Pharmacology: Pharmacodynamics: The cysteinyl leukotrienes (LTC4, LTD4, LTE4), are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is a potent, orally active compound with antiinflammatory properties which significantly improves parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC4, LTD4, and LTE4 at the CysLT1 receptor without any agonist activity.
In asthmatic patients, montelukast causes potent inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4. Doses as low as 5 mg cause substantial blockage of LTD4 induced bronchoconstriction. Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.
Clinical Studies- Asthma: In clinical studies, Montelukast is effective in adult and pediatric patients for the prophylaxis and chronic treatment of asthma, including the prevention of day- and night time symptoms, the treatment of aspirin-sensitive asthmatic patients, and the prevention of exercise-induced bronchoconstriction. Montelukast is effective alone or in combination with other agents used in the maintenance treatment of chronic asthma. Montelukast and inhaled corticosteroid may be used concomitantly with additive effects to control asthma or to reduce the inhaled corticosteroid dose while maintaining clinical stability.
Adults 15 years of age and older: In two similarly-designed 12-week double-blind placebo-controlled studies in adult asthmatic patients 15 years of age and older, Montelukast Tablets, 10 mg once daily in the evening, demonstrated significant improvements in parameters of asthma control measuring asthma symptoms, asthma-related outcomes, respiratory function and "as- needed" β-agonist use.
Montelukast Tablet significantly improved patient-reported daytime symptoms and nocturnal awakenings, compared with placebo. Asthma-specific outcomes, including asthma attacks, corticosteroid rescue, discontinuations due to worsening asthma, asthma exacerbations and asthma-free days were also significantly better than placebo. Physicians' and patients' global asthma evaluations and asthma-specific quality-of-life evaluations (in all domains, including normal daily activity and asthma symptoms) were significantly better than placebo. Montelukast caused significant improvements in morning forced expiratory volume in 1 second (FEV1), AM and PM peak expiratory flow rate (PEFR) and significantly decreased the use of "as-needed" β-agonist, compared with placebo. The treatment effect was achieved after the first dose and was maintained throughout the 24-hour dosing interval. Treatment effect also remained constant during continuous once-daily administration in extension studies for up to one year. Withdrawal of Montelukast Tablet after 12 weeks of use did not cause rebound worsening of asthma. Compared with inhaled beclomethasone (200 1- g twice daily with a spacer device), Montelukast demonstrated a more rapid initial response although over the full duration of the 12-week study, beclomethasone provided a greater average treatment effect. However, a high percentage of patients treated with Montelukast Tablet achieved similar clinical responses compared with inhaled beclomethasone.
Pediatric patients 6 to 14 years of age: In pediatric patients 6 to 14 years of age, one 5-mg chewable tablet daily in the evening, significantly decreased asthma exacerbations, and improved parents' global evaluations and the pediatric asthma specific quality-of-life evaluations, compared with placebo.
Montelukast Tablet also significantly improved morning FEV1 and decreased total daily "as- needed" β-agonist use. Treatment effect was achieved after the first dose and remained constant during once-daily administration for up to 6 months.
Growth Rate in Pediatric Patients: Two controlled clinical studies have demonstrated that Montelukast Tablet did not affect the growth rate of prepubertal pediatric patients with asthma.
Growth rate was evaluated in a double-blind study of 71 pediatric patients aged 6 to 11 years (67 completed the study and were evaluated for growth): 35 patients were treated in a crossover fashion with Montelukast Tablet and placebo; 32 patients were treated in a crossover fashion with inhaled budesonide and placebo. Growth rate as measured by lower leg length growth was similar in patients treated with Montelukast Tablet 5 mg once daily for 3 weeks compared with placebo, whereas growth rate was significantly lower (p=0.002) in patients treated with inhaled budesonide dosed at 200 mcg (one puff of 200 mcg) twice daily for 3 weeks, compared with placebo.
