SINGULAIR instructions for use, description of the drug SINGULAIR: contraindications, side effects, dosages, composition

Instructions for use SINGULAIR® (SINGULAIR)

Suction

Montelukast is rapidly and almost completely absorbed after oral administration. Eating regular food does not affect bioavailability and Cmax when taking film-coated tablets and chewable tablets. In adults, when taking film-coated tablets on an empty stomach, 10 mg Cmax is achieved after 3 hours. Bioavailability when taken orally is 64%. When taking 5 mg chewable tablets on an empty stomach, Cmax in adults is achieved after 2 hours. Bioavailability is 73%.

The pharmacokinetics of montelukast remains almost linear when administered orally in doses greater than 50 mg. When taking montelukast in the morning and evening hours, no differences in pharmacokinetics were observed.

Distribution

Montelukast is more than 99% bound to plasma proteins. Vd of montelukast averages 8-11 liters.

When taking the drug in the form of film-coated tablets 10 mg 1 time/day, a moderate (about 14%) cumulation of the active substance in plasma is observed.

Metabolism

Montelukast is actively metabolized in the liver. When using the drug in therapeutic doses, Css metabolites are not detected in plasma in adults and children.

It is assumed that the isoenzymes CYP3A4 and CYP2C9 are involved in the metabolism of montelukast, while at therapeutic concentrations montelukast does not inhibit the isoenzymes CYP3A4, CYP2C9, CYP1A2, CYP2A6, CYP2C19 and CYP2D6.

Removal

T1/2 of montelukast in young healthy adults ranges from 2.7 to 5.5 hours, clearance averages 45 ml/min. After oral administration of montelukast, 86% of its amount is excreted in feces within 5 days and less than 0.2% in urine. This indicates that montelukast and its metabolites are eliminated through biliary excretion.

Pharmacokinetics in special clinical situations

The pharmacokinetics of montelukast in women and men is similar.

When taking the drug in the form of film-coated tablets 10 mg 1 time / day, the pharmacokinetic profile and bioavailability are similar in elderly and young patients.

In patients with mild to moderate hepatic impairment and clinical manifestations of cirrhosis, a slowdown in the metabolism of montelukast was observed, accompanied by an increase in AUC by approximately 41% after a single dose of 10 mg. The excretion of montelukast in these patients is slightly increased compared to healthy people (average T1/2 - 7.4 hours). No dose adjustment of montelukast is required for patients with mild to moderate hepatic impairment. There are no data on the nature of the pharmacokinetics of montelukast in patients with severe liver failure (more than 9 points on the Child-Pugh scale).

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

There were no clinically significant differences in pharmacokinetics in patients of different races.

Singulair®

Children aged 2 to 5 years with bronchial asthma

Clinical studies of the drug Singulair® involved 573 patients aged 2 to 5 years. In a 12-week placebo-controlled study in the Singulair treatment group, the only observed adverse effect assessed as drug-related in >1% of patients compared with placebo was thirst. The differences in the frequency of this side effect were not statistically significant.

In total, 426 patients aged 2 to 5 years were treated with Singulair® for at least 3 months, 230 were treated for 6 months or longer, and 63 patients were treated for 12 months or longer in the studies. With longer treatment, the side effect profile did not change.

Children aged 2 to 14 years with seasonal allergic rhinitis

A 2-week, placebo-controlled clinical trial using Singulair® for the treatment of seasonal allergic rhinitis included 280 patients aged 2 to 14 years. Patients took Singulair® 1 time/day in the evening and was generally well tolerated. The safety profile of the drug in children was similar to that of placebo. In this clinical study, there were no adverse reactions considered to be related to the drug that were observed in ≥1% of patients taking Singulair® and more often than in the group of patients taking placebo.

Side effects reported during post-marketing use of the drug

Infectious and parasitic diseases:

upper respiratory tract infections.

From the blood coagulation system:

increased tendency to bleed.

From the immune system:

hypersensitivity reactions, incl. anaphylaxis; very rarely (<1/10,000) - eosinophilic infiltration of the liver.

From the mental side:

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

From the nervous system:

dizziness, drowsiness, paresthesia/hypesthesia; very rarely (<1/10,000) - convulsions.

