Singulair

According to clinical studies, Singulair inhibits bronchospasm after inhalation at a dose of 5 mg. Montelukast when administered orally is an active compound that binds to CysLT1 -receptors with high selectivity and affinity.

Indications Singulara

As an additional treatment in bronchial asthma in patients with persistent mild to moderate asthma insufficiently controlled by inhaled corticosteroids, as well as in case of insufficient clinical control of asthma with short-acting β-adrenoreceptor agonists used when necessary. In patients with asthma taking Singulair®, this medicinal product also relieves symptoms of seasonal allergic rhinitis.

Prevention of asthma, the dominant component of which is exercise-induced bronchospasm.

Relief of symptoms of seasonal and year-round allergic rhinitis. The risks of neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of Singulair®, therefore Singulair® should be used as a standby drug in patients with inadequate response or intolerance to alternative therapy.

Release form

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

• excipients: hydroxypropyl cellulose, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate;
• Tablet shell: hydroxypropylcellulose, methylhydroxypropylcellulose, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), carnauba wax.

Film-coated tablets.

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

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent eicosanoids of inflammation secreted by various cells, including mast cells and eosinophils. These important proasthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). The type 1 CysLT receptor (CysLT1) is found in human airways (including airway smooth muscle cells and macrophages in the airways) as well as other pro-inflammatory cells (including eosinophils and certain myeloid stem 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 secreted from the nasal mucosa after exposure to allergen in the development of both early and late type reactions, and this is accompanied by symptoms of allergic rhinitis. According to studies, intranasal administration of CysLT resulted in increased nasal airway resistance and increased symptoms of nasal congestion.

Montelukast when administered orally is an active compound that binds to CysLT1-receptors with high selectivity and affinity. According to clinical studies, montelukast inhibits bronchospasm after inhalation of LTD4at a dose of 5 mg. Bronchodilation was observed within 2 hours after oral administration; this effect was additive to bronchodilation induced by β-agonists. Treatment with montelukast inhibited both the early and late phases of bronchoconstriction induced by antigenic stimulation. Montelukast compared with placebo reduced peripheral blood eosinophil counts in adult patients and children. In a separate study, taking montelukast significantly reduced the number of eosinophils in the airways (as measured by sputum) and peripheral blood and improved clinical control of asthma.

In studies involving adults, montelukast at a dose of 10 mg once daily compared with placebo demonstrated significant improvements in morning PEF1 (change from baseline by 10.4% and 2.7%, respectively), morning peak expiratory flow rate (PEFR) ( change from baseline by 24.5 l/min and 3.3 l/min, respectively), and a significant reduction in total β-agonist use (change from baseline -26.1% and -4.6%, respectively). Improvement in patient-reported measures of daytime and nighttime asthma symptoms was significantly better than for placebo.

Studies involving adults have demonstrated the ability of montelukast to complement the clinical effect of inhaled corticosteroids (change (in %) in the initial rate for inhaled beclomethasone plus montelukast compared with beclomethasone, respectively, for PEF1: 5.43 % and 1.04 %; use of β-agonists: -8.70 % and 2.64 %). Compared with inhaled beclomethasone (200 μg twice daily, spacer device), montelukast demonstrated a faster initial response, although beclomethasone resulted in a more pronounced mean therapeutic effect over the 12-week study (% change in initial rate for OFV1: 7.49 % and 13.3 %; 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 EFV1 of approximately 11% or more from baseline, whereas 42% of patients treated with montelukast achieved the same response).

A clinical trial was conducted to evaluate montelukast as an agent for the symptomatic treatment of seasonal allergic rhinitis in patients over 15 years of age with asthma and concomitant seasonal allergic rhinitis. In this study, it was demonstrated that montelukast tablets when administered at a dose of 10 mg once daily compared to placebo demonstrated a statistically significant improvement in the mean daily rhinitis symptom score. The mean daily rhinitis symptom score is the average of nasal symptoms assessed during the day (mean nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (mean nasal congestion on awakening, difficulty falling asleep, and frequency of nocturnal awakenings). Compared to placebo use, significantly better results were obtained in the overall evaluation of allergic rhinitis treatment by patients and physicians. Assessing the efficacy of this treatment in asthma was not the primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast at a dose of 5 mg once daily compared with placebo significantly improved respiratory function (change from baseline SPF1: 8.71% vs. 4.16%, change in morning PSV: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of β-agonist use as needed (change from baseline of -11.7% vs. +8.2%).

A significant reduction in exercise-associated bronchospasm (EAB) was demonstrated during the 12-week study in adults (maximum reduction in EFV1 22.33% for montelukast versus 32.40% for placebo, time to recovery within 5% of initial EFV1 44.22 min (versus 60.64 min). This effect was observed over the 12-week study period. A reduction in BFN was also demonstrated during a short study involving children aged 6 to 14 years (maximum reduction in OFV1 18.27% vs. 26.11%; time to recovery within 5% of initial OFV1 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the interval when administered once daily.

In aspirin-sensitive patients receiving current therapy with inhaled and/or oral corticosteroids, treatment with montelukast compared with placebo resulted in a significant improvement in asthma control (change in initial PEF1 is 8.55% vs -1.74% and change in reduction in total β-agonist use -27.78% vs 2.09%).