In a 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study the effect of Montelukast Tablet on growth rate was evaluated in 360 patients aged 6 to 8 years; 120 patients treated with Montelukast Tablet. The observed mean linear growth rates in the placebo run-in period were similar in the three treatment arms. The mean growth rate in patients treated with Montelukast Tablet 5 mg once daily was similar to that of placebo during the treatment period, while the mean growth rate in patients treated with inhaled beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg ex-valve) twice daily with a spacer device was significantly below the mean growth rate of patients receiving Montelukast (p<0.001) or placebo (p<0.001) (see FIGURE 1).
Across the distribution of growth rates during treatment, growth rates for the beclomethasone group were reduced compared to those of Montelukast Tablet. The Montelukast Tablet and placebo groups had similar growth rates (see FIGURE 2). Both Montelukast Tablet and inhaled beclomethasone demonstrated significant benefit versus placebo in the exploratory efficacy endpoints of rescue medication use in these patients with mild asthma. (See Figures 1 and 2.)
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Pediatric patients 6 months to 5 years of age: In a 12-week, placebo-controlled study in pediatric patients 2 to 5 years of age, Montelukast Tablet 4 mg once daily consistently improved parameters of asthma control irrespective of concomitant controller therapy use compared with placebo. Sixty percent of patients were not on any other controller therapy.
Montelukast Tablet significantly improved day time symptoms (including coughing, wheezing, trouble breathing and activity limitation) and nighttime symptoms compared with placebo. Montelukast Tablet also significantly decreased "as-needed" β-agonist use and corticosteroid rescue compared with placebo. Patients receiving Montelukast Tablet had significantly more days without asthma than those receiving placebo. A treatment effect was achieved after the first dose. In addition, total blood eosinophil counts were significantly decreased.
Efficacy of Montelukast Tablet is supported in pediatric patients 6 months to 2 years of age by extrapolation from the demonstrated efficacy in patients 2 years of age and older with asthma, and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug's effect are substantially similar among these populations.
Effects in patients on concomitant inhaled corticosteroids: Separate studies in adults demonstrated the ability of Montelukast Tablet to add to the clinical effect of inhaled corticosteroid and allow steroid tapering when used concomitantly. In a placebo-controlled study, patients taking initial inhaled corticosteroid doses of approximately 1600 1- g per day reduced their steroid use by approximately 37% during a placebo run-in period. Montelukast Tablet allowed a further 47% reduction of the inhaled corticosteroid dose, compared with 30% for placebo. In another study, Montelukast Tablet provided additional clinical benefit to a similar population of patients maintained but not adequately controlled on inhaled corticosteroid (beclomethasone 400 μg/day). Complete abrupt removal of beclomethasone in patients receiving both Montelukast Tablet and beclomethasone caused clinical deterioration in some patients, suggesting that tapering as tolerated rather than abrupt removal is preferred. In aspirin-sensitive patients, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, Montelukast Tablet resulted in significant improvement in the parameters of asthma control.
Effects on exercise-induced bronchoconstriction: Montelukast Tablet, 10 mg once daily, prevented exercise-induced bronchoconstriction (EIB) in adults 15 years of age and older. In a 12-week study, Montelukast Tablet significantly inhibited the extent and duration of fall in FEV1 over 60 minutes after exercise, the maximal percent fall in FEV1 after exercise, and the time to recovery to within 5% of the pre-exercise FEV1. Protection was consistent through the treatment period indicating that tolerance did not occur. In a separate cross-over study, protection was observed after two once-daily doses. In pediatric patients 6 to 14 years of age, using the 5-mg chewable tablet, a similarly designed cross-over study demonstrated similar protection and the protection was maintained throughout the dosing interval (24 hours).
Effects on asthmatic inflammation: In clinical studies Montelukast Tablet inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Because inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effects of Montelukast Tablet on eosinophils in the peripheral blood and airway were examined. In Phase IIb/III clinical studies, Montelukast Tablet significantly decreased peripheral blood eosinophils approximately 15% from baseline, compared with placebo. In pediatric patients 6 to 14 years of age, Montelukast Tablet decreased peripheral blood eosinophils 13% over the 8-week treatment period, compared with placebo.
Montelukast Tablet also significantly decreased airway eosinophils in sputum, compared with placebo. In this study, peripheral blood eosinophils decreased and clinical asthma endpoints improved with treatment with Montelukast Tablet.
