Allergic Rhinitis and Co-morbid Asthma: All Clinician Needs to Know and Consideration of Fexofenadine and Montelukast Combination

Epidemiology and Key Determinants of Allergic Rhinitis (AR) and Asthma:

Asthma affects approximately up to 18% of the global population (2), while AR impacts nearly 40% of individuals (3). Notably, over 75% of asthma patients exhibit AR, regardless of its allergic or non-allergic nature. Conversely, up to 40% of those with AR may also have asthma. Asthma tends to be more prevalent in individuals with moderate-to-severe persistent rhinitis than other allergic rhinitis (4). The ARIA Asia-Pacific workshop report highlights a substantial correlation between AR and asthma in India, indicating coexistence rates of 75% in children and 80% among adults (5). The CARAS survey revealed a 65.24% prevalence of coexisting AR among 1161 asthmatic patients across 10 Indian cities. Figure 1 illustrates the higher prevalence of perennial AR in asthmatics reported in southern regions of India. The study also noted a greater occurrence of concomitant AR and asthma in males than females, emphasising the relevance of allergic sensitisation to various allergens and exposure to trigger factors (6).

The International Study on Asthma and Allergies in Childhood (ISAAC) identified multiple risk factors for asthma and AR, including maternal smoking, sedentary lifestyle, paracetamol use during infancy, exposure to pollution, male gender, and being underweight at birth. (7).

Figure 1: Prevalence of perennial AR across different asthma severities (Recreated from The CARAS Study by Jaggi et al).

Concept of United Airway Disease:

With shared epidemiological, pathological, and physiological features, asthma and AR are coined as "one airway, one disease." Their immunopathology mirrors each other, featuring a cellular influx of eosinophils, mast cells, and T-helper type 2 (Th2) cells. Enhanced bronchial hyperresponsiveness is a common physiological trait in both conditions. Proposed mechanisms supporting the united airway theory include the nasal–bronchial reflex and the impact of nasal congestion leading to mouth breathing. This causes bronchoconstriction due to inhalation of cool and dry air. Inflammatory mediators from the upper airway may be aspirated into the lower airway, linking local inflammation in one system to a distant organ (8). The coexistence of asthma in individuals with AR can exacerbate asthma, leading to increased hospitalizations and higher medical expenses. Adults with moderate/severe perennial AR and asthma experience comparable functional impairment in their quality of life. Thus, effective management of AR is crucial, especially for patients concurrently dealing with asthma. (9)

Individualizing Allergic Rhinitis (AR) therapy is essential, considering the level of disease control and assessment of ongoing treatments. Similarly, asthma-related AR treatment follows a stepwise approach (step up or step down), with modifications made based on the degree of disease control. Primary therapeutic options for AR encompass anti-histamines (AH), leukotriene receptor antagonists (LRA), corticosteroids, fixed combinations of steroids and anti-histamines, and topical chromones (10).

Fexofenadine and Montelukast: Practical Pharmacology Glance

Fexofenadine, a second-generation antihistamine (AH) of the piperidine class, acts as an inverse agonist at the H1 receptor, binding to its inactive form for antihistaminic effects. It undergoes minimal hepatic metabolism (<5%) and primarily unchanged urinary excretion, reducing the risk of hepatic cytochrome P (CYP)-mediated interactions. Its multi-location H1 receptor binding leads to prolonged dissociation times, extending its duration of action. Moreover, its hydrophilicity prevents easy passage through the blood-brain barrier (11).

Montelukast, a highly selective leukotriene receptor antagonist (LTRA), exhibits a strong affinity for cysteinyl leukotriene receptors, particularly leukotrienes D4 and E4. By binding with high affinity, it reduces eosinophil recruitment and activation in the airways and suppresses the release of pro-inflammatory cytokines from airway cells. Montelukast's anti-inflammatory effects include reducing sputum eosinophilia and inflammatory cells in airway mucosa, complementing with other anti-allergic agents like antihistamines (12).

