Singulair chewable tablets 4 mg No. 28

Instructions for use Singulair chewable tablets 4 mg No. 28

Composition

active ingredient: montelukast;

1 chewable tablet contains montelukast sodium 4.16 mg (equivalent to montelukast 4 mg);

excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, red iron oxide (E 172), croscarmellose sodium, cherry flavor, aspartame (E 951), magnesium stearate.

Dosage form

Chewable tablets.

Main physicochemical properties: 4 mg chewable tablets: pink oval biconvex tablets debossed with “SINGULAIR” on one side and “MSD 711” on the other.

Pharmacotherapeutic group

Means for systemic use in obstructive airway diseases. Leukotriene receptor blockers.

ATX code R03D C03.

Pharmacological properties

Pharmacodynamics.

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids secreted by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in the human airways and induce responses such as bronchospasm, mucus secretion, increased vascular permeability, and increased eosinophil numbers.

Montelukast is an orally administered active compound that binds with high selectivity and affinity to CysLT1 receptors. In clinical studies, montelukast inhibits bronchospasm after inhalation of 5 mg LTD4. Bronchodilation is observed within 2 hours after oral administration, and this effect was additive to that produced by β-agonists. Treatment with montelukast inhibited both the early and late phases of antigen-induced bronchoconstriction. Montelukast reduces peripheral blood eosinophils compared to placebo in adults and children. In a separate study, montelukast significantly reduced airway eosinophils (as measured by sputum). In adults and children 2 to 14 years of age, montelukast reduced peripheral blood eosinophils and improved clinical control of asthma compared to placebo.

In studies in adults, montelukast 10 mg once daily demonstrated significant improvements compared with placebo in morning FEV1 (change from baseline of 10.4% and 2.7%, respectively), morning peak expiratory flow rate (PEFV) (change from baseline of 24.5 L/min and 3.3 L/min, respectively), and a significant reduction in total β-agonist use (change from baseline of -26.1% and -4.6%, respectively). Improvement in patient-reported daytime and night-time asthma symptoms was significantly greater than with placebo.

Studies in adults have demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroids (change (%) from baseline for inhaled beclomethasone with montelukast compared to beclomethasone for FEV1: 5.43% and 1.04%, respectively; β-agonist use: -8.70% and 2.64%). Compared with inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast demonstrated a more rapid initial response, although beclomethasone produced a greater mean therapeutic effect over the 12-week study (change from baseline for montelukast compared to beclomethasone for FEV1: 7.49% and 13.3%, respectively; β-agonist use: -28.28% and -43.89%). However, compared with beclomethasone, more patients treated with montelukast achieved a similar clinical response (i.e., 50% of patients treated with beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, while 42% of patients treated with montelukast achieved the same response).

In a 12-week, placebo-controlled study in children 2 to 5 years of age, montelukast 4 mg once daily improved asthma control compared with placebo, regardless of concomitant controller therapy (inhaled/nebulized corticosteroids, inhaled/nebulized sodium cromoglicate). 60% of patients were not receiving other controller therapy. Montelukast improved daytime symptoms (including cough, wheezing, shortness of breath, and activity limitation) and night-time symptoms compared with placebo. Montelukast also reduced the frequency of use of as-needed β-agonists and corticosteroid rescue for worsening asthma compared with placebo. Patients treated with montelukast had more days free of asthma symptoms than patients treated with placebo. The therapeutic effect was achieved after the first dose.

In a placebo-controlled study in children 6 months to 5 years of age with intermittent (but not persistent) asthma, treatment with montelukast 4 mg once daily or in 12-day courses for 12 months, with each course initiated at the onset of an intermittent episode, was continued. There was no significant difference between patients treated with montelukast 4 mg and those treated with placebo in the number of asthma episodes progressing to an asthma attack (defined as an asthma episode requiring an unscheduled visit to a physician, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroids).

In an 8-week study in children aged 6 to 14 years, montelukast 5 mg once daily compared with placebo significantly improved respiratory function (change from baseline in FEV1: 8.71% vs. 4.16%, change in morning PSV: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline by -11.7% vs. +8.2%).

In a 12-month study comparing the efficacy of montelukast and inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast was non-inferior to fluticasone in increasing the percentage of days without rapid-acting rescue medication (primary endpoint). Over the 12-month treatment period, the percentage of days without rapid-acting rescue medication increased from 61.6 to 84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The difference in the percentage mean square (LS) increase in days without rapid-acting rescue medication between groups was statistically significant (–2.8 with a 95% CI of –4.7, –0.9), but within the pre-specified clinical non-inferiority range.

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 for the increase in FEV1 was -0.02 L with a 95% CI of 0.06, 0.02. The mean percent increase from baseline in FEV1 was 0.6% in the montelukast group and 2.7% in the fluticasone group. The difference in LS from baseline in FEV1 was significant: -2.2% with a 95% CI of 3.6, -0.7.

The number of days on β-agonist 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 for the percentage of days on β-agonist was significant: 2.7 with a 95% CI of 0.9, 4.5.

