Singulair^® (Tablets) Instructions for Use

ATC Code

R03DC03 (Montelukast)

Active Substance

Montelukast (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Leukotriene receptor antagonist. Drug for the treatment of bronchial asthma and allergic rhinitis

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other systemic agents for the treatment of obstructive airway diseases; leukotriene receptor antagonists

Pharmacological Action

Cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent inflammatory mediators – eicosanoids that are released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors. Cysteinyl leukotriene type I receptors (CysLT₁ receptors) are present in human airways (including bronchial smooth muscle cells, macrophages) and other pro-inflammatory cells (including eosinophils and some myeloid stem cells). Cysteinyl leukotrienes correlate with the pathophysiology of bronchial asthma and allergic rhinitis.

In asthma, leukotriene-mediated effects include bronchospasm, increased mucus secretion, increased vascular permeability, and increased eosinophil count. In allergic rhinitis, following allergen exposure, cysteinyl leukotrienes are released from pro-inflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction, which manifests as symptoms of allergic rhinitis. Intranasal challenge with cysteinyl leukotrienes has been shown to increase nasal airway resistance and nasal obstruction symptoms.

Montelukast is a highly active oral drug that significantly improves inflammation parameters in bronchial asthma. According to biochemical and pharmacological analysis, Montelukast binds with high affinity and selectivity to CysLT₁ receptors without interacting with other pharmacologically important receptors in the airways (such as prostanoid receptors, cholinergic or β-adrenergic receptors). Montelukast inhibits the physiological action of cysteinyl leukotrienes LTC₄, LTD₄, LTE₄ by binding to CysLT₁ receptors without exerting an agonist effect on these receptors.

Montelukast inhibits CysLT receptors in the airways, as evidenced by its ability to block bronchospasm development in response to inhaled LTD₄ in patients with bronchial asthma. A dose of 5 mg is sufficient to block LTD₄-induced bronchospasm.

Montelukast causes bronchodilation within 2 hours after oral administration and may complement bronchodilation induced by beta₂-adrenergic agonists.

Use of montelukast in doses greater than 10 mg/day once daily does not increase the drug’s efficacy.

Pharmacokinetics

Absorption

After oral administration, Montelukast is rapidly and almost completely absorbed. In adults following an oral dose of 10 mg film-coated tablets under fasting conditions, the mean peak plasma concentration (C_max) is achieved in 3 hours. The mean oral bioavailability is 64%. Food intake does not affect the C_max in plasma or the bioavailability of the drug.

Distribution

The plasma protein binding of montelukast is over 99%. The steady-state volume of distribution (V_d) averages 8-11 L.

Studies with radiolabeled montelukast in rats indicate minimal penetration across the blood-brain barrier. In addition, concentrations of the radiolabeled drug at 24 hours after administration were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses in adults and children, the plasma concentrations of montelukast metabolites at steady state are undetectable.

In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes 3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. According to in vitro studies in human liver microsomes, Montelukast at therapeutic plasma concentrations does not inhibit cytochrome P450 isoenzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6.

Excretion

The plasma clearance of montelukast in healthy adults averages 45 mL/min. Following an oral dose of radiolabeled montelukast, 86% of the administered radioactivity is excreted in the feces over 5 days and less than 0.2% is excreted in the urine, confirming that Montelukast and its metabolites are excreted almost exclusively via the bile.

The elimination half-life (T_1/2) of montelukast in young healthy adults ranges from 2.7 to 5.5 hours.

The pharmacokinetics of montelukast are nearly linear following oral administration of doses greater than 50 mg. No differences in pharmacokinetics are observed between morning and evening dosing. Following once-daily administration of montelukast 10 mg, there is a moderate (approximately 14%) accumulation of the active substance in plasma.

Pharmacokinetics in Special Clinical Situations

The pharmacokinetics of montelukast are similar in women and men.

Following a single 10 mg oral dose of montelukast, the pharmacokinetic profile and bioavailability are similar in elderly and young adult patients. The plasma T_1/2 of montelukast is slightly longer in elderly subjects. No dose adjustment is required for elderly patients.

No clinically significant differences in pharmacokinetic effects were identified in patients based on race.

In patients with mild to moderate hepatic insufficiency and clinical manifestations of liver cirrhosis, a decrease in montelukast metabolism was observed, accompanied by an increase in AUC of approximately 41% following a single 10 mg dose. The clearance of montelukast in these patients is slightly reduced compared to healthy subjects (mean T_1/2 – 7.4 hours). No dose adjustment for montelukast is required for patients with mild to moderate hepatic insufficiency. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale).

Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal impairment. No dose adjustment is required in this category of patients.

Indications

• Prophylaxis and long-term treatment of bronchial asthma in adults and children 15 years of age and older, including prevention of daytime and nighttime symptoms of the disease, treatment of bronchial asthma in patients with hypersensitivity to acetylsalicylic acid, and prevention of exercise-induced bronchospasm;
• Relief of daytime and nighttime symptoms of seasonal and/or perennial allergic rhinitis in adults and children 15 years of age and older.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally once a day, regardless of meals. For the treatment of bronchial asthma, the drug Singulair^® should be taken in the evening. For the treatment of allergic rhinitis, the drug can be taken at any time of day at the patient’s discretion. Patients with bronchial asthma and allergic rhinitis should take 1 tablet of Singulair^® once daily in the evening.

Children aged 2 to 5 years with bronchial asthma and/or allergic rhinitis are prescribed a dose of 4 mg (1 chewable tablet)/day.

General recommendations

The therapeutic effect of Singulair^® on parameters reflecting the course of bronchial asthma develops within the first day. The patient should continue taking Singulair^® both during the period of achieving control over asthma symptoms and during periods of asthma exacerbation.

For elderly patients, patients with renal impairment, and patients with mild or moderate hepatic impairment, as well as based on gender, no special dose adjustment is required.

Prescription of Singulair^® concurrently with other treatments for bronchial asthma

Singulair^® can be added to a patient’s treatment with bronchodilators and inhaled corticosteroids (see section “Drug Interactions”).

Adverse Reactions

In general, Singulair^® is well tolerated by patients. Side effects are usually mild and generally do not require discontinuation of the drug. The overall incidence of side effects during treatment with Singulair^® is comparable to that with placebo.

Children aged 2 to 5 years with bronchial asthma

Clinical studies of Singulair^® included 573 patients aged 2 to 5 years. In a 12-week placebo-controlled clinical study, the only adverse event (AE) assessed as drug-related, observed in >1% of patients taking Singulair^®, and more frequently than in the placebo group, was thirst. The difference in the frequency of this AE between the two treatment groups was not statistically significant.

A total of 426 patients aged 2 to 5 years received treatment with Singulair^® for at least 3 months, 230 for 6 months or longer, and 63 patients for 12 months or longer. With longer-term treatment, the AE profile did not change.

Children aged 2 to 14 years with seasonal allergic rhinitis

A 2-week placebo-controlled clinical study using Singulair^® for the treatment of seasonal allergic rhinitis included 280 patients aged 2 to 14 years. Patients took Singulair^® once daily in the evening; the drug was generally well tolerated. The safety profile of the drug in children was similar to the safety profile of placebo. In this clinical study, no AEs were reported that were considered drug-related, occurred in ≥1% of patients taking Singulair^®, and more frequently than in the placebo group.

Children aged 6 to 14 years with bronchial asthma

The safety profile of the drug in children was generally similar to that in adults and comparable to the safety profile of placebo.

In an 8-week placebo-controlled clinical study, the only AE assessed as drug-related, observed in >1% of patients taking Singulair^®, and more frequently than in the placebo group, was headache. The difference in frequency between the two treatment groups was not statistically significant.

In studies assessing growth rate, the safety profile in patients of this age group was consistent with the previously described safety profile of Singulair^®.

With longer-term treatment (more than 6 months), the AE profile did not change.

Adults and children aged 15 years and older with bronchial asthma

In two similarly designed 12-week placebo-controlled clinical studies, the only AEs assessed as drug-related, observed in ≥1% of patients taking Singulair^®, and more frequently than in the placebo group, were abdominal pain and headache. The differences in the frequency of these AEs between the two treatment groups were not statistically significant. With longer-term treatment (over 2 years), the side effect profile did not change.

Adults and children aged 15 years and older with seasonal allergic rhinitis

Patients took Singulair^® once daily in the morning or evening; the drug was generally well tolerated. The safety profile of the drug was similar to that of placebo. In placebo-controlled clinical studies, no AEs were reported that were considered drug-related, occurred in ≥1% of patients receiving Singulair^®, and more frequently than in the placebo group. In a 4-week placebo-controlled clinical study, the safety profile of the drug was similar to that in the 2-week studies. The incidence of drowsiness with the drug in all studies was the same as with placebo.