Pharmacokinetics

Montelukast is rapidly absorbed after oral administration. After administration of 10 mg film-coated tablets in adults on an empty stomach, the average maximum concentration (Cmax) in plasma was reached after 3 hours (Tmax). The average bioavailability during oral administration is 64%. The intake of regular food did not affect the bioavailability and Cmax during oral administration. Safety and efficacy have been confirmed in clinical trials with 10 mg film-coated tablets regardless of meal time.

For chewable tablets of 5 mg, Cmax in adults was reached 2 hours after ingestion on an empty stomach. The average oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution

More than 99% of montelukast binds to plasma proteins. The volume of distribution of montelukast in the stationary phase averages 8 to 11 liters. In rat studies using radioactively labeled montelukast, passage across the blood-brain barrier was minimal. In addition, concentrations of radioisotope-labeled material in all other tissues 24 hours after dose administration were also minimal.

Metabolism

Montelukast is actively metabolized. In studies with therapeutic doses, steady-state plasma concentrations of montelukast metabolites were not determined in adults and infant 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 (CYP WA4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg of montelukast. According to the results of in vitro studies using human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 ZA4, 2C9, 1A2, 2A6, 2C19 and 2D6. The participation of metabolites in the therapeutic action of montelukast is minimal.

Withdrawal

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

Pharmacokinetics in different groups of patients

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

When taking high doses of montelukast (20 and 60 times the dose recommended for adults), a decrease in plasma theophylline concentration was observed. This effect is not observed when taking the recommended dose of 10 mg once daily.

Dosing and administration

The dose for patients (age 15 years and older) with asthma or with asthma and concomitant seasonal allergic rhinitis is 10 mg (1 tablet) per day, in the evening. To relieve symptoms of allergic rhinitis, the time of administration is adjusted individually.

General recommendations. The therapeutic effect of the medicinal product Singulair® on asthma control parameters occurs within 1 day. The medicinal product can be used independently from meals. Patients should be advised to continue taking the drug Singulair® even if asthma control is achieved, as well as during periods of asthma exacerbation. Singulair® should not be used concomitantly with medicinal products containing the active substance montelukast.

No dose adjustment is necessary in elderly patients, with impaired renal function or mild to moderate hepatic impairment. No data are available for patients with severe hepatic impairment. Dosage for men and women is the same.

Use of the medicine Singulair® depending on other asthma treatment.

Singulair® medicine can be added to an existing asthma treatment regimen.

Inhaled corticosteroids: Sing ulair® may be used as an adjunctive treatment in patients in whom inhaled corticosteroids together with short-acting β-agonists, used as needed, do not provide satisfactory clinical control of the disease.

Singulair® medicine should not drastically replace inhaled corticosteroids (see section "Administration details").

Children : Use in children from 15 years of age. Children under 15 years of age should use the medicinal product in the form of chewable tablets.

Contraindications

Hypersensitivity to the components of the medicinal product. Children under 15 years of age (for 10 mg dose).

Side effects Singulara

Montelukast has been evaluated in clinical trials:

• 10 mg film-coated tablets - in about 4,000 patients with asthma aged 15 years and older;
• 10 mg film-coated tablets - in approximately 400 patients with asthma and seasonal allergic rhinitis aged 15 years and older;
• 5 mg chewable tablets - in approximately 1,750 asthma patients aged 6 to 14 years.

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

Table 1

Classes of organ systems	Adult patients and Children from 15 years old (two 12-week studies; n=795)
Nervous system	Headache
Gastrointestinal tract (GIT) disorders	Abdominal pain

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

Post-marketing period

Adverse reactions reported in the post-marketing period are listed according to organ system classes and using specific terms in Table 2. The frequency is established according to the data of relevant clinical trials.

Table 2

Class of organ systems	Adverse Reactions	Frequency*
Infections and infestations	Upper respiratory tract infections †	Very often
Blood and lymphatic system disorders	Tendency to increase bleeding.	Infrequently
	Thrombocytopenia	Very rarely
Immune system	Hypersensitivity reactions, including anaphylaxis	Infrequently
	Eosinophilic infiltration of the liver	Very rarely
On the mental side	Sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behavior or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor §)	Infrequently
	Attention deficit disorder, memory impairment, tics.	Infrequently
	Hallucinations, disorientation, suicidal thoughts and behavior (suicidality), obsessive-compulsive disorder, dysphemia	Very rarely
Nervous system	Dizziness, drowsiness, paresthesia/hypoesthesia, seizures	Infrequently
On the heart side	Palpitation	Infrequently
Respiratory system, chest and mediastinal organs.	Nosebleed	Infrequently
	Churg-Stross syndrome (see section "Administration details"), pulmonary eosinophilia	Very rarely
Gastrointestinal disorders	Diarrhea ‡, nausea ‡, vomiting ‡	Frequently
	Dry mouth, dyspepsia.	Infrequently
Hepatobiliary system	Increase in serum transaminases (ALT, AST)	Frequently
	Hepatitis (including cholestatic, hepatocellular and mixed liver disease)	Very rarely
Skin and subcutaneous tissues	Rash ‡	Frequently
	Hematoma, hives, itching.	Infrequently
	Angioedema	Infrequently
	Nodular erythema, erythema multiforme	Very rarely
Musculoskeletal and connective tissue disorders	Arthralgia, myalgia, including muscle cramps	Infrequently
Kidney and urinary tract disorders	Enuresis in children	Infrequently
General disorders and adverse reactions caused by taking the drug	Pyrexia ‡	Frequently
	Asthenia/fatigue, malaise, edema	Infrequently
*Frequency is defined according to the frequency of reports in the clinical trials database: very frequent (≥ 1/10), frequent (≥ 1/100 to < 1/10), infrequent (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000). † This adverse reaction was reported with a frequency of "very common" in patients using montelukast and in patients receiving placebo during clinical trials. ‡ This adverse reaction was reported with a frequency of "frequently" in patients using montelukast as well as in patients receiving placebo during clinical trials. § Rarely.

