Singular - instructions for use, dose, side effects, contraindications

Excipients: mannitol 201.35 mg, microcrystalline cellulose 66.0 mg, giprolose (hydroxypropylcellulose) 9.0 mg, iron 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 an embossed inscription SINGULAIR on one side and MSD 275 on the other side.

Pharmacotherapeutic group:Leukotriene receptor blocker

ATX: & nbsp

R.03.D.C.03 Montelukast

Pharmacodynamics:

Cysteinyl leukotrienes (LTFROM₄, LTD₄, LTE₄) are strong mediators of inflammation - eicosanoids, which are excreted by different cells, including mast cells and eosinophils. These important proastmatic mediators are linked to cysteinyl leukotriene receptors.Cysteinyl leukotriene type I receptors (CysLT₁receptors) 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). Cysteinyl leukotrienes correlate with pathophysiology of bronchial asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchospasm, increased mucus secretion, increased vascular permeability, and an increase in the number of eosinophils. With allergic rhinitis after the exposure of the allergen, cysteinyl leukotrienes are released from the proinflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction, which is manifested by the symptoms of allergic rhinitis. With an intranasal test with cysteinyl leukotrienes, an increase in the resistance of the airway nasal passages and symptoms of nasal obstruction was demonstrated. Montelukast - highly active when administered medication, which significantly improves the inflammation in bronchial asthma. According to biochemical and pharmacological analysis montelukast with high affinity and selectivity is associated with CysLT₁receptors and, without interacting with other pharmacologically important receptors in the airways (such as prostaglandin, cholinergic or β-adrenergic receptors). Montelukast inhibits the physiological action of cysteinyl leukotrienes LTC_4, LTD₄ and LTE₄ by binding to CysLT₁-receptors and, without exerting a stimulating effect on these receptors. Montelukast inhibits CysLT-receptors in the respiratory tract, which is confirmed by the ability to block the development of bronchospasm in response to inhalation LTD₄ in patients with bronchial asthma. Doses of 5 mg are sufficient for arresting bronchospasm induced LTD₄.

Montelukast causes bronchodilation within 2 hours after ingestion and may supplement the bronchodilation caused by β₂-adrebutmimetics.

Pharmacokinetics:

Suction

Montelukast quickly and almost completely absorbed after ingestion. When receiving fasting tablets chewing 5 mg maximum concentration (C_max) in adults is achieved in 2 hours. The average bioavailability with oral administration is 73%.Eating does not have a clinically significant effect with prolonged use.

Distribution

Montelukast binds to plasma proteins more than 99%. The volume distribution of Montelukast in a state of equilibrium concentration averages 8-11 liters. Studies with radiolabeled Montelukast. conducted on rats, indicate a minimal penetration through the blood-brain barrier. In addition, the concentrations of the labeled preparation 24 hours after 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 equilibrium state in plasma is not determined.

Research in vitro using human liver microsomes showed that cytochrome 1450: 3A4, 2C8 and 2C9 isoenzymes participate in the metabolism of montelukast. According to the results of the studies conducted in vitro in microsomes of human liver, montelukast in the therapeutic concentration in the blood plasma does not inhibit cytochrome isoenzymes P450: 3A4, 2C9, 1A2, 2A6, 2C19 and 2D6.

Excretion

Plasma clearance of montelukast in healthy adults is an average of 45 ml / min. After ingestion of radioactively labeled montelukast, 86% of its quantity is excreted with 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 ranges from 2.7 to 5.5 hours. The pharmacokinetics of montelukast retains a practically linear character when administered in doses over 50 mg. When taking montelukast in the morning and evening hours, there is no difference in pharmacokinetics. When 10 mg montelukast is administered 1 time a moderate (about 14%) cumulation of the active substance in the plasma is observed.

The mastery of pharmacokinetics in different groups of patients

Floor

The pharmacokinetics of montelukast in women and men is similar.

Elderly patients

With a single oral administration of 10 mg montelukast, the pharmacokinetic profile and bioavailability are similar in elderly patients and young patients. The half-life of Montelukast from plasma is somewhat longer in older people. Correction of the dose of the drug in the elderly is not required.

Rice

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

Liver failure

In patients with hepatic insufficiency of mild and moderate severity and clinical manifestations of cirrhosis, a decrease in metabolism of montelukast was noted, accompanied by an increase in the area under the pharmacokinetic curve "concentration-time" (AUC) approximately 41% after a single dose of 10 mg. The excretion of montelukast in these patients is slightly increased in comparison with healthy subjects (mean half-life is 7.4 hours). Dose changes montelukast for patients with hepatic insufficiency of mild and moderate severity is not required. Data on the character of the pharmacokinetics of montelukast in patients with severe Hepatic insufficiency (more than 9 points on the Child-Pugh scale) is not present.

Renal insufficiency

Because the montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast in patients with renal insufficiency has not been evaluated. A dose adjustment for this group of patients is not required.

Indications:

- 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 increased sensitivity to acetylsalicylic acid and the prevention of bronchospasm caused by physical exertion.