The rate of patients with an asthma attack (an asthma attack is defined as a period of worsening asthma requiring treatment with oral steroids, an unscheduled visit to the doctor, emergency room, or hospitalization) was 32.2% in the montelukast group and 25.6% in the fluticasone group; the odds ratio (95% CI) was significant: 1.38 (1.04, 1.84).

The proportion of patients using systemic (mostly oral) corticosteroids during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between-group difference in LS was significant: 7.3% with a 95% CI of 2.9; 11.7.

Significant reductions in exercise-induced bronchospasm (EIB) were demonstrated in a 12-week study in adults (peak FEV1 decrease 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 observed throughout the 12-week study period. Reductions in EIB were also demonstrated in a short-term study in children aged 6 to 14 years (peak FEV1 decrease 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 patients receiving current inhaled and/or oral corticosteroid therapy, treatment with montelukast compared with placebo resulted in significantly improved asthma control (change from baseline in FEV1 of 8.55% vs. -1.74% and change from baseline in reduction in total β-agonist use of 27.78% vs. 2.09%).

Pharmacokinetics.

Absorption

Montelukast is rapidly absorbed after oral administration. After administration of 10 mg film-coated tablets to adults in the fasted state, mean peak plasma concentrations (Cmax) were achieved at 3 hours (Tmax). Mean oral bioavailability was 64%. Oral bioavailability and Cmax were not affected by food intake. Safety and efficacy were demonstrated in clinical studies with 10 mg film-coated tablets administered without regard to mealtime.

After administration of 4 mg chewable tablets on an empty stomach, Cmax is reached 2 hours after dosing in children aged 2 to 5 years. The mean Cmax is 66% higher and the mean Cmin is lower than in adults after administration of 10 mg tablets.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. In studies in rats with radiolabeled montelukast, passage across the blood-brain barrier was minimal. In addition, radiolabeled material concentrations in all other tissues were also minimal 24 hours after dosing.

Metabolism

Montelukast is extensively metabolized. Steady-state plasma concentrations of montelukast metabolites were not determined in studies using therapeutic doses in adults and pediatric patients.

Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. In addition, cytochromes CYP 3A4 and 2C9 play a minor role in the metabolism of montelukast, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetics of montelukast in healthy volunteers given 10 mg of montelukast daily. In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effects of montelukast is minimal.

Breeding

The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% is excreted in the feces within 5 days and less than 0.2% in the urine. This, together with the oral bioavailability of montelukast, indicates that montelukast and its metabolites are almost entirely excreted in the bile.

Pharmacokinetics in different patient groups

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are excreted in the bile, dose adjustment is not considered necessary for patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score greater than 9).

A decrease in plasma theophylline concentrations has been observed at high doses of montelukast (20 and 60 times the recommended adult dose). This effect is not observed at the recommended dose of 10 mg once daily.

Indication

As add-on treatment for bronchial asthma in patients aged 2 to 5 years with mild to moderate persistent asthma inadequately controlled with inhaled corticosteroids, as well as with inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed.

As an alternative treatment to low-dose inhaled corticosteroids for patients aged 2 to 5 years with mild persistent asthma who have not had a recent history of serious asthma attacks requiring oral corticosteroids and who are unable to use inhaled corticosteroids (see section 4.2).

Prevention of asthma, the dominant component of which is exercise-induced bronchospasm, in patients aged 2 years and older.

Relief of symptoms of seasonal and perennial allergic rhinitis. The risks of psychoneurological symptoms in patients with allergic rhinitis may outweigh the benefits of using Singulair®, so Singulair® should be used as a reserve drug in patients with inadequate response to or intolerance to alternative therapy.

Contraindication

Hypersensitivity to any of the components of the drug. Children under 2 years of age.

Interaction with other medicinal products and other types of interactions

Singulair® can be administered with other drugs commonly used for the prevention or long-term treatment of asthma. In drug-drug interaction studies, the recommended clinical dose of montelukast had no clinically important effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug interaction study involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) have shown that montelukast is not an inhibitor of CYP 2C8 in vivo. Therefore, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8 and, to a lesser extent, 2C9 and 3A4. In a clinical drug interaction study with montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No dose adjustment of montelukast is required when used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should consider the increased risk of adverse reactions.

Based on in vitro studies, no clinically significant interactions are expected with less potent CYP 2C8 inhibitors (e.g. trimethoprim). Co-administration of montelukast with itraconazole, a potent CYP 3A4 inhibitor, did not result in a significant increase in systemic exposure to montelukast.

Application features

Patients should be advised that oral Singulair® should never be used to treat acute asthma attacks and that they should always carry appropriate rescue medication. In the event of an acute attack, a short-acting inhaled β-agonist should be used. Patients should consult their physician as soon as possible if they require more short-acting β-agonist than usual.

Do not abruptly switch from inhaled or oral corticosteroid medications to Singulair®.

There is no evidence to suggest that the dose of oral corticosteroids can be reduced when montelukast is co-administered.

