Singular chewable tablets 4 mg 28 pcs. (Montelukast)

Release form

1 tablet contains:

Active ingredient: Montelukast sodium 4.16 mg, which corresponds to the content of montelukast 4 mg.

Excipients:

Mannitol - 161.08 mg

Microcrystalline cellulose - 52.8 mg

Hyprolose (hydroxypropyl cellulose) - 7.2 mg

Iron oxide red - 0.36 mg

Sodium croscarmellose - 7. 2 mg

Cherry flavoring - 3.6 mg

Aspartame - 1.2 mg

Magnesium stearate - 2.4 mg.

Pharmacological action of

Pharmacotherapeutic group: Leukotriene receptor

blocker ATX: R.03.DC03

Pharmacodynamics:

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent mediators of inflammation, different inflammation cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors.

Cysteinyl leukotriene receptors of type I (CysLT1 receptors) are present in the human airways (including the cells of the smooth muscles of the bronchi, macrophages) and other proinflammatory 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 eosinophils. In allergic rhinitis, after exposure to the allergen, cysteinyl leukotrienes are released from the pro-inflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction, which is manifested by symptoms of allergic rhinitis. An intranasal test with cysteinyl leukotrienes has been shown to increase the resistance of the airways and nasal obstruction.

Montelukast is a highly active oral drug that significantly improves inflammation in bronchial asthma. According to biochemical and pharmacological analysis of

, 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 ( -adrenergic receptors).

Montelukast inhibits the physiological effect of the cysteinyl leukotrienes LTC4, LTD4 and LTE4 by binding to CysLT1 receptors without stimulating these receptors.

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

Montelukast causes bronchodilation within 2 hours after ingestion and may supplement bronchodilation caused by 2-adrenergic agonists.

The use of montelukast in doses exceeding 10 mg per day, taken once, the effectiveness of the drug does not increase.

Pharmacokinetics:

Absorption

Montelukast is rapidly and almost completely absorbed after oral administration. In adults, when taken on an empty stomach, coated tablets of 10 mg, the maximum concentration (C max) is reached after 3 hours (T max). The average oral bioavailability is 64%. Eating does not affect Cmax in blood plasma and the bioavailability of the drug.

Distribution of

Montelukast binds to plasma proteins by more than 99%. The volume of distribution of montelukast in equilibrium concentration is an average of 8-11 liters.

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

Metabolism

Montelukast is extensively metabolized. In the study of therapeutic doses in adults and children, the concentration of montelukast metabolites in the equilibrium state in the plasma is not determined.

In vitro studies using human liver microsomes have shown that isoenzymes of cytochrome P450: 3A4, 2C8 and 2C9 are involved in the metabolism of montelukast. According to the results of in vitro studies on human liver microsomes,

montelukast in therapeutic plasma concentrations does not inhibit cytochrome P450 isoenzymes: 3A4, 2C9, 1A2, 2A6, 2C19 and 2D6.

Excretion of

Plasma clearance of montelukast in healthy adults averages 45 ml / min. After ingestion of radioactively labeled Montelukast, 86% of its amount is excreted in feces for 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 is from 2.7 to 5.5 hours. The pharmacokinetics of montelukast remains almost linear when ingested doses of more than 50 mg. When taking montelukast in the morning and evening hours, differences in pharmacokinetics are not observed. When taking 10 mg of montelukast once a day, moderate (about 14%) cumulation of the active substance in plasma is observed.

Pharmacokinetics in retail patient groups

Gender

The pharmacokinetics of montelukast in women and men are similar.

Elderly patients

With a single oral administration of 10 mg of montelukast, the pharmacokinetic profile and bioavailability are similar in elderly and young patients. The half-life of montelukast from plasma is somewhat longer in older people. No dose adjustment in the elderly is required.

Race

There were no differences in the clinically significant pharmacokinetic effects in patients of different races.

Hepatic insufficiency

Patients with mild to moderate hepatic insufficiency and clinical manifestations of cirrhosis showed a slowdown in Montelukast metabolism, accompanied by an increase in the area under the concentration-time pharmacokinetic curve (AUC) of approximately 41% after a single dose of 10 mg. The excretion of montelukast in these patients is slightly increased compared with healthy subjects (average half-life is 7.4 hours). Montelukast dose changes for patients with mild to moderate liver failure are not required. There is no data on the nature of the pharmacokinetics of montelukast 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 in patients with renal insufficiency have not been evaluated. No dose adjustment for this group of patients is required.

Indications

Prevention and long-term treatment of bronchial asthma in children aged 2 years and older: to control the day and night symptoms of

disease Relieve symptoms of allergic rhinitis in children 2 years of age and older.