Effects in Patients with Asthma and Seasonal Allergic Rhinitis: In a clinical study in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis, montelukast 10-mg tablets administered once daily demonstrated a statistically significant improvement in the primary variable, Daily Rhinitis Symptoms score (average of the Daytime Nasal Symptoms score [mean of nasal congestion, rhinorrhea, sneezing, nasal itching] and the Nighttime Symptoms score [mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores]), compared with placebo. Global evaluations of allergic rhinitis by patients and physicians, and global evaluations of asthma by patients and physicians, were also significantly improved, compared with placebo.
Clinical Studies - Allergic Rhinitis: The efficacy of Montelukast Tablet for the treatment of seasonal allergic rhinitis was investigated in similarly designed randomized, 2-week, double-blind, placebo-controlled trials including 4924 patients (1751 patients were treated with Montelukast Tablet). Patients were 15 years of age and older with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study initiation.
In a combined analysis of three pivotal studies, Montelukast Tablet 10-mg tablets administered to 1189 patients once daily in the evening resulted in a statistically significant improvement in the primary endpoint, daytime nasal symptoms score, and its individual components (nasal congestion, rhinorrhea, nasal itching and sneezing); nighttime symptoms score, and its individual components (nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings); composite symptoms score (composed of the daytime nasal and nighttime symptoms scores); and global evaluations of allergic rhinitis by patients and by physicians, compared with placebo.
In a separate 4-week study in which Montelukast Tablet was administered once daily in the morning, the efficacy over the initial 2 weeks was significantly different from placebo and consistent with the effect observed in studies using evening dosing. Additionally, the effect over the entire 4 weeks was consistent with the 2-week results.
In patients with seasonal allergic rhinitis aged 15 years and older who received Montelukast Tablet, a median decrease of 13% in peripheral blood eosinophil counts was noted, compared with placebo, over the double-blind treatment periods.
The efficacy of Montelukast Tablet for the treatment of perennial allergic rhinitis was investigated in two, similarly designed randomized, 6-week, double-blind, placebo-controlled studies including 3235 patients (1632 patients were treated with Montelukast Tablet). Patients were 15 to 82 years of age with a history of perennial allergic rhinitis, positive skin test results to relevant perennial allergens (including dust mites, animal dander, and mold spores), and active symptoms of perennial allergic rhinitis at study initiation.
In one study, Montelukast 10-mg tablets administered to 1000 patients once daily resulted in a statistically significant improvement in the primary endpoint, Daytime Nasal Symptoms score, and its individual components (nasal congestion, rhinorrhea, and sneezing), compared with placebo. Montelukast Tablet also demonstrated patient-perceived improvement of allergic rhinitis as assessed by the secondary endpoints of Global Evaluation of Allergic Rhinitis by Patient, and Rhinoconjunctivitis Quality-of-Life overall score (average of scores for the 7 domains of activity, sleep, non-nose/non-eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotions), compared with placebo.
The efficacy of Montelukast Tablet for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age, and for the treatment of perennial allergic rhinitis in pediatric patients 1 year to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug's effect are substantially similar among these populations.
Pharmacokinetics: Absorption: Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved three hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the Cmax is achieved in two hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted state, Cmax is achieved 2 hours after administration. The mean Cmax is 66% higher while mean Cmin is lower than in adults receiving a 10 mg tablet.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.
Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
In vitro studies using human liver microsomes indicate that cytochromes P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination: The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in Patients: Elderly Patients, and Patients with Renal or Hepatic Insufficiency: No dosage adjustment is necessary for the elderly, for patients with renal insufficiency or mild to moderate hepatic insufficiency. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9).
Paediatric Patients: In children 6 to 11 months of age, the systemic exposure to montelukast and the variability of plasma montelukast concentrations were higher than those observed in adults. Based on population analyses, the mean AUC was 60% higher and mean Cmax was 89% higher than those observed in adults. The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC was 33% higher and the mean Cmax was 60% higher than those observed in adults. Safety and tolerability of montelukast in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above.
The safety and effectiveness in pediatric patients younger than 1 year of age with perennial allergic rhinitis and in patients below the age of 12 months with asthma have not been established.