Rationale of AH and LTRAs for AR with co-morbid Asthma:

• Antihistamines (AH) effectively alleviate rhinorrhea, nasal itching, and sneezing, while leukotriene receptor antagonists (LTRAs) target nasal airway resistance and vascular permeability (13).
• AHs outperform LTRAs in relieving daytime AR symptoms, while LTRAs have an advantage in managing nighttime symptoms (14).
• Both agents offer comparable efficacy for composite symptoms, daytime eye symptoms, and overall quality of life among AR patients (14).
• Their combined action effectively reduces symptoms by blocking two mediators with complementary effects (15).
• The nasal challenge with Adenosine monophosphate (AMP) is a novel approach to assess the upper airway hyperresponsiveness in AR. AHs and LTRAs demonstrate efficacy in attenuating AMP response in the upper airway supporting the unified allergic airway concept (16).
• Clinical studies have established that a fixed-dose combination (FDC) tablet of 120 mg fexofenadine and 10 mg montelukast proved superior in reducing nasal congestion compared to individual monotherapy (15).
• Evidence has indicated that among patients with persistent AR and newly diagnosed asthma, the addition of montelukast to fexofenadine produced the same improvement in serum Intercellular adhesion molecule-1 (ICAM-1) concentration, nasal symptom score, anterior rhinoscopic score, and asthma symptom score as the low-dose glucocorticosteroid fluticasone added to fexofenadine (17).

Guidelines on Fexofenadine and Montelukast for Allergic Rhinitis (AR) with comorbid Asthma:

The various international and national guidelines consider the use of AH and LTRAs in appropriate cases for the management of AR and co-morbid asthma.

Table : Antihistamines and Leukotriene Receptor Antagonists: Guidelines Review

Clinical efficacy of Fexofenadine and montelukast combination:

• Montelukast + Fexofenadine Benefits Nasal Symptoms in Allergic Rhinitis: In a 4-week prospective, randomized, double-blind, parallel, active-controlled comparative trial, the efficacy and safety of montelukast-levocetirizine and montelukast-fexofenadine combinations were assessed in 70 patients diagnosed with allergic rhinitis (AR). Patients were randomly allocated to Group A (montelukast-levocetirizine 10mg and 5 mg once daily) or Group B (montelukast-fexofenadine 10 mg and 120 mg once daily). The primary efficacy endpoint was the Total Nasal Symptom Score (TNSS), encompassing rhinorrhea, nasal itching, nasal obstruction, and sneezing using a 4-point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The montelukast-fexofenadine group exhibited a significantly greater mean reduction in TNSS compared to the montelukast-levocetirizine group (9.46 vs. 8). Thus, the study concludes that the montelukast-fexofenadine combination demonstrates superior efficacy in ameliorating nasal symptoms associated with A (21).
• Comparing Efficacy of Montelukast + Fexofenadine vs. Montelukast + Levocetirizine in AR: In a multicenter randomized, open-label, prospective, two-arm design study, the effectiveness and safety of the fixed-dose combination (FDC) of montelukast 10 mg + fexofenadine 120 mg (MF) were compared to montelukast 10 mg + levocetirizine 5 mg (ML) in AR patients; both administered once daily for 14 days. There were 118 participants, 56 in the MF group and 62 in the ML group where the total symptom score, comprising total nasal symptom score (TNSS) and total ocular symptom score (TOSS) were evaluated. The MF group showed a 93.86% symptom reduction, exceeding the ML group's 87.71%. The changes in TNSS and TOSS at the end of the study were 92.52% and 95.34% in the MF group as compared to 85.58% and 92.23% in the ML group. These findings highlight MF's efficacy in alleviating nasal and ocular symptoms in AR patients (22).
• Montelukast and Fexofenadine combination is the preferred option for AR-Latest 2024 Study: A cross-sectional, observational survey, conducted through digital questionnaires, delved into the perspectives and clinical preferences of Indian physicians regarding the clinical management of AR. Among the various pharmacological agents, about 52% of physicians believe that the montelukast-fexofenadine combination is 60-90% effective; while about 14% of physicians suggest that the combination is > 90% effective. This study highlights that montelukast and fexofenadine combination is preferred and is effective in reducing symptoms of AR. Figure 4 shows drug preference for combination with montelukast (23).

Figure 2: Drug preference among physicians.

Take Home Messages:

• Allergic rhinitis and asthma are common systemic inflammatory conditions that often co-occur, with AR serving as a primary predisposing factor for asthma development.
• Asthma and AR share epidemiologic, pathologic, and physiologic features, emphasising the concept of "one airway, one disease."
• Combining AH and LTRAs proves effective in managing AR symptoms.
• Fixed-dose combination tablet of AH and LTRAs offers superior relief for allergic rhinitis symptoms, including nasal congestion, by targeting multiple mediators with complementary effects.
• The Montelukast and Fexofenadine combination is superior to Montelukast and Levocetirizine, efficacious, and tolerable, and physicians prefer it in treating AR.
• Most recently published Indian studies indicate that more than half of the physicians agree that the montelukast-fexofenadine combination shows 60-90% efficacy in treating moderate-to-severe AR.