Singulair

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

Composition:

Active substance: montelukast;

One film-coated tablet contains 10.4 mg of montelukast sodium (equivalent to 10 mg of montelukast);

Excipients: hydroxypropylcellulose, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate;

Tablet coating: hydroxypropylcellulose, methylhydroxypropylcellulose, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), carnauba wax.

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: beige, square tablets with rounded edges, film-coated, imprinted with "SINGULAIR" on one side and "MSD 117" on the other.

Pharmacotherapeutic group. Drugs for systemic use in obstructive airway 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). The CysLT type 1 receptor (CysLT1) is located in the human airways (including airway smooth muscle cells and airway macrophages), as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLT protein is released from the nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. Studies have shown that intranasal administration of CysLT increases nasal airway resistance and exacerbates nasal congestion symptoms.

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

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%, 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). Improvement in patient-reported daytime and nighttime asthma symptoms was significantly better than with placebo.

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

A clinical trial was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older with asthma and concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets once daily demonstrated a statistically significant improvement in the daily rhinitis symptom score compared to placebo. The daily rhinitis symptom score is the mean of daytime nasal symptoms (nasal congestion, rhinorrhea, sneezing, nasal itching) and nighttime symptoms (nasal congestion upon awakening, difficulty falling asleep, frequency of nighttime awakenings). Patients and physicians reported significantly better overall assessment of allergic rhinitis treatment with montelukast compared to placebo. Evaluation of efficacy in asthma was not a primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily significantly improved respiratory function compared to placebo (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%).

A 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 once-daily dosing interval.

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

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. Following a 10 mg film-coated tablet dose administered to adults under fasting conditions, the mean peak plasma concentration (Cmax) was reached within 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 were confirmed in clinical trials with the 10 mg film-coated tablets administered regardless of meal timing.

For the 5 mg chewable tablets, the Cmax in adults was achieved within 2 hours after administration under fasting conditions. The mean oral bioavailability is 73%, decreasing 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, 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 were not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, cytochromes CYP 3A4 and 2C9 play a minor role in its metabolism. However, itraconazole (a CYP3A4 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 cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination

The 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 Specific Patient Populations

Dose adjustment is not required 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 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).

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 add-on therapy for asthma in patients with mild to moderate persistent asthma not adequately controlled by inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenoceptor agonists as needed. In patients with asthma who are taking Singulair®, this medicinal product also relieves symptoms of seasonal allergic rhinitis.

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 benefit of Singulair® treatment; therefore, Singulair® should be used as a reserve agent in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product. Pediatric population under 15 years of age (for the 10 mg dose).

Interaction with other medicinal products and other forms of interaction.

Singulair® may be administered 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 clinically significant effect on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who concurrently took phenobarbital, the area under the 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 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) 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 established 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 coadministered 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 for the treatment of acute asthma attacks, and that they should always have an appropriate 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.

Montelukast should not be used to abruptly displace therapy with inhaled or oral corticosteroids.

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

In isolated cases, systemic eosinophilia has been reported in patients receiving anti-asthmatic agents, including montelukast, sometimes presenting with clinical features of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. These cases have usually (but not always) been associated with a reduction in dose or withdrawal of corticosteroid therapy. A causal relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

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

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any harmful effects on pregnancy or embryonic/fetal development.

Available data from published prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing major congenital malformations in children, have not established a risk associated with the use of the drug. 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.

Effect on ability to drive and use machines.

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 recommended dose for patients (aged 15 years and older) with asthma or asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. For relief of allergic rhinitis symptoms, the time of administration may be adjusted individually.

General recommendations. The therapeutic effect of Singulair® on asthma control parameters develops within 1 day. Singulair® may be taken regardless of food intake. Patients should be advised to continue taking Singulair® even when asthma is well controlled and during asthma exacerbations. Singulair® should not be used concomitantly with medicinal products containing montelukast as the active ingredient.

No dose adjustment is necessary for elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data available on the use of Singulair® in patients with severe hepatic impairment. Dosage is the same for men and women.

Use of Singulair® in relation to other asthma treatments.

Singulair® may be added to existing asthma treatment regimens.

Inhaled corticosteroids. Singulair® may be used as add-on therapy in patients whose disease is not adequately controlled with inhaled corticosteroids and as-needed short-acting β-agonists.

Singulair® should not abruptly replace inhaled corticosteroids (see section "Special precautions").

Children. Singulair® is indicated for use in patients aged 15 years and older. Children under 15 years of age should be administered the medicinal product in the form of chewable tablets.

Overdose.

There is no specific information regarding the treatment of Singulair® overdose. In chronic asthma studies, 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 Singulair® overdose 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 observed clinical and laboratory findings were consistent with the safety profile of Singulair® in adults and children. Most cases of overdose were not associated with adverse reactions. The most commonly reported 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:

• 10 mg film-coated tablets – in approximately 4000 asthma patients aged 15 years and older;
• 10 mg film-coated tablets – in approximately 400 asthma patients with seasonal allergic rhinitis aged 15 years and older;
• 5 mg chewable tablets – in approximately 1750 asthma patients aged 6 to 14 years.

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

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 by organ system classes and using standardized terms in Table 2. Frequencies are based on data from the relevant clinical studies.

Table 2

Shelf life. 3 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.

By prescription only.

Manufacturer.

Merck Sharp & Dohme B.V., Netherlands.

Organon Heist bv, Belgium.

Manufacturer's address and location of business operations.

Waarderweg 39, 2031 BN Haarlem, Netherlands.

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