Summary of Product Characteristics Updated 23-May-2016 | Consilient Health Ltd
General recommendationsThe therapeutic effect of Montelukast on parameters of asthma control occurs within one day. Patients should be advised to continue taking Montelukast even if their asthma is under control, as well as during periods of worsening asthma.No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.Montelukast as an alternative treatment option to low-dose inhaled corticosteroids for mild persistent asthma:Montelukast is not recommended as monotherapy in patients with moderate persistant asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids (see Section 4.1). Mild persistent asthma is defined as asthma symptoms more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.Montelukast as prophylaxis of asthma for 2 to 5 year old patients in whom the predominant component is exercise-induced bronchoconstriction.In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant manifestation of persistent asthma that requires treatment with inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with montelukast. If satisfactory response is not achieved, an additional or different therapy should be considered.Therapy with Montelukast in relation to other treatments for asthma When treatment with Montelukast is used as add-on therapy to inhaled corticosteroids, Montelukast should not be abruptly substituted for inhaled corticosteroids (see Section 4.4).
Other available strength/pharmaceutical forms:10 mg tablets are available for adults and adolescents 15 years of age and older.5 mg chewable tablets are available for paediatric patients 6 to 14 years of age. Method of administrationThis medicinal product is to be given to a child under adult supervision.The dosage for paediatric patients 2−5 years of age is one 4 mg chewable tablet daily to be taken in the evening. If taken in connection with food, Montelukast should be taken 1 hour before or 2 hours after food. No dosage adjustment within this age group is necessary. Safety and efficacy of 4 mg chewable tablets have not been established in the paediatric population below 2 years of age.
Special information about some of the ingredientsMontelukast contains aspartame. Contains a source of phenylalanine. May be harmful for children with phenylketonuria.
PregnancyAnimal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.Montelukast may be used during pregnancy only if it is considered to be clearly essential.
Breast-feedingStudies in rats have shown that montelukast is excreted in milk (see section 5.3). It is not known if montelukast is excreted in human milk.Montelukast may be used in nursing mothers only if it is considered to be clearly essential.
|System Organ Class||Adult patients aged 15 and over (Two 12-week trials; n=795)||Paediatric patients aged 6 to 14 (One 8- week study; n=201) (Two 56-week trials; n=615)||Paediatric patients aged 2 to 5 (One 12- week trial; n=461) (One 48-week trial; n=278)|
|Nervous system disorders||Headache||Headache|
|Gastrointestinal disorders||Abdominal pain||Abdominal pain|
|General disorders and administration site conditions||Thirst|
Postmarketing experienceAdverse reactions reported in post-marketing are listed, by System Organ Class and specific Adverse Experience term, in the table below. Frequency Categories were estimated based on relevant clinical trials.
|System Organ Class||Frequency Category||Adverse experience term|
|Infections and infestations||Very Common||Upper respiratory infection|
|Blood any lymphatic system disorders||Rare||Increased bleeding tendency|
|Immune system disorders||Uncommon||Hypersensitivity reactions including anaphylaxis|
|Very Rare||Hepatic eosinophilic infiltration|
|Psychiatric disorders||Uncommon||dream abnormalities including nightmares, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, depression|
|Very Rare||Hallucinations, disorientation, suicidal thinking and behaviour (suicidality)|
|Nervous system disorders||Uncommon||Diziness, drowsiness, Paraesthesia/hypoesthesia, seizure|
|Respiratory, thoracic and mediastinal disorders||Uncommon||Epistaxis|
|Very Rare||Churg-Strauss Syndrome (CSS) (see section 4.4)|
|Gastrointestinal disorders||Common||Diarrhoea, nausea, vomiting|
|Uncommon||Dry mouth, dyspepsia|
|Hepatobiliary disorders||Common||elevated levels of serum transaminases (ALT, AST)|
|Very Rare||hepatitis (including cholestatic, hepatocellular and mixed-pattern liver injury).|
|Skin and subcutaneous tissue disorders||Common||Rash|
|Uncommon||Bruises, urticaria, pruritus|
|Very Rare||Erythrema nodosum, erythrema multiforme|
|Muskosceletal and connective tissue disorders||Uncommon||Arthralgia, myalgia, including muscular cramps|
|General disorders and administration site conditions||Common||Pyrexia|
|Uncommon||Asthenia/fatigue, malaise, oedema|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.Healthcare professionals are asked to report any suspected adverse reactions via:Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
Mechanism of actionThe 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 receptors (CysLT) found in the human airway and cause airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor.
Pharmacodynamic effectsIn clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within two hours of oral administration. The bronchodilation effect caused by a beta-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum). In adult and paediatric patients 2 to 14 years of age, montelukast, compared with placebo, decreased peripheral blood eosinophils while improving clinical asthma control.