From the cardiovascular system:

cardiopalmus.

From the respiratory system:

nosebleeds.

From the digestive system:

diarrhea, dyspepsia, nausea, vomiting, pancreatitis.

From
the liver and biliary tract:
increased activity of ALT and AST in the blood; very rarely (<1/10,000) - hepatitis (including cholestatic, hepatocellular and mixed liver lesions).

For the skin and subcutaneous tissues:

tendency to form hematomas, erythema nodosum, erythema multiforme, itching, rash.

Allergic reactions:

angioedema, urticaria.

From the musculoskeletal system:

arthralgia, myalgia, including muscle cramps.

General reactions:

asthenia (weakness)/fatigue, edema, pyrexia.

In general, Singulair® is well tolerated by patients. Side effects are usually mild and, as a rule, do not require discontinuation of the drug. The overall incidence of side effects when treated with Singulair® is comparable to their frequency when taking placebo.

Consequences of drinking alcohol

If alcohol and medicine were consumed at the same time, the following consequences arise:

increased heart rate, which leads to increased blood pressure and the risk of developing an attack of bronchial asthma;
a negative effect on the brain, due to which the patient’s behavior changes, becomes aggressive, he can attack people;
nausea and vomiting occurs, if they are prolonged, this leads to dehydration of the body, further thickening of the secretion in the bronchi;
there is an active effect on the liver tissue with foci of inflammation and tissue necrosis if the patient consumes the drug with alcohol for a long time;
Allergic reactions occur on the body, accompanied by redness, inflammation, and swelling of tissues.

If the rules were violated once, the consequences may not develop. But if treatment is always accompanied by drinking alcohol, attacks of bronchial asthma become more frequent.

Leukotriene receptor antagonist - singular in the treatment of bronchial asthma in children

With the help of the antileukotriene drug Singulaira, children with mild to moderate forms of bronchial asthma can be effectively treated. At the same time, accompanying allergic manifestations reliably decrease and even disappear

In 1979, Bengt Samuelson and colleagues discovered a new group of arachidonic acid metabolites produced by the lipoxygenase pathway from leukocytes. These components became known as leukotrienes (LT). It was soon discovered that the slow-reacting substance of anaphylaxis consists of three cystenyl-containing leukotrienes: LTC4, LTD4 and LTE4 [1]. LTS4 is formed first, which is sequentially transformed with the help of enzymes into LTD4 and LTE4. In humans, each cystenyl leukotriene (CLT) has potential biological activity. LTs do not accumulate in cells, but after cellular activation they are formed from arachidonic acid, which is released from phospholipid membranes under the influence of phospholipase A2. Arachidonic acid is metabolized by lipoxygenase enzyme 5 to form LTA4. The unstable and inactive leukotriene LTA4 forms LTB4 and LTS4. LTS4, under the influence of enzymes, is sequentially metabolized into LTD4 and LTE4 extracellularly by systematic cleavage of the LTS4 peptide side chain. LTE4 is then destroyed or excreted in the urine. LTS4 and LTD4 cause smooth muscle spasm, increased eosinophil counts, edema, and mucus secretion. LTs can activate receptors on other cells. CLTs activate a specific class of receptors called CLT receptors [2]. LT can be formed by mast cells, basophils, eosinophils, and macrophages.

It turned out that cystenyl leukotrienes have the most powerful constrictor effect on the smooth muscles of the respiratory tract in vitro, 10 thousand times stronger than histamine [3], and cause other effects characteristic of bronchial asthma, such as tissue edema, mucus secretion, stimulation cellular infiltration of lung tissue, which made it possible to classify cystenyl leukotrienes as mediators of asthmatic airway obstruction. As a result of these observations, a potentially new class of anti-asthma drugs, the antileukotrienes, was discovered. Antileukotriene drugs are divided into leukotriene antagonists and leukotriene synthesis inhibitors.

