provide significantly improved rhinitis outcomes in patients with allergic rhinitis and asthma.