Use during pregnancy and lactation

Clinical studies of the drug SingularВ® involving pregnant women have not been conducted. SingularВ® should be used during pregnancy and during breastfeeding only in cases where the expected benefit to the mother outweighs the potential risk to the fetus or baby.

During the post-registration use of the drug SingularВ®, the development of congenital limb defects in newborns whose mothers took SingularВ® during pregnancy was reported. Most of these women also took other medications to treat asthma during pregnancy. A causal relationship between the administration of the drug SingularВ® and the development of congenital limb defects has not been established.

It is not known whether montelukast with breast milk is excreted. Since many drugs are excreted in breast milk, this must be taken into account when prescribing the drug SingularВ® to breast-feeding mothers.

Special instructions

The effectiveness of the drug Singular® for oral administration in the treatment of acute attacks of bronchial asthma has not been established, therefore, the drug Singular® in tablets is not recommended for the treatment of acute attacks of bronchial asthma. Patients should be instructed to always carry emergency medications for the relief of asthma attacks (short-acting inhaled beta-2 agonists).

You should not stop taking the drug Singular® during an exacerbation of asthma and the need to use emergency drugs to relieve seizures (short-acting inhaled beta-2 agonists).

Patients with a confirmed allergy to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) should not take these drugs during the treatment with Singulyar®, since Singulyar®, while improving respiratory function in patients with allergic bronchial asthma, however, cannot completely prevent the bronchoconstriction caused by them NSAIDs.

Dose of inhaled glucocorticosteroids, used simultaneously with the drug Singular®, can be gradually reduced under the supervision of a doctor, however, a sharp replacement of inhaled or oral glucocorticosteroids with the drug Singular® cannot be carried out.

Neuropsychiatric disorders have been described in patients taking the drug Singular® (see section Side effects). Given that these symptoms could have been caused by other factors, it is not known whether they are associated with the administration of the drug Singular®. The physician needs to discuss AE data with patients and / or their parents / guardians. Patients and / or their parents / guardians need to be explained that in case of such symptoms, it is necessary to inform the attending physician.

In rare cases, patients receiving anti-asthma drugs, including leukotriene receptor antagonists, experienced one or more of the following AEs: eosinophilia, rash, worsening pulmonary symptoms, cardiac complications and / or neuropathy, sometimes diagnosed as Charge-Strauss syndrome, systemic eosinophilic vasculitis.

These cases have sometimes been associated with a dose reduction or discontinuation of oral glucocorticosteroid therapy. Although a causal relationship between these AEs and therapy with antagonists of leukotriene receptors has not been established, caution should be exercised in patients taking the drug Singular®: appropriate clinical observation should be carried out in such patients.

The drug Singular® coated tablets, 10 mg contains lactose monohydrate. Patients with a rare form of hereditary galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption should not take the drug Singular® coated tablets, 10 mg.

Use in elderly patients

There were no differences in the profiles of efficacy and safety of the drug Singular® related to the age of the patients.

Influence on ability to drive a vehicle:

It is not expected that taking the drug Singular® will affect the ability to drive vehicles and operate machinery. Nevertheless, individual reactions to the drug may be different. Some side effects (such as dizziness and drowsiness), which have been reported to occur very rarely when using the drug Singular®, may affect the ability of some patients to drive vehicles and operate machinery.

Composition

1 coated tablet, contains: Active ingredient:

montelukast - 4 mg

Excipients:

microcrystalline cellulose,

lactose,

croscarmellose sodium,

magnesium,

magnesium.

Composition of the coating of the tablet: hyprolose, hypromellose, titanium dioxide, dyes iron oxide red and iron oxide yellow and carnauba wax.

Dosage and administration

Inside 1 time / day, regardless of food intake.

For the treatment of bronchial asthma, the drug Singular should be taken in the evening.

In the treatment of allergic rhinitis, the drug can be taken at any time of the day at the request of the patient.

Patients with asthma and allergic rhinitis should take 1 tablet of the drug Singular® 1 time per day in the evening.

Children aged 2 to 5 years

For bronchial asthma and / or allergic rhinitis - 1 chewable tablet 4 mg per day.

General recommendations

The therapeutic effect of the drug Singular® on indicators reflecting the course of bronchial asthma develops during the first day. The patient should continue to take Singular® both during the period of achieving control over the symptoms of bronchial asthma, and during periods of exacerbation of bronchial asthma.

For elderly patients, patients with renal failure, as well as patients with mild or moderate hepatic impairment, as well as gender-specific special dose selection is not required.

Purpose of the drug Singular® simultaneously with other types of treatment for bronchial asthma

The drug Singular® can be added to the treatment of a patient with bronchodilators and inhaled GCS.

