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INSTRUCTIONS for the use of the drug for medical use Singulyar®
REGISTRATION NUMBER P N016104 / 02-230315 TRADE NAME: Singular® INTERNATIONAL NON-PATENT NAME: montelukastDOSAGE FORM: chewable tablets
COMPOSITION 1 chewable tablet contains:Active ingredient: montelukast sodium 5.2 mg (equivalent to 5.0 mg free acid). Adjuvants: mannitol 201.35 mg, microcrystalline cellulose 66.0 mg, hyprolosis, (hydroxypropylcellulose) 9.0 mg, ferric oxide red 0, 45 mg, croscarmellose sodium 9.0 mg, cherry flavoring 4.5 mg, aspartame 1.5 mg, magnesium stearate 3.0 mg.
DESCRIPTION Pink, round, biconvex tablets with extruded SINGULAIR lettering on one side and MSD 275 on the other side.
PHARMACOTHERAPY GROUP Leukotriene receptor blocker.ATH CODE: R03DC03
Pharmacodynamics Cysteine leukotrienes (LTC4, LTD4, LTЕ4) are strong inflammatory mediators – eicosanoids, which are secreted by various cells, including mast cells and eosinophils. These important prostatic mediators bind to cysteinyl with leukotriene receptors. Cysteine type I leukotriene receptors (CysLT1 receptors) are present in the human respiratory tract (including bronchial smooth muscle cells, macrophages) and other pro-inflammatory cells (including eosinophils and some myeloid stem cells). Cysteine leukotrienes correlate with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchospasm, an increase in mucus secretion, an increase in vascular permeability, and an increase in the number of eosinophils. In allergic rhinitis, after exposure to an allergen, leukotriene cysteinyl is released from pro-inflammatory cells of the nasal mucosa during the early and late phases of an allergic reaction, which is manifested by symptoms of allergic rhinitis. An intranasal cysteinyl test with leukotrienes has been shown to increase the resistance of the airway nasal passages and the symptoms of nasal obstruction. Montelukast is a highly active drug when taken orally, which significantly improves inflammation in bronchial asthma. According to biochemical and pharmacological analysis, Montelukast binds to CysLT1 receptors with high affinity and selectivity, without interacting with other pharmacologically important receptors in the respiratory tract (such as prostaglandin, cholinergic or β-adrenergic receptors). Montelukast inhibits the physiological action of the cysteinyl leukotrienes LTC4, LTD4 and LT4 by binding to CysLT1 receptors, without having a stimulating effect on these receptors. Montelukast inhibits CysLT receptors in the respiratory tract, as evidenced by the ability to block the development of bronchospasm in response to LTD4 inhalation in patients with bronchial asthma. A dose of 5 mg is enough to relieve bronchospasm induced by LTD4. Montelukast causes bronchodilation within 2 hours after ingestion and may complement bronchodilation caused by β2-adrenomimetics.Pharmacokinetics Suction Montelukast is rapidly and almost completely absorbed after oral administration. When taken on an empty stomach chewable 5 mg tablets, the maximum concentration (Cmax) in adults is reached after 2 hours. Average oral bioavailability is 73%. Eating does not have a clinically significant effect with prolonged use.Distribution Montelukast binds to plasma proteins more than 99%. The volume of distribution of montelukast in a state of equilibrium concentration averages 8-11 liters. Studies with radioactively labeled montelukast performed on rats indicate minimal penetration through the blood-brain barrier. In addition, the concentrations of the labeled drug 24 hours after the administration were minimal in all other tissues.Metabolism Montelukast is actively metabolized. In the study of therapeutic doses in adults and children, the concentration of Montelukast metabolites in the state of equilibrium plasma concentration is not determined. In vitro studies using human liver microsomes have shown that cytochrome P450: 3A4, 2C8 and 2C9 isoenzymes are involved in the metabolism of montelukast. According to the results of studies conducted in vitro in human liver microsomes, montelukast at therapeutic plasma concentrations does not inhibit cytochrome P450: 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6 isoenzymes.Removal Montelukast plasma clearance in healthy adults averages 45 ml / min. After ingestion of radioactively labeled montelukast, 86% of its amount is excreted in the feces within 5 days and less than 0.2% in urine, which confirms that montelukast and its metabolites are excreted almost exclusively with bile. The half-life of montelukast in young healthy adults ranges from 2.7 to 5.5 