Overdose

No specific information on the treatment of overdose with Singulair® is available. In chronic asthma studies montelukast was administered in doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies - up to 900 mg/day for about one week, with no clinically significant adverse reactions.

Acute overdose with Singulair® has been reported in post-marketing use and in clinical studies. They included administration of the drug in adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory data obtained were consistent with the safety profile in patients and children. In most cases of overdose, no adverse reactions were reported. The most frequently observed adverse reactions were consistent with the safety profile of Singulair® medicinal product and included: abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.

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

Interactions with other drugs

Singulair can be administered together with other medicines commonly used for the prophylaxis or long-term treatment of asthma. In a drug-drug interaction study, the recommended clinical dose of montelukast had no important 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 concomitantly taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Since montelukast is metabolized by CYP ZA4, 2C8 and 2C9, caution should be exercised, especially in children, if montelukast is administered concomitantly with CYP ZA4, 2C8 and 2C9 inducers, e.g. Phenytoin, phenobarbital and rifampicin.

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

In in vitro studies, montelukast was found to be a substrate of CYP 2C8 and to a lesser extent 2C9 and 3A4. In a clinical drug interaction study involving montelukast and gemfibrozil (a CYP 2C8 and 2C9 inhibitor), gemfibrozil increased the systemic exposure of montelukast 4.4-fold. In concomitant use with gemfibrozil or other CYP 2C8 inhibitors dose adjustment of montelukast is not required, but the physician should take into account the increased risk of adverse reactions.

According to the results of in vitro studies, clinically important interactions with less potent CYP 2C8 inhibitors (e.g. Trimethoprim) are not expected to occur. Concomitant administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, did not lead to a significant increase in systemic exposure of montelukast.

Storage conditions

Store in the original package at a temperature not exceeding 30 °С.

Keep out of reach of children.

Special instructions

Patients should be warned that Singulair® for oral use is never used for the treatment of acute asthma attacks and that they should always carry an appropriate emergency medicine with them. Short-acting inhaled β-agonists should be used in an acute attack. Patients should consult their physician as soon as possible if they require more short-acting β-agonist than usual.

Therapy with inhaled or oral corticosteroids should not be abruptly substituted for montelukast.

There is no evidence that the dose of oral corticosteroids can be reduced with concomitant use of montelukast.

Neuropsychiatric reactions such as behavioral changes, depression and suicidality have been reported in patients of all ages taking montelukast (see Adverse Reactions section). Manifestations can be serious and may persist if treatment is not discontinued. Therefore, use of montelukast should be discontinued if neuropsychiatric symptoms occur. Patients and/or caretakers should be alert to neuropsychiatric reactions and report to their physician if behavioral changes occur.

In isolated cases, patients receiving anti-asthmatic agents, including montelukast, may have systemic eosinophilia, sometimes together with clinical manifestations of vasculitis, the so-called Churg-Stross syndrome, treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with dose reduction or withdrawal of the corticosteroid agent. The possibility that leukotriene receptor antagonists may be associated with the occurrence of Churg Stross syndrome cannot be refuted or confirmed. Clinicians should be mindful of the possibility of patients experiencing 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.

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

Patients with rare inherited conditions such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this medicine.

The drug contains less than 1 mmol (23 mg) of sodium per tablet, which means it is virtually free of sodium.

Use during pregnancy or lactation.

Pregnancy. Animal studies show no harmful effects on pregnancy or embryonic/fetal development.

Available data from published prospective and retrospective cohort studies of montelukast use in pregnant women evaluating for significant congenital malformations in children have not established a risk associated with the use of the drug. The available studies have methodological limitations, including small sample sizes, in some cases retrospective data collection, and incompatible comparison groups.

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

Breastfeeding. Studies in rats have shown that montelukast passes into milk. It is not known whether montelukast is excreted with breast milk in women.

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

Ability to affect reaction speed when driving motor transport or other mechanisms.

Montelukast is not expected to affect the patient's ability to drive motor vehicles or other mechanisms. However, very rarely drowsiness or dizziness has been reported.

Shelf life

3 years.

Do not use the medicinal product after the expiration date indicated on the package.