In isolated cases, patients receiving anti-asthma agents, including montelukast, may experience systemic eosinophilia, sometimes with clinical manifestations of vasculitis, the so-called Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with a reduction in the dose or withdrawal of the corticosteroid. The possibility that leukotriene receptor antagonists may be associated with the development of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the possibility that patients may develop eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and/or neuropathy. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

Montelukast treatment prevents patients with aspirin-dependent asthma from using aspirin or other nonsteroidal anti-inflammatory drugs.

Singulair® contains aspartame, which is a source of phenylalanine. Patients with phenylketonuria should note that 1 chewable tablet of 4 mg contains phenylalanine in an amount equivalent to 0.674 mg of phenylalanine per dose.

This medicine contains less than 1 mmol (23 mg) sodium per tablet, i.e. essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy: Animal studies do not indicate harmful effects on pregnancy or embryonal/fetal development.

Available data from published prospective and retrospective cohort studies of montelukast use in pregnant women evaluating major birth defects in offspring have not established a drug-related risk. The available studies have methodological limitations, including small sample sizes, in some cases retrospective data collection, and inconsistent comparison groups.

Singulair® should be used during pregnancy only if clearly needed.

Breastfeeding: Studies in rats have shown that montelukast is excreted in milk. It is not known whether montelukast is excreted in human milk.

Singulair® can be used during breastfeeding only if it is considered absolutely necessary.

Ability to influence reaction speed when driving vehicles or other mechanisms

Montelukast is not expected to affect the patient's ability to drive or use machines. However, drowsiness or dizziness have been reported very rarely.

Method of administration and doses

Patients with asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet of 4 mg once a day. The time of administration is selected individually to relieve the symptoms of allergic rhinitis.

For the treatment of asthma, the dose for children aged 2 to 5 years is 1 chewable tablet (4 mg) per day, in the evening. Singulair® should be taken 1 hour before or 2 hours after a meal. No dose adjustment is necessary for this age group. Singulair® chewable tablet (4 mg) is not recommended for children under 2 years of age.

General recommendations: The therapeutic effect of Singulair® on asthma control occurs within 1 day. Patients should be advised to continue taking Singulair® even if asthma control is achieved, as well as during periods of asthma exacerbation.

No dose adjustment is necessary for patients with renal impairment or mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. The dosage is the same for boys and girls.

As an alternative treatment to low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. Montelukast should be considered as an alternative to low-dose inhaled corticosteroids in children aged 2 to 5 years with mild persistent asthma only in patients who have not had a recent serious asthma attack requiring oral corticosteroids and who are unable to use inhaled corticosteroids (see section 4.3). Mild persistent asthma is defined as asthma symptoms occurring more than once a week but less than once a day, nocturnal symptoms occurring more than twice a month but less than once a week, and normal lung function between episodes. If adequate asthma control is not achieved, the need for additional or different anti-inflammatory therapy should be determined at a later stage (usually within 1 month), based on the sequential asthma management system. Patients should be periodically assessed for asthma control.

Prevention of asthma in patients 2 to 5 years of age whose primary asthma component is exercise-induced bronchospasm. Singulair® is indicated for the prevention of exercise-induced bronchospasm in patients 2 to 5 years of age, which may be the primary manifestation of persistent asthma requiring inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with montelukast. If an adequate response is not achieved, additional or alternative therapy should be considered.

Use of Singulair® in conjunction with other asthma treatments: When Singulair® is used as add-on therapy to inhaled corticosteroids, Singulair® should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

Children. Used for children aged 2 to 5 years.

Overdose

There is no specific information on the treatment of overdose with Singulair®. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies, up to 900 mg/day for approximately one week, without clinically important adverse reactions.

Acute overdoses of Singulair® have been reported in post-marketing experience and during clinical trials. These included doses exceeding 1000 mg in adults and children (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory data obtained were consistent with the safety profile in adults and children. In most cases of overdose, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the safety profile of Singulair® and included: abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

Side effects

Montelukast has been used in clinical trials in patients with persistent asthma: 4 mg chewable tablets were administered to 851 children aged 2 to 5 years.

Montelukast was evaluated in a clinical study in patients with intermittent asthma.

In clinical trials, the following adverse reactions were observed commonly (≥ 1/100 to < 1/10) in patients treated with montelukast and at a greater frequency than in patients treated with placebo.

Table 1

In clinical studies with prolonged treatment of a small number of adult patients for 2 years and children aged 6 to 14 years for 12 months, the safety profile did not change.

A total of 502 children aged 2 to 5 years were treated with montelukast for at least 3 months, 338 for 6 months or longer, and 534 for 12 months or longer. The safety profile in these patients was unchanged with extended treatment.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed by system organ class and by special terms in Table 2. The frequencies are based on clinical trial data.

Table 2

Expiration date

2 years.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging

14 tablets in a blister. 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Merck Sharp & Doom B.V., Netherlands.

Organon Heist bv, Belgium.

Location of the manufacturer and address of its place of business

Vaarderweg 39, 2031 BN Haarlem, Netherlands.

Industrial Park 30, 2220, Heist-op-den-Berg, Belgium.