In the Russian national program “Bronchial asthma in children. Treatment strategy and prevention”, adopted in 1997 [4], it is noted that asthma in children, regardless of severity, is a chronic inflammation in the respiratory tract, and to control the course of the disease it is necessary to use drugs with anti-inflammatory activity that act on acute and chronic inflammation. As is known, about 70% of children with bronchial asthma are patients with mild and moderate forms of the disease. These are exactly what a pediatric allergist and pulmonologist encounters every day in his daily work. To prevent the development of severe bronchial asthma and disability in children, it is necessary to develop adequate treatment regimens for these particular forms of the disease.

A feature of the course of bronchial asthma in children is also that they often have other concomitant allergic manifestations, for example, allergic rhinitis, conjunctivitis, skin and gastrointestinal allergic manifestations. This predetermines the need for systemic action on various parts of the pathogenesis of allergies.

Montelyukast (singular) is a specific (selective) active antagonist of cystenyl receptors taken orally. It is prescribed to children from 6 years of age at a dose of 5 mg once a day before bedtime in the form of a tablet that should be chewed.

Controlled multicentric studies of Singulair showed that the drug reduces asthma symptoms (daytime, nighttime), improves pulmonary function, reduces the number of exacerbations, reduces the frequency of taking bronchodilators, reduces bronchial hyperresponsiveness, including to physical activity, and is effective in patients with hypersensitivity to aspirin [ 5]. A double-blind study conducted in 336 children aged 6 to 14 years [6] showed that after eight weeks of treatment, patients had improved respiratory function (FEV1).

Singulair is not used to treat acute attacks. Today it is recommended for the treatment of children with mild to moderate bronchial asthma. According to our data, with a similar duration of treatment (1 month) with Singular - instead of Intal - the frequency of attacks and the need for bronchodilators in children significantly decreases. With an increase in the duration of therapy with Singular (more than two months), the daily variation in peak expiratory flow, determined by monitoring the function of external respiration using a peak flow meter, statistically significantly decreases. A very important positive effect of treatment with Singular is a significant reduction or disappearance in some children of concomitant allergic manifestations (in particular, rhinoconjunctivitis), and positive dynamics of the skin process.

Considering that bronchial asthma is a chronic disease, the duration of therapy is determined by the course of the disease and can last throughout life. Singulair can be used in combination therapy along with other prophylactic drugs. It prevents bronchoconstriction due to triggers (physical activity, allergen), improves the bronchodilator effect of salbutamol on lung function, and reduces the symptoms of nocturnal asthma.

Recent studies have shown that after the administration of oral corticosteroids, cells in the inflamed tissues of the airways continue to secrete leukotrienes. Thus, leukotriene antagonists have additional potential for clinical benefit in patients receiving inhaled or oral corticosteroid therapy.

References
1. S.-E. Dahlen. Leukotriens and related lipoxygenase products. Asthma: Basic Mechanisms and Clinical Management. Acad. Press Ltd, 1988, p. 216. 2. P. J. Barnes. New aspects of asthma. J. Int. Med. 1992, 231, p. 453–461. 3. S.-E. Dahlen. Airway Hyperresponsiveness — Is it Really Important for asthma? Leucotriens as Mediators of Airway Obstruction and Brobchial Hyperresponsiveness, 1993, p. 188–205. 4. National program “Bronchial asthma in children. Treatment strategy and prevention." Moscow, 1997. 5. Reiss TF, Sorkness Ch. A., Stricner W., Botto A. et al. Effect of montelukast (MK-0476), a potent cysteinil leucotriene receptor antagonist, on bronchodilation in asthmatic subject treated with and without inhaled corticosteroids. Thorax, 1997, 52, p. 45–48. 6. Knorr B., Matz J., Bernstein JA et al. Montelucast for Chronic Asthma in 6 to 14 year old Children. A randomized, double-blind trial. JAMA, 1998, Vol. 279, no. 15, p. 1181–1186.

A little history

In 1938, Feldberg and Kelaway, studying shock pulmonary tissue during cobra venom poisoning, discovered a substance that caused a slow and prolonged contraction of the smooth muscles of the respiratory tract. Thus, a new pathway for the release of mediators was identified, fundamentally different from the mechanism of histamine release previously described by Henry Dale. This mediator is called a “slow-reacting substance.” Subsequently, many specialists investigated the nature of this component. It was proven that it is formed in the lungs as a result of an allergen-induced reaction, on the basis of which Brocklehurst proposed the extended name “slow-reacting substance of anaphylaxis.”