Clinical efficacy and safetyIn studies in adults, montelukast 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total beta-agonist use (-26.1% vs - 4.6% change from baseline). Improvement in patient-reported daytime and night-time asthma symptoms scores was significantly better than placebo.Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclomethasone, respectively for FEV1: 5.43% vs 1.04%; beta-agonist use: -8.70% vs 2.64%). Compared with inhaled beclomethasone (200 μg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided a greater average treatment effect (% change from baseline for montelukast vs beclomethasone, respectively for FEV1: 7.49% vs 13.3%; beta-agonist use: -28.28% vs -43.89%). However, compared with beclomethasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g. 50% of patients treated with beclomethasone achieved an improvement in FEV1 of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once daily improved parameters of asthma control compared with placebo irrespective of concomitant controller therapy (inhaled/nebulised corticosteroids or inhaled/nebulised sodium cromoglycate). Sixty percent of patients were not on any other controller therapy. Montelukast improved daytime symptoms (including coughing, wheezing, trouble breathing and activity limitation) and night- time symptoms compared with placebo. Montelukast also decreased 'as needed' beta- agonist use and corticosteroid rescue for worsening asthma compared with placebo. Patients receiving montelukast had more days without asthma than those receiving placebo. A treatment effect was achieved after the first dose.Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients 6 to 14 years of age (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline and decrease in total beta-agonist use -27.78% vs 2.09% change from baseline).
Paediatric populationIn a 12-month, placebo-controlled study in paediatric patients 2 to 5 years of age with mild asthma and episodic exacerbations, montelukast 4 mg once daily significantly (p≤ 0.001) reduced the yearly rate of asthma exacerbation episodes (EE) compared with placebo (1.60 EE vs. 2.34 EE, respectively), [EE defined as ≥3 consecutive days with daytime symptoms requiring beta-agonist use, or corticosteroids (oral or inhaled), or hospitalization for asthma]. The percentage reduction in yearly EE rate was 31.9%, with a 95% CI of 16.9, 44.1.In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased 'as-needed' beta-agonist use (-11.7% vs +8.2% change from baseline).In a 12-month study comparing the efficacy of montelukast to inhaled fluticasone on asthma control in paediatric patients 6 to 14 years of age with mild persistent asthma, montelukast was non-inferior to fluticasone in increasing the percentage of asthma rescue-free days (RFDs). Averaged over the 12- month treatment period, the percentage of asthma RFDs increased from 61.6 to 84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The between group difference in LS mean increase in the percentage of asthma RFDs was -2.8 with a 95% CI of -4.7, -0.9. Both montelukast and fluticasone also improved asthma control on secondary variables assessed over the 12 month treatment period:− FEV1 increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the fluticasone group. The between-group difference in LS mean increase in FEV1 was -0.02 L with a 95% CI of -0.06, 0.02. The mean increase from baseline in % predicted FEV1 was 0.6% in the montelukast treatment group, and 2.7% in the fluticasone treatment group. The difference in LS means for the change from baseline in the % predicted FEV1 was -2.2% with a 95% CI of -3.6, -0.7.− The percentage of days with beta-agonist use decreased from 38.0 to 15.4 in the montelukast group, and from 38.5 to 12.8 in the fluticasone group. The between group difference in LS means for the percentage of days with beta-agonist use was 2.7 with a 95% CI of 0.9, 4.5.− The percentage of patients with an asthma attack (an asthma attack being defined as a period of worsening asthma that required treatment with oral steroids, an unscheduled visit to the doctor's office, an emergency room visit, or hospitalisation) was 32.2 in the montelukast group and 25.6 in the fluticasone group; the odds ratio (95% CI) being equal to 1.38 (1.04, 1.84).− The percentage of patients with systemic (mainly oral) corticosteroid use during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between group difference in LS means was 7.3% with a 95% CI of 2.9; 11.7.In a placebo-controlled study in paediatric patients 6 months to 5 years of age who had intermittent asthma but did not have persistent asthma, treatment with montelukast was administered over a 12-month period, either as a once-daily 4 mg regimen or as a series of 12-day courses that each were started when an episode of intermittent symptoms began. No significant difference was observed between patients treated with montelukast 4 mg or placebo in the number of asthma episodes culminating in an asthma attack, defined as an asthma episode requiring utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital or treatment with oral, intravenous, or intramuscular corticosteroid.
AbsorptionMontelukast 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.
DistributionMontelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 litres. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours post-dose were minimal in all other tissues.
BiotransformationMontelukast 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.
EliminationThe plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled 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:No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.
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