Side effects

In general, the drug Singular® is well tolerated. Side effects are usually mild and. as a rule, do not require discontinuation of the drug. The overall incidence of side effects during treatment with Singular® is comparable to their frequency with placebo.

Children aged 2 to 5 years with bronchial asthma

573 patients aged 2 to 5 years participated in clinical trials of the drug Singular®. In a 12-week, placebo-controlled clinical trial, the only adverse event (AE) rated as associated with taking the drug was observed in> 1% of patients taking the drug Singular®, and more often than in the placebo group, there was thirst. Differences in the frequency of this AE between the two treatment groups were statistically insignificant.

A total of 426 patients aged 2 to 5 years have been treated with Singular® for at least 3 months. 230 for 6 months or more, and 63 patients for 12 months or more. With longer treatment, the AE profile has not changed.

Children 2 to 14 years old with seasonal allergic rhinitis

280 patients aged 2 to 14 years participated in a 2-week placebo-controlled clinical trial using the drug Singular® for the treatment of seasonal allergic rhinitis. The drug Singular® 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 safety profile of placebo.

AEs were not reported in this clinical study. which would be regarded as associated with taking the drug, would be observed in? 1% of patients taking the drug Singular® and more often than in the group of patients taking placebo.

Children 6 to 14 years old with bronchial asthma

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

In an 8-placebo placebo-controlled clinical trial, the only AE rated as drug-related was observed in> 1% of patients taking Singular® and more often than in the placebo group of patients, there was a headache.

The difference in frequency between the two treatment groups was not statistically significant. In studies evaluating the growth rate, the safety profile in patients of this age group corresponded to the previously described safety profile of the drug Singular®. With longer treatment (more than 6 months), the AE profile has not changed.

Adults and children 15 years of age and older with bronchial asthma

In two 12-week, placebo-controlled clinical trials with a similar design, the only AEs rated as drug-related were observed in? 1% of patients taking Singular® and more often than in the placebo group of patients, there was abdominal pain and headache.

Differences in the frequency of AE data between the two treatment groups were statistically insignificant. With a longer treatment (for 2 years), the AE profile has not changed.

Adults and children 15 years of age and older with seasonal allergic rhinitis

The drug Singular® was taken by patients once a day in the morning or evening and was generally well tolerated, the safety profile of the drug was similar to the safety profile of placebo. In placebo-controlled clinical trials, AEs that were regarded as associated with the drug were not observed, were observed in? 1% of patients taking the drug Singular®, and more often than in the group of patients taking 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 with a placebo.

Adults and children 15 years of age and older with perennial allergic rhinitis

The drug Singular® 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 with placebo.

In these clinical trials, AEs that were regarded as related to the drug were not observed in 21% of patients taking the drug Singular®, and more often than in the group of patients taking placebo. The frequency of drowsiness when taking the drug was the same as when taking a placebo.

Generalized analysis of clinical trial results

A generalized analysis of 41 placebo-controlled clinical trials (35 studies involving patients aged 15 years and over 6 studies involving patients aged 6 to 14 years) was performed using approved methods for assessing suicide. Among 9929 patients taking the drug Singular®, and 7780 patients taking the placebo in these studies, one patient with suicidal mood was identified in the group of patients taking the drug Singular®. None of the treatment groups committed suicide, suicidal attempts, or other preparatory actions that indicated suicidal behavior.

A separate analysis was conducted of 46 placebo-controlled clinical trials (35 studies involving patients aged 15 years and older and 11 studies involving patients aged 3 months to 14 years) to assess adverse behavioral effects (NPE). Among I 1673 patients who took Singular® in these studies, and 8827 patients who took placebo, the percentage of patients with at least one NPE was 2.73% among those taking Singular® and 2.27% among those taking placebo: ratio the odds were 1.12 (95% confidence interval [0.93 1.361).

During the post-registration use of the drug, the following AEs were reported:

infectious and parasitic diseases: upper respiratory tract infections

disorders of the blood and lymphatic system: increased bleeding tendency, thrombocytopenia

disorders of the immune system: hypersensitivity reactions, including anaphylaxis, very rare (<1/10000) eosinophilic liver infiltration

mental disorders: agitation including aggressive behavior or hostility, anxiety, depression, disorientation, impaired attention, pathological dreams, hallucinations, insomnia, memory impairment, psychomotor activity ( including irritability, restlessness and tremor), somnambulism, suicidal thoughts and behavior (suicidality)

disorders of the nervous system: dizziness, drowsiness, paresthesia / hypesthesia, very rarely (<1/10000) convulsions

disorders of the heart: heart palpitations

disorders of the respiratory system, chest and mediastinal organs: nosebleeds, pulmonary eosinophilia