Singulair, 28 pcs., 10 mg, film-coated tablets

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

Children aged 2 to 5 years with bronchial asthma

Clinical studies of the drug Singulair® involved 573 patients aged 2 to 5 years. In a 12-week placebo-controlled clinical trial, the only adverse event (AE) assessed as drug-related occurring in >1% of Singulair-treated patients and more frequently than in placebo-treated patients was thirst. The differences in the incidence of this AE between the two treatment groups were not statistically significant.

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

Children aged 2 to 14 years with seasonal allergic rhinitis

A 2-week, placebo-controlled clinical trial using Singulair® for the treatment of seasonal allergic rhinitis included 280 patients aged 2 to 14 years. The drug Singulair® 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. There were no AEs recorded in this clinical study. that would be considered drug-related would occur in ≥1% of patients taking Singulair® and more often than in the group of patients taking 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 comparable to the safety profile of placebo.

In an 8-week, placebo-controlled clinical trial, the only AE assessed as drug-related, occurring in >1% of patients treated with 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 growth rate studies, the safety profile in patients in this age group was consistent with the previously described safety profile of Singulair®. With longer treatment (more than 6 months), the AE profile did not change.

Adults and children aged 15 years and older with asthma

In two 12-week placebo-controlled clinical trials with a similar design, the only AEs assessed as drug-related that occurred in ≥1% of patients treated with Singulair® and more frequently than in the placebo group were abdominal pain and headache. The differences in the incidence of these AEs between the two treatment groups were not statistically significant. With longer treatment (for 2 years), the AE profile did not change.

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

The drug Singulair® 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, there were no AEs that were considered drug-related, occurring in ≥1% of patients treated with Singulair or more frequently than in the placebo group. In the 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 year-round allergic rhinitis

The drug Singulair® was taken by patients once a day and was generally well tolerated. The drug's safety profile was similar to that observed in patients with seasonal allergic rhinitis and placebo. In these clinical studies, there were no AEs that were considered drug-related, occurring in ≥1% of patients treated with Singulair or more frequently than in the placebo group. The incidence of drowsiness while taking the drug was the same as when taking placebo.

Generalized analysis of clinical trial results

A pooled analysis was conducted of 41 placebo-controlled clinical trials (35 studies involving patients aged 15 years or older; 6 studies involving patients aged 6 to 14 years) using validated methods for assessing suicidality. Among the 9,929 patients treated with Singulair® and the 7,780 patients treated with placebo in these studies, one patient was identified as suicidal in the group of patients treated with Singulair®. There were no suicides, suicide attempts, or other preparatory acts indicative of suicidal behavior in any of the treatment groups.

Separately, a pooled analysis of 46 placebo-controlled clinical trials (35 studies in patients aged 15 years and older; 11 studies in patients aged 3 months to 14 years) was conducted to assess adverse behavioral effects (AEs). Among the 1,673 patients treated with Singulair® and the 8,827 patients treated with placebo in these studies, the percentage of patients with at least one AE was 2.73% among those taking Singulair® 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 identified AEs were reported:

infectious and parasitic diseases: upper respiratory tract infections;

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

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

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);

Nervous system disorders: dizziness, drowsiness, paresthesia/hypoesthesia, very rarely (< 1/10000) convulsions;

cardiac disorders: 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: increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the blood, very rarely (< 1/10000) hepatitis (including cholestatic, hepatocellular and mixed liver lesions);

disorders of the track and subcutaneous tissues: angioedema, tendency to form hematomas, erythema nodosum, erythema multiforme, itching, rashes, urticaria;

Musculoskeletal and connective tissue disorders: 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.

Singular

Children aged 2 to 5 years with bronchial asthma

Children aged 2 to 14 years with seasonal allergic rhinitis

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

In an 8-week placebo-controlled clinical trial, the only AE assessed as drug-related occurring in >1% of patients treated with 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 growth rate studies, the safety profile in patients in this age group was consistent with the previously described safety profile of Singulair®.

