Singulair

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SINGULAIR® (SINGULAIR®)

Composition:

Active substance: montelukast;

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

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

Pharmaceutical form. Chewable tablets.

Main physicochemical properties: 4 mg chewable tablets: pink, oval, biconvex tablets, embossed with "SINGULAIR" on one side and "MSD 711" on the other.

Pharmacotherapeutic group. Drugs for systemic use in obstructive respiratory diseases. Leukotriene receptor antagonists.

ATC code R03DC03.

Pharmacological Properties

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils. These key pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and provoke responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and recruitment of eosinophils.

Montelukast, following oral administration, is an active compound that binds selectively and with high affinity to CysLT1 receptors. Clinical studies have shown that montelukast inhibits LTD4-induced bronchoconstriction at a dose of 5 mg. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to bronchodilation induced by β-agonists. Montelukast treatment suppresses both early and late phases of bronchoconstriction provoked by antigen challenge. Compared to placebo, montelukast reduces peripheral blood eosinophil counts in adult and pediatric patients. In a separate study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum). In adults and children aged 2 to 14 years, montelukast reduces peripheral blood eosinophil counts and improves clinical asthma control compared to placebo.

In clinical trials involving adults, montelukast 10 mg once daily demonstrated significant improvement compared to placebo in morning forced expiratory volume in 1 second (FEV1) (change from baseline: 10.4% vs. 2.7%), morning peak expiratory flow rate (PEFR) (change from baseline: 24.5 L/min vs. 3.3 L/min), and significantly reduced overall use of β-agonists (change from baseline: –26.1% vs. –4.6%). Patient-reported daytime and nighttime asthma symptoms were significantly improved compared to placebo.

Studies in adults have demonstrated that montelukast enhances the clinical effect of inhaled corticosteroids (change in baseline FEV1: 5.43% for inhaled beclomethasone plus montelukast vs. 1.04% for beclomethasone alone; β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast showed a faster initial response, although over a 12-week study, beclomethasone produced a greater mean therapeutic effect (change from baseline FEV1: 7.49% for montelukast vs. 13.3% for beclomethasone; β-agonist use: –28.28% vs. –43.89%). However, a higher proportion of patients receiving montelukast achieved a similar clinical response (i.e., 50% of patients on beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, compared to 42% of patients on montelukast).

In a 12-week, placebo-controlled study in children aged 2 to 5 years, montelukast 4 mg once daily improved asthma control compared to placebo, regardless of concomitant controller therapy (inhaled/nebulized corticosteroids, inhaled/nebulized sodium cromoglycate). Sixty percent of patients were not receiving other controller therapy. Montelukast improved daytime symptoms (including cough, wheezing, shortness of breath, and activity limitation) and nighttime symptoms compared to placebo. Montelukast also reduced the frequency of as-needed β-agonist use and emergency use of corticosteroids during asthma exacerbations compared to placebo. Patients receiving montelukast had more asthma-symptom-free days than those receiving placebo. Therapeutic effect was observed after the first dose.

In a 12-month, placebo-controlled study in children aged 2 to 5 years with mild asthma and episodic exacerbations, montelukast 4 mg once daily significantly reduced (p ≤ 0.001) the annual rate of asthma exacerbation episodes (AE) compared to placebo (1.60 AE vs. 2.34 AE, respectively) [AE defined as ≥3 consecutive days of daytime symptoms requiring β-agonist or corticosteroid (oral or inhaled) use, or hospitalization for asthma treatment]. The annual AE rate reduction was 31.9%, with a 95% CI of 16.9, 44.1.

In a placebo-controlled study in children aged 6 months to 5 years with intermittent (but not persistent) asthma, treatment with montelukast was administered either continuously for 12 months at 4 mg once daily or in 12-day courses initiated at the onset of each intermittent symptom episode. No significant difference was observed between patients receiving 4 mg montelukast and those receiving placebo in the number of asthma episodes progressing to asthma attacks (defined as an asthma episode requiring unscheduled physician visit, emergency department visit, or hospitalization; 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 significantly improved respiratory function compared to placebo (change from baseline FEV1: 8.71% vs. 4.16%; change in morning PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline: –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 not inferior to fluticasone in increasing the percentage of days without use of fast-acting rescue medication (primary endpoint). Over the 12-month treatment period, the percentage of days without rescue medication use 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 least-squares (LS) mean percentage increase in days without rescue medication use was statistically significant (–2.8 with 95% CI –4.7, –0.9), but within the pre-specified margin for non-inferiority.