Adults and children aged 15 years and older with perennial allergic rhinitis

Patients took Singulair^® once daily in the evening; the drug was generally well tolerated. The safety profile of the drug was similar to that observed in the treatment of patients with seasonal allergic rhinitis and with placebo. In these clinical studies, no AEs were reported that were considered drug-related, occurred in ≥1% of patients receiving Singulair^®, and more frequently than in the placebo group. The incidence of drowsiness with the drug was the same as with placebo.

Pooled analysis of clinical trial results

A pooled analysis of 41 placebo-controlled clinical trials (35 studies involving patients aged 15 years and older, 6 studies involving patients aged 6 to 14 years) was conducted using approved methods for suicidality assessment. Among 9929 patients receiving Singulair^® and 7780 patients receiving placebo in these studies, 1 patient with suicidal ideation was identified in the group of patients receiving Singulair^®. There were no completed suicides, suicide attempts, or other preparatory acts indicating suicidal behavior in either treatment group.

A separate pooled analysis of 46 placebo-controlled clinical trials (35 studies involving patients aged 15 years and older; 11 studies involving patients aged 3 months to 14 years) was conducted to assess adverse behavioral effects (ABEs). Among 11673 patients taking Singulair^® in these studies and 8827 patients taking placebo, the percentage of patients having at least one ABE was 2.73% among patients receiving Singulair^® and 2.27% among patients receiving placebo; the odds ratio was 1.12 (95% confidence interval [0.93; 1.36]).

Adverse events reported during the post-marketing use of the drug are listed in the table below according to system-organ classes and specific adverse events. Frequency categories were estimated based on relevant clinical trials.

¹Frequency category: defined for each adverse reaction based on the frequency indicated in the clinical trial database: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000).

²This adverse event, which was categorized as “very common” in patients receiving Montelukast, was also categorized as “very common” in patients receiving placebo in clinical trials.

³Frequency category: rare.

⁴ This adverse event, which was categorized as “common” in patients receiving Montelukast, was also categorized as “common” in patients receiving placebo in clinical studies.

Contraindications

• Hypersensitivity to any component of the drug;
• Pediatric age under 15 years;
• Lactase deficiency, lactose intolerance, and glucose-galactose malabsorption.

Use in Pregnancy and Lactation

The drug Singulair^® should be used during pregnancy and breastfeeding only if the expected benefit to the mother outweighs the potential risk to the fetus or child.

According to available published data from prospective and retrospective cohort studies on the use of montelukast in women during pregnancy, which assessed major congenital malformations in their children, no risks associated with the drug were identified. The available studies have methodological limitations, including small sample size, in some cases retrospective data collection, and non-comparable control groups.

It is not known whether Singulair^® is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when prescribing Singulair^® during breastfeeding.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild to moderate hepatic impairment.

There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale).

Use in Renal Impairment

No dose adjustment is required for patients with renal impairment.

Pediatric Use

Contraindicated in children under 15 years of age.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

The efficacy of oral Singulair^® in the treatment of acute asthma attacks has not been established; therefore, Singulair^® tablets are not recommended for the treatment of acute asthma attacks. Patients should be instructed to always have rescue medication for acute asthma attacks (inhaled short-acting beta₂-agonists) with them.

Treatment with Singulair^® should not be discontinued during an asthma exacerbation or when the need for rescue medication (inhaled short-acting beta₂-agonists) arises.

Patients with confirmed allergy to acetylsalicylic acid and other NSAIDs should not take these drugs during treatment with Singulair^®, because Singulair^®, while improving respiratory function in patients with allergic asthma, cannot completely prevent NSAID-induced bronchoconstriction in these patients.

The dose of inhaled corticosteroids used concomitantly with Singulair^® may be gradually reduced under medical supervision; however, a sharp replacement of inhaled or oral corticosteroids with Singulair^® should not be performed.

Neuropsychiatric disorders have been reported in patients taking Singulair^® (see the “Adverse Reactions” section). Given that these symptoms could have been caused by other factors, it is not known whether they are related to the use of Singulair^®. The physician should discuss these adverse events with patients and/or their parents/caregivers. Patients and/or their caregivers should be informed that if such symptoms occur, they should inform their physician.