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

Adults and children aged 15 years and older with asthma

In two 12-week placebo-controlled clinical studies with a similar design, the only AEs assessed as drug-related occurring in ≥1% of patients treated with Singulair® and more frequently than in the placebo group were abdominal pain and headache. The differences in the incidence of these AEs between the two treatment groups were not statistically significant. With longer treatment (for 2 years), the AE profile did not change.

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

Patients took Singulair® 1 time/day in the morning or evening, the drug was generally well tolerated, and the safety profile of the drug was similar to the safety profile of placebo. In placebo-controlled clinical trials, there were no AEs that were considered drug-related, occurring in ≥1% of patients treated with Singulair, or more frequently than in the placebo group. In the 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 when taking the drug in all studies was the same as when taking placebo.

Adults and children aged 15 years and older with year-round allergic rhinitis

Patients took Singulair® 1 time/day in the morning or evening; overall, the drug was well tolerated. The drug's safety profile was similar to that observed in patients with seasonal allergic rhinitis and placebo. In these clinical studies, there were no AEs that were considered drug-related, occurring in ≥1% of patients taking Singulair, or more frequently than in the placebo group. The incidence of drowsiness while taking the drug was the same as when taking placebo.

Generalized analysis of clinical trial results

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

Separately, a pooled analysis of 46 placebo-controlled clinical trials (35 studies in patients aged 15 years and older; 11 studies in patients aged 3 months to 14 years) was conducted to assess adverse behavioral effects. Among the 11,673 patients treated with Singulair® and 8,827 patients treated with placebo in these studies, the percentage of patients experiencing at least one adverse behavioral effect 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]).

AEs registered during post-registration use of the drug

Infectious and parasitic diseases: upper respiratory tract infections.

From the blood coagulation system: increased tendency to bleeding.

From the immune system: hypersensitivity reactions, incl. anaphylaxis; very rarely (<1/10,000) - eosinophilic infiltration of the liver.

From the psyche: 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 thoughts and behavior (suicidality).

From the nervous system: dizziness, drowsiness, paresthesia/hypesthesia; very rarely (<1/10,000) - convulsions.

From the cardiovascular system: rapid heartbeat.

From the respiratory system: nosebleeds, pulmonary eosinophilia.

From the digestive system: diarrhea, dyspepsia, nausea, vomiting, pancreatitis.

From the liver and biliary tract: increased activity of ALT and AST in the blood; very rarely (<1/10,000) - hepatitis (including cholestatic, hepatocellular and mixed liver lesions).

From the skin and subcutaneous tissues: tendency to form hematomas, erythema nodosum, erythema multiforme, itching, rash.

Allergic reactions: angioedema, urticaria.

From the musculoskeletal system: arthralgia, myalgia, including muscle cramps.

From the urinary system: enuresis in children.

General reactions: asthenia (weakness)/fatigue, edema, pyrexia.

Singular and beer

Singulair and beer don't mix. The drug eliminates inflammation, swelling, and secretion in the bronchi. When treating bronchial asthma, drinking beer is contraindicated.

The risk of developing adverse reactions increases (thrombocytopenia, bleeding, liver infiltration with eosinophils, increased heart rate, numbness of the extremities, drowsiness).

Ethanol increases diuresis, the patient becomes dehydrated. The blockage of the bronchi with thick secretions intensifies.

There is a large load on the liver with the development of inflammation. This threatens jaundice and fibrosis. Intoxication of the body can lead to damage to the central nervous system. Bleeding occurs more often.

Use of the drug for alcoholism

During chronic alcoholism, the liver is the first to suffer. First, hepatitis forms, which progresses to the stage of cirrhosis. This is one of the contraindications to taking the medicine, as it can also cause inflammation of the liver.

Ethanol, together with the active ingredient of the drug, penetrates the blood-brain barrier. They form similar adverse reactions in the form of hallucinations, delirium, convulsions, and depression.

If a person has chronic alcoholism, all conditions worsen. The function of the alcoholic's immune system is significantly reduced, as the body is exhausted. When used simultaneously with the drug, viral and infectious diseases occur with greater frequency. This aggravates the patient's condition with bronchial obstruction.