Montelukast and fluticasone also improved asthma control on secondary endpoints 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 LS mean difference in FEV1 increase was –0.02 L (95% CI –0.06, 0.02). The mean percentage increase from baseline predicted FEV1 was 0.6% in the montelukast group and 2.7% in the fluticasone group. The LS mean difference in baseline-adjusted predicted FEV1 was significant: –2.2% (95% CI –3.6, –0.7).

The percentage of days with β-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 LS mean difference in percentage of days with β-agonist use was significant: 2.7 (95% CI 0.9, 4.5).

The proportion of patients experiencing an asthma attack (defined as a worsening of asthma requiring oral steroids, unscheduled physician visit, emergency care, or hospitalization) was 32.2% in the montelukast group and 25.6% in the fluticasone group; the risk ratio (95% CI) was significant: 1.38 (1.04, 1.84).

The proportion of patients requiring systemic (primarily oral) corticosteroids during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between-group LS mean difference was significant: 7.3% (95% CI 2.9, 11.7).

Significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximum decrease in FEV1: 22.33% for montelukast vs. 32.40% for placebo; time to recovery within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the dosing interval with once-daily administration.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, montelukast treatment significantly improved asthma control compared to placebo (change from baseline FEV1: 8.55% vs. –1.74%; change from baseline in total β-agonist use: –27.78% vs. +2.09%).

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets on an empty stomach in adults, the mean peak plasma concentration (Cmax) is achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect bioavailability or Cmax following oral administration. Safety and efficacy have been confirmed in clinical trials with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is achieved within 2 hours after administration on an empty stomach. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

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

Distribution

Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution averages 8 to 11 liters. In rat studies using radiolabeled montelukast, passage across the blood-brain barrier was minimal. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after dose administration were also minimal.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and pediatric patients are not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, CYP 3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetics of montelukast in healthy volunteers receiving 10 mg daily. In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% is excreted in feces within 5 days and less than 0.2% in urine. Combined with the oral bioavailability of montelukast, this indicates that montelukast and its metabolites are almost entirely eliminated via the biliary route.

Pharmacokinetics in Special Patient Populations

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

At high doses of montelukast (20 and 60 times the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect is not seen at the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As add-on therapy for the treatment of asthma in patients aged 2 to 5 years with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, and in patients with inadequate clinical asthma control using short-acting β-adrenergic agonists as needed.

As an alternative treatment instead of low-dose inhaled corticosteroids in patients aged 2 to 5 years with mild persistent asthma, in whom no severe asthma attacks requiring oral corticosteroids have occurred recently, and who are unable to use inhaled corticosteroids (see section "Dosage and administration").

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

Relief of symptoms of seasonal and perennial allergic rhinitis. The risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of using Singulair®; therefore, Singulair® should be used as a reserve medication in patients with inadequate response or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product. Age under 2 years.

Interaction with other medicinal products and other forms of interaction.

Singulair® may be prescribed concomitantly with other medicinal products commonly used for the prevention or long-term treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no significant clinical effect on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients taking phenobarbital concomitantly, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is coadministered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, clinical drug interaction data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) demonstrated 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, of CYP 2C9 and 3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dose adjustment of montelukast is not required; however, physicians should be aware of the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with weaker inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Singulair® for oral use should never be used for the treatment of acute asthma attacks, and that they must always have with them an appropriate rescue medication. In acute attacks, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they require a greater number of doses of short-acting β-agonists than usual.

Singulair® must not be used to abruptly displace inhaled or oral corticosteroids.

There are no data to confirm that the dose of oral corticosteroids can be reduced when montelukast is administered concomitantly.

In isolated cases, patients receiving anti-asthma medications, including montelukast, have been observed to develop systemic eosinophilia, sometimes in conjunction with clinical signs of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with a reduction in dose or discontinuation of corticosteroid treatment. The possibility that leukotriene receptor antagonists may be linked to the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the potential for eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients presenting with such symptoms should be re-evaluated and their treatment regimen reconsidered.