disorders of the gastrointestinal tract: diarrhea, dyspepsia, nausea, vomiting, pancreatitis

disorders of the liver and biliary tract from an increase: (ALT) and aspartate aminotransferase (ACT) in the blood, very rarely (<1/10000) hepatitis (including cholestatic, hepatocellular and mixed liver lesions)

disorders of the rut and subcutaneous tissue: angioedema, tendency to form hematomas, erythema nodosum, erythema multiforme, pruritus, rash, urticaria

disorders of the musculoskeletal and connective tissue: arthralgia, myalgia, including muscle cramps:

disorders of the kidneys and urinary tract: enuresis in children

general disorders and disorders at the injection site: asthenia (weakness) / fatigue, edema, pyrexia.

Drug Interactions

The drug Singular® can be prescribed along with other drugs, which are usually used for the prevention and long-term treatment of bronchial asthma and / or the treatment of allergic rhinitis. The recommended therapeutic dose of montelukast did not have a clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol / norethisterone 35/1), terfenadine, digoxin and warfarin.

The AUC value of montelukast decreases while taking phenobarbital by about 40%, so this does not require changes in the dosage regimen of the drug Singular®.

In vitro studies have shown that montelukast inhibits the CYP 2C8 isoenzyme of the cytochrome P450 system, however, when studying the in vivo drug interaction of montelukast and rosiglitazone (metabolized by the CYP 2C8 isoenzyme of the cytochrome P450 system), it was shown that montelukast did not inhibit the CYP 2C8 isoenzyme. Thus, the effect of montelukast on CYP 2C8-mediated metabolism of drugs (for example, paclitaxel, rosiglitazone, repaglinide) is not expected.

In vitro studies have shown that montelukast is a substrate of CYP2C8 isoenzymes. 2C9 and 3A4. Data from a clinical study of drug interactions in relation to montelukast and gemfibrozil (an inhibitor of both CYP2C8 and 2C9) demonstrate that gemfibrozil increases the effect of systemic exposure to montelukast by 4.4 times.

Co-administration of itraconazole, a potent inhibitor of CYP3A4, together with gemfibrozil and montelukast did not lead to an additional increase in the effect of systemic exposure to montelukast.exceeding the approved dose of 10 mg for adult patients (for example, when used at a dose of 200 mg / day for adult patients for 22 weeks and up to 900 mg / day for about one week, no clinically significant adverse effects were observed).

Thus, when taken with gemfibrozil, dose adjustment of montelukast is not required. Based on 9 in vitro studies, clinically significant drug interactions with other known CYP2C8 inhibitors (e.g., trimethoprim) are not expected. In addition, the combined administration of montelukast with itraconazole alone did not lead to a significant increase in the effect of systemic exposure to montelukast.

Combined treatment with bronchodilators

The drug Singular® is a reasonable addition to monotherapy with bronchodilators, if the latter do not provide adequate control of bronchial asthma. Upon reaching the therapeutic effect of treatment with the drug Singular®, a gradual reduction in the dose of bronchodilators can begin.

Combined treatment with inhaled glucocorticosteroids

Treatment with Singular® provides an additional therapeutic effect for patients using inhaled glucocorticosteroids. Upon reaching stabilization, a gradual reduction in the dose of glucocorticosteroid can be started under the supervision of a doctor. In some cases, the complete cancellation of inhaled glucocorticosteroids is acceptable, however, a sharp replacement of inhaled glucocorticosteroids with the drug Singular® is not recommended.

Overdose

There is no specific information on the treatment of an overdose of the drug Singular®. Overdose symptoms were not observed during clinical trials of long-term (22 weeks) treatment of adult patients with bronchial asthma with daily doses of Singulyar® up to 200 mg, or during short (about 1 week) clinical trials with daily doses of up to 900 mg.

There have been cases of acute overdose (taking at least 1000 mg of the drug per day) with the drug Singular® in the post-registration period and during clinical trials in adults and children. Clinical and laboratory data showed the comparability of the safety profiles of the drug Singular® in children, adults and elderly patients.

The most common side effects were thirst, drowsiness, vomiting, psychomotor agitation, headache, and abdominal pain. These side effects are consistent with the safety profile of Singular®.

Treatment in case of acute overdose is symptomatic.

There is no evidence of the effectiveness of peritoneal dialysis or hemodialysis of montelukast.

Storage Conditions

The product should be stored out of the reach of children, in a dry, dark place at 15 ° C to 30 ° C.

Montelukast active ingredient

Dosage form

tablet chewable

Appointment

Vzrosl m on purpose doctor

Indications

bronchial asthma, Bronchospasm

Possible product names

Singular tablets 4 mg, 28 pcs.



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