hours. The pharmacokinetics of montelukast remains almost linear when ingesting doses of over 50 mg. When taking montelukast in the morning and evening hours, no pharmacokinetic differences were observed. When taking 10 mg of montelukast 1 time per day, a moderate (about 14%) cumulation of the active substance in plasma is observed.Features of pharmacokinetics in different groups of patients Gender Pharmacokinetics of montelukast is similar in women and men. Elderly Patients With a single dose of 10 mg of Montelukast, the pharmacokinetic profile and bioavailability are similar in the elderly and young patients. The half-life of montelukast from plasma is somewhat longer in the elderly. Dose adjustment of the drug in the elderly is not required. Race No differences in clinically significant pharmacokinetic effects in patients of different races. Hepatic insufficiency In patients with mild to moderate hepatic insufficiency and clinical manifestations of liver cirrhosis, montelukast metabolism slowed down, accompanied by an increase in the area under the concentration-time pharmacokinetic curve (AUC) by approximately 41% after a single dose of the drug at a dose of 10 mg. The withdrawal of montelukast in these patients increases slightly compared with healthy subjects (the average half-life is 7.4 hours). Changes in the dose of Montelukast are not required for patients with mild to moderate hepatic insufficiency. There are no data on the nature of montelukast pharmacokinetics in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale). Renal failure Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast have not been evaluated in patients with renal insufficiency. Adjustment of the drug dose for this group of patients is not required.
INDICATIONS FOR USE
• Prevention and long-term treatment of bronchial asthma in children aged 6 to 14 years, including the prevention of day and night symptoms of the disease, the treatment of bronchial asthma in patients with hypersensitivity to acetylsalicylic acid and the prevention of bronchospasm caused by exercise. • Relief of day and night symptoms of seasonal and / or year-round allergic rhinitis in children aged 6 to 14 years.
• Hypersensitivity to any of the components of the drug. • Children’s age up to 6 years. • Phenylketonuria.
USE IN PREGNANCY AND DURING BREASTFEEDING
Clinical research of the drug Singulyar® with participation of pregnant women was not conducted. The drug Singulyar® should be used during pregnancy and during lactation only if the expected benefit to the mother outweighs the potential risk to the fetus or baby. During the post-registration use of the drug Singulyar®, the development of congenital limb defects in newborns whose mothers took the drug Singulyar® during pregnancy was reported. Most of these women also took other medications for the treatment of bronchial asthma during pregnancy. The causal relationship between taking the drug Singular® and the development of congenital defects of the extremities has not been established. It is not known whether the drug Singulyar® is excreted in breast milk. Since many drugs are excreted in breast milk, it is necessary to take this into account when administering the drug Singulyar® to breastfeeding mothers.
METHOD OF ADMINISTRATION AND DOSES
Inside once a day, regardless of the meal. For the treatment of bronchial asthma, the dose of the drug Singular® should be taken in the evening. In the treatment of allergic rhinitis dose may be taken at any time of the day at the request of the patient. Patients suffering from bronchial asthma and allergic rhinitis should take one tablet of the drug Singulyar® 1 time per day in the evening.Children aged 6 to 14 years The dose for children 6-14 years old is one chewable tablet 5 mg per day. Dose selection for this age group is not required.General recommendations The therapeutic effect of the drug Singulyar® on the indicators reflecting the course of bronchial asthma develops during the first day. The patient should continue to take Singulyar® both in the period to achieve control over the symptoms of bronchial asthma, and in periods of exacerbation of bronchial asthma. For elderly patients, patients with renal insufficiency, as well as patients with mild or moderately impaired liver function, and also depending on the gender, a special dose selection is not required.Purpose of the drug Singulyar® along with other types of treatment of bronchial asthma The drug Singulyar® can be added to the treatment of a patient with bronchodilators and inhaled glucocorticosteroids (see Section “Interaction with other medications”).