In rare cases, patients receiving anti-asthmatic drugs, including leukotriene receptor antagonists, experienced one or more of the following adverse events: eosinophilia, rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, sometimes diagnosed as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. These cases were sometimes associated with a reduction in dose or withdrawal of oral corticosteroid therapy. Although a causal relationship of these adverse events with leukotriene receptor antagonist therapy has not been established, caution is advised in patients taking Singulair^®; such patients should be subjected to appropriate clinical monitoring.

Singulair^®, 10 mg film-coated tablets contain lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Singulair^® in this dosage form.

Use in elderly patients

No differences in the efficacy and safety profiles of Singulair^® related to patient age have been identified.

Effect on ability to drive and operate machinery

Singulair^® is not expected to affect the ability to drive and operate machinery. Nevertheless, individual reactions to the drug may vary. Some side effects (such as dizziness and drowsiness), which have been reported very rarely with the use of Singulair^®, may affect the ability of some patients to drive and operate machinery.

Overdose

Symptoms

No symptoms of overdose were observed during long-term (22 weeks) clinical studies in adult asthma patients with daily doses of Singulair^® up to 200 mg, or during short-term (about 1 week) clinical studies with daily doses up to 900 mg.

There have been cases of acute overdose (ingestion of at least 1000 mg/day) of Singulair^® in the post-marketing period and during clinical studies in adults and children. Clinical and laboratory findings indicated comparable safety profiles of Singulair^® in children, adults, and elderly patients. The most common adverse effects were thirst, drowsiness, vomiting, psychomotor hyperactivity, headache, and abdominal pain. These adverse effects are consistent with the safety profile of Singulair^®.

Treatment

There is no specific information on the treatment of overdose with Singulair^®. Treatment in case of acute overdose is symptomatic. There are no data on the effectiveness of peritoneal dialysis or hemodialysis for montelukast.

Drug Interactions

Singulair^® can be prescribed concomitantly with other drugs commonly used for the prophylaxis and chronic treatment of asthma and/or the treatment of allergic rhinitis. Montelukast at the recommended therapeutic dose did not have a clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

The AUC of montelukast is decreased by approximately 40% when co-administered with phenobarbital, but this does not require a change in the dosage regimen of Singulair^®.

In vitro studies have shown that Montelukast inhibits the cytochrome P450 isoenzyme CYP2C8; however, in an in vivo drug interaction study of montelukast and rosiglitazone (metabolized by the cytochrome P450 isoenzyme CYP2C8), Montelukast did not inhibit the CYP2C8 isoenzyme. Thus, no effect of montelukast on CYP2C8-mediated drug metabolism (e.g., paclitaxel, rosiglitazone, repaglinide) is anticipated.

In vitro studies have shown that Montelukast is a substrate for CYP2C8, 2C9, and 3A4. Data from a clinical drug interaction study with montelukast and gemfibrozil (an inhibitor of both CYP2C8 and 2C9) demonstrate that gemfibrozil increases the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, a potent CYP3A4 inhibitor, together with gemfibrozil and montelukast did not lead to an additional increase in the systemic exposure of montelukast. The effect of gemfibrozil on the systemic exposure of montelukast is not considered clinically significant based on safety data from the use of doses exceeding the approved 10 mg dose for adult patients (e.g., 200 mg/day for adult patients for 22 weeks and up to 900 mg/day for patients taking the drug for approximately one week, no clinically significant adverse effects were observed). Therefore, no dose adjustment of montelukast is required when co-administered with gemfibrozil. Based on in vitro studies, clinically significant drug interactions with other known inhibitors of CYP2C8 (e.g., trimethoprim) are not anticipated. Furthermore, co-administration of montelukast with itraconazole alone did not lead to a significant increase in the systemic exposure of montelukast.

Combination therapy with bronchodilators

Singulair^® is a reasonable addition to monotherapy with bronchodilators if the latter do not provide adequate control of asthma. Once a therapeutic effect from treatment with Singulair^® is achieved, a gradual reduction in the dose of bronchodilators can be initiated.

Combination therapy with inhaled corticosteroids

Treatment with Singulair^® provides additional therapeutic effect in patients using inhaled corticosteroids. Once the condition is stabilized, a gradual reduction in the dose of corticosteroids under medical supervision can be initiated. In some cases, complete discontinuation of inhaled corticosteroids may be possible; however, a sharp replacement of inhaled glucocorticoids with Singulair^® is not recommended.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place, protected from light, at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.