Singulair

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

Composition:

Active substance: montelukast;

One chewable tablet contains montelukast sodium 5.2 mg (equivalent to montelukast 5 mg);

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: 5 mg chewable tablets: pink, round, biconvex tablets, embossed with "SINGULAIR" on one side and "MSD 275" on the other.

Pharmacotherapeutic group. Agents 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 important 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.

Orally administered montelukast is an active compound that binds selectively and with high affinity to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits LTD4-induced bronchoconstriction following inhalation. 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 both adult and pediatric patients. In one study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum). In adults and children aged 2 to 14 years, montelukast, compared to placebo, reduces peripheral blood eosinophil counts and improves clinical asthma control.

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

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

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily, compared to placebo, significantly improved respiratory function (change from baseline in 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 comparative study of efficacy between montelukast and inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast demonstrated non-inferior efficacy 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 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 was statistically significant (–2.8 with 95% CI –4.7, –0.9), but within the pre-specified margin for clinical non-inferiority.

Montelukast and fluticasone also improved asthma control relative to 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 percent increase from baseline predicted FEV1 was 0.6% in the montelukast group and 2.7% in the fluticasone group. The LS mean difference from baseline in predicted FEV1 was significant: –2.2% (95% CI –3.6, –0.7).

The proportion 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 period of worsening asthma requiring treatment with 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 who used 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 concomitant therapy with inhaled and/or oral corticosteroids, treatment with montelukast, compared to placebo, resulted in significant improvement in asthma control (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in overall 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 to adults, the mean peak plasma concentration (Cmax) was achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. A standard meal does not affect the bioavailability or Cmax of montelukast after oral administration. Safety and efficacy have been confirmed in clinical studies with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is reached 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.

Distribution

Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution averages between 8 and 11 liters. In rat studies using radiolabeled montelukast, penetration across the blood-brain barrier was minimal. Furthermore, 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 pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg 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 effect of montelukast is minimal.

Elimination

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of isotopically labeled 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 bile.

Pharmacokinetics in Specific Patient Populations

Dosage 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 eliminated via bile, dosage 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).

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) was associated with decreased plasma theophylline concentrations. This effect is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As an add-on therapy in the treatment of bronchial asthma in patients with mild to moderate persistent asthma that is not adequately controlled by inhaled corticosteroids, and in cases of inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed.

As an alternative treatment instead of low-dose inhaled corticosteroids in patients with mild persistent asthma who have not experienced severe asthma attacks requiring oral corticosteroids in the recent past, 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.

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

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

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 plasma concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is administered concomitantly 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) indicate 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, but physicians should be aware of the increased risk of adverse reactions.

Based on in vitro data, 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 to treat acute asthma attacks, and that they must always have a suitable emergency medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they require a greater amount of short-acting β-agonist than usual.

Inhaled or oral corticosteroids should not be abruptly replaced with SINGULAIR®.

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is used concomitantly.

In isolated cases, patients receiving anti-asthma medications, including montelukast, have been observed to develop systemic eosinophilia, sometimes accompanied by clinical manifestations of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with reduction in dose or discontinuation of corticosteroid treatment. The possibility that leukotriene receptor antagonists may be linked to the emergence 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 use aspirin or other nonsteroidal anti-inflammatory drugs.

Singulair® contains aspartame, a source of phenylalanine. Patients with phenylketonuria should be informed that one 5 mg chewable tablet contains a quantity of phenylalanine equivalent to 0.842 mg of 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/fetal development.

Available data from published prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing significant congenital malformations in children, have not established a risk associated with the use of the medicinal product. However, the available studies have methodological limitations, including small sample size, retrospective data collection in some cases, 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 into milk. It is unknown whether montelukast is excreted in human breast milk.

Singulair® may be used during breastfeeding only if considered absolutely necessary.

Ability to influence 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.

Dosage and Administration

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 5 mg once daily. The time of administration should be individually adjusted to best relieve symptoms of allergic rhinitis.

For treatment of asthma, the dose for children aged 6 to 14 years is 1 chewable tablet (5 mg) daily, taken in the evening. SINGULAIR® should be taken at least 1 hour before or 2 hours after eating. Dose adjustment is not required for this age group.

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 to 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 with mild persistent asthma should only be considered 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 more than twice a month but less than once a week, and normal lung function between episodes. If adequate asthma control is not achieved (usually within 1 month), the need for additional or alternative anti-inflammatory therapy should be assessed based on a stepwise asthma management approach. Patients should be periodically evaluated for asthma control.

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

Children. For use in children aged 6 to 14 years.

Overdose.

There is no specific information on the treatment of overdose with SINGULAIR®. In clinical studies of chronic asthma, montelukast was administered to adult patients at doses up to 200 mg/day for 22 weeks and up to 900 mg/day for approximately one week in short-term studies, 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 clinical and laboratory findings were consistent with the safety profile observed in adult and pediatric patients. 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, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

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

Adverse reactions

Montelukast was evaluated in clinical studies: approximately 1750 children aged 6 to 14 years received the 5 mg chewable tablets.

In clinical studies, the adverse reactions listed below were observed frequently (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and at a higher frequency than in patients receiving placebo treatment.

Table 1

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

Post-marketing period

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

Table 2

Shelf life. 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.