In general, the drug Singulyar® is well tolerated. Side effects are usually mild and, as a rule, do not require discontinuation of the drug. The overall frequency of side effects during treatment with the drug Singular® is comparable to their frequency when taking a placebo.Children from 2 to 5 years old with asthma 573 patients aged from 2 to 5 years took part in clinical trials of the drug Singulyar®. In a 12-week placebo-controlled clinical trial, the only adverse event (AE), assessed as associated with taking the drug, was observed in > 1% of patients who took the drug Singulyar®, and more often than in the group of patients who took a placebo, was thirst. The differences in the frequency of this AE were statistically insignificant. A total of 426 patients aged from 2 to 5 years received treatment with Singulyar® for at least 3 months, 230 – for 6 months or more, and 63 patients for 12 months or more. With longer treatment, the AH profile has not changed.Children aged 2 to 14 years with seasonal allergic rhinitis A 2-week placebo-controlled clinical study using the drug Singulyar® for the treatment of seasonal allergic rhinitis was attended by 280 patients aged from 2 to 14 years. The drug Singulyar® was taken by patients once a day in the evening and was generally well tolerated, the safety profile of the drug was similar to the placebo safety profile. In this clinical study, no adverse events were registered that were regarded as associated with taking the drug, would be observed in ≥ 1% of patients who took the drug Singular®, and more often than in the group of patients who took placebo.Children aged 6 to 14 years with bronchial asthma The safety profile of the drug in children was generally similar to the safety profile in adults and is comparable to the safety profile of placebo. In an 8-week placebo-controlled clinical trial, the only AEs rated as being related to drug intake observed in > 1% of patients taking the drug Singular®, and more often than in the group of patients taking placebo, had a headache. The difference in frequency between the two treatment groups was not statistically significant. In studies assessing the growth rate, the safety profile in patients of this age group corresponded to the previously described safety profile of Singulyar®. With longer treatment (more than 6 months), the AE profile has not changed.Adults and children aged 15 and over with asthma In two 12-week placebo-controlled clinical trials with a similar design, the only adverse events (AEs) assessed as associated with taking the drug, observed in ≥ 1% of patients taking the drug Singular®, and more often than in the group of patients taking placebo, there was an abdominal pain and a headache. The differences in the frequency of AE data between the two treatment groups were not statistically significant. With longer treatment (within 2 years), the AE profile has not changed.Adults and children aged 15 years and older with seasonal allergies and rhinitis The drug Singulyar® was taken by patients once a day, in the morning or in the evening, and was generally well tolerated, the safety profile of the drug was similar to the placebo safety profile. In placebo-controlled clinical trials, adverse events were not registered, which would be regarded as associated with the administration of the drug, would be observed in ≥ 1% of patients who took the drug Singulyar®, and more often than in the group of patients who took placebo. In a 4-week, placebo-controlled clinical study, the safety profile of the drug was similar to that in 2-week studies. The frequency of drowsiness when taking the drug in all studies was the same as when taking a placebo.Adults and children aged 15 and over with year-round allergic rhinitis The drug Singulyar® was taken by patients once a day and was generally well tolerated. The safety profile of the drug was similar to the safety profile observed in the treatment of patients with seasonal allergic rhinitis and when taking a placebo. In these clinical trials, adverse events were not registered, which would be regarded as associated with taking the drug, would be observed in ≥ 1% of patients who took the drug Singulyar®, and more often than in the group of patients who took placebo. The frequency of drowsiness when taking the drug was the same as when taking a placebo.Generalized analysis of the results of clinical studies A generalized analysis of 41 placebo-controlled clinical studies (35 studies involving patients aged 15 years and older; 6 studies involving patients aged 6 to 14 years) was conducted using approved methods for assessing suicidality. Among the 9929 patients who took the drug Singulyar®, and 7780 patients who took placebo in these studies, one patient was identified with a suicidal attitude in the group of patients who took the drug Singulyar®. None of the treatment groups committed any suicides, suicidal attempts, or other preparatory actions that indicated suicidal behavior. Separately, a generalized analysis of 46 placebo-controlled clinical studies (35 studies involving patients aged 15 years and older; 11 studies involving patients aged 3 months to 14 years) was carried out to evaluate adverse behavioral effects (AEDs). Among the 11673 patients who took the drug Singulyar® in these studies, and 8827 patients who took placebo, the percentage of patients who have at least one IPE was 2.73% among patients who took the drug Singulyar® and 2.27% among those who took placebo ; odds ratio was 1.12 (95% confidence interval [0.93; 1.36]). During postregistrational use of the drug, the following identified AEs were reported: infectious and parasitic diseases: infections of the upper respiratory tract, disorders of the blood and lymphatic system: increased tendency to bleeding, disorders of the immune system: hypersensitivity reactions, including anaphylaxis, are very seldom (