Treatment with montelukast does not permit patients with aspirin-sensitive asthma to take aspirin or other nonsteroidal anti-inflammatory drugs.

SINGULAIR® contains aspartame, a source of phenylalanine. Patients with phenylketonuria should be informed that one 4 mg chewable tablet contains a quantity of phenylalanine equivalent to 0.674 mg phenylalanine per dose.

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not demonstrated any harmful effects on pregnancy or embryonal/foetal development.

Available data from published prospective and retrospective cohort studies on montelukast use in pregnant women assessing major congenital malformations in offspring have not established a drug-related risk. However, the available studies have methodological limitations, including small sample size, in some cases retrospective data collection, and non-comparable control 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 breast milk.

SINGULAIR® may be used during breastfeeding only if clearly necessary.

Ability to affect reaction speed when driving or operating machinery.

Montelukast is not expected to affect a patient's ability to drive or operate machinery. However, very rare cases of somnolence or dizziness have been reported.

Method of Administration and Dosage

The medicinal product should be administered to children under adult supervision. The tablets should be chewed before swallowing.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is 1 chewable tablet of 4 mg once daily. The timing of administration for relief of allergic rhinitis symptoms should be individually adjusted.

For treatment of asthma, the dose for children aged 2 to 5 years is 1 chewable tablet (4 mg) daily, taken in the evening. SINGULAIR® should be taken once daily at least 1 hour before or 2 hours after eating. Dose adjustment is not required for this age group. The medicinal product SINGULAIR® in the form of chewable tablets (4 mg) is not recommended for children under 2 years of age.

General recommendations. The therapeutic effect of SINGULAIR® on asthma control parameters begins within 1 day. Patients should be advised to continue taking SINGULAIR® even when asthma is well controlled, as well as during asthma exacerbations.

Dose adjustment is not required for patients with renal impairment or mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. Dosage is the same for boys and girls.

As an alternative treatment instead of low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The use of montelukast as an alternative to low-dose inhaled corticosteroids in children aged 2 to 5 years with mild persistent asthma should be considered only for patients who have not had recent severe asthma attacks requiring oral corticosteroids and who are unable to use inhaled corticosteroids (see section "Indications"). 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 alternative anti-inflammatory therapy should be assessed within the following period (usually within 1 month), based on a stepwise asthma management approach. Patients should be periodically evaluated for asthma control.

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

Use of SINGULAIR® in relation to other asthma treatments. When SINGULAIR® is used as add-on therapy to inhaled corticosteroids, SINGULAIR® should not abruptly replace inhaled corticosteroids (see section "Special precautions").

Children. For use in children aged 2 to 5 years.

Overdose.

There is no specific antidote or treatment for overdose with SINGULAIR®. In chronic asthma studies, montelukast was administered to adult patients at doses up to 200 mg/day for 22 weeks, and in short-term studies up to 900 mg/day for approximately one week, without clinically significant adverse reactions.

During post-marketing use and clinical trials, cases of acute overdose with SINGULAIR® have been reported. These included ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The reported clinical and laboratory findings were consistent with the safety profile of SINGULAIR® in adults and children. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the known safety profile of SINGULAIR® and included: abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Montelukast was administered during clinical studies to patients with persistent asthma: 851 children aged 2 to 5 years received 4 mg chewable tablets.

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

During clinical studies, the adverse reactions listed below were observed commonly (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and more frequently than in patients receiving placebo treatment.

Table 1

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

A total of 502 children aged 2 to 5 years received montelukast treatment for at least 3 months, 338 for 6 months or longer, and 534 for 12 months or longer. With prolonged treatment, the safety profile in these patients remained unchanged.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed by organ system classes and using standardized terminology in Table 2. Frequencies are based on data from clinical studies.

Table 2

Expiry date. 2 years.

Do not use the medicinal product 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 pack. 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Merck Sharp & Dohme B.V., Netherlands.

Organon Heist bv, Belgium.

Manufacturer's address and place of business.

Waarderweg 39, 2031 BN Haarlem, Netherlands.

Industriepark 30, 2220 Heist-op-den-Berg, Belgium.