- Cupping of day and night symptoms of seasonal and / or all-year-round allergic rhinitis in children aged 6 to 14 years.

Contraindications:

- Hypersensitivity to any of the components of the drug.

- Children under 6 years.

- Phenylketonuria.

Pregnancy and lactation:

Clinical studies of the preparation Singular® with the participation of pregnant women have not been conducted. The Singular® drug should be used during pregnancy and during lactation only if the expected benefit to the mother exceeds the potential risk to the fetus or child. During the post-marketing use of the Singular® preparation, the development of birth defects in the newborns was reported in mothers who received the Singular® preparation during pregnancy. Most of these women also took other medications to treat bronchial asthma during pregnancy.The causal relationship between taking Singular® and developing congenital limb defects has not been established.

It is not known whether Singulary ® is excreted in breast milk. Because many drugs are excreted in breast milk, it is necessary to take into account the ego when prescribing Singulary® to breast-feeding mothers.

Dosing and Administration:

Inside 1 time per day, regardless of the reception of poverty.

For treatment bronchial asthma a drug Singular® should be taken in the evening. In the treatment allergic rhinitis the dose can 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 preparation Singular® 1 time per day in the evening.

Children aged 6 to 14 years

The dose for children 6-14 years is one tablet chewing 5 mg per day. The choice of dose for this age group is not required.

General recommendations

The therapeutic effect of the preparation Singulary® on the indicators reflecting the course of bronchial asthma develops during the first day. The patient should continue to take Singular® both during the period when the symptoms of bronchial asthma are controlled, and during periods of exacerbation of bronchial asthma.

For elderly patients, patients with renal insufficiency, as well as patients with mild or moderate liver function disorders, and also depending on gender, a special dose selection is not required.

The purpose of the preparation is Singular® concomitantly with other treatments for bronchial asthma

The preparation of Singular® can be added to the treatment of the patient with bronchodilators and inhaled glucocorticosteroids (see section "Interaction with other medicinal products").

Side effects:

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

Children aged 2 to 5 years with bronchial asthma

In clinical studies of the preparation Singular®, 573 patients aged 2-5 years took part. In a 12-week, placebo-controlled clinical trial, the only undesirable event (AE) estimated to be associated with taking the drug, observed in> 1% of patients taking Singular®, and more often than in the placebo group,there was a 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 were treated with Singular® for at least 3 months. 230 for 6 months or longer, and 63 patients for 12 months or longer. With longer treatment, the profile of AE did not change.

Children aged 2 to 14 years with seasonal allergic rhinitis

In a 2-week placebo-controlled clinical trial using the Singular® preparation for the treatment of seasonal allergic rhinitis, 280 patients aged 2 to 14 years took part. The Singular® preparation was taken by patients once a day in the evening and was generally well tolerated, the drug safety profile was similar to the placebo safety profile. In this clinical study, AEs were not registered. which would be regarded as associated with taking the drug, would be observed in ≥1% of patients taking Singular® and more often 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 of adults and was comparable to the placebo safety profile.

In an 8-day, placebo-controlled clinical trial, a single AEV, estimated to be associated with drug intake,> 1% of patients taking Singular® and a headache was more frequent than in the placebo group. The frequency difference between the two treatment groups was statistically insignificant. In studies evaluating the rate of growth, the safety profile of patients of this age group was consistent with the previously described safety profile of the Singular® preparation. With longer treatment (more than 6 months), the profile of AH did not change.

Adults and children aged 15 years and older with bronchial asthma

In two 12-week, placebo-controlled clinical trials with a similar design, the only AEs evaluated as drug-related, observed in ≥1% of patients taking Singular®, and more often than in the placebo group, were abdominal pain and a headache. Differences in the frequency of AE data between the two treatment groups were statistically insignificant. With longer treatment (within 2 years), the profile of AE did not change.

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

The Singular® preparation was taken by patients once or twice a day in the morning or in the evening and was generally well tolerated, the drug safety profile was similar to the placebo safety profile. In placebo-controlled clinical trials, AEs that were considered to be associated with drug administration were not observed in ≥ 1% of patients taking Singular® and more often than in the placebo group. In a 4-week, placebo-controlled clinical trial, the drug safety profile was similar to that in a 2-week study. 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

The preparation Singulary® was taken by patients once a day and was generally well tolerated. The drug safety profile 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 considered to be drug-related were not observed, ≥1% of patients taking Singular® and more often than in the placebo group were observed. The incidence of drowsiness when taking the drug was the same as when taking a placebo.

Generalized analysis of results clinical research

A generalized analysis of 41 placebo-controlled clinical trials was conducted (35 studies involving patients aged 15 years and older, 6 studies involving patients aged 6 to 14 years) using approved methods for assessing suicidality. Among 9929 patients taking Singular® and 7780 patients taking placebo in these studies, one patient was identified with a suicidal mood in the group of patients taking Singular®. In none of the treatment groups were there any suicides, suicidal attempts or other preparatory actions that indicated suicidal behavior.

Separately, a generalized analysis of 46 placebo-controlled clinical trials (35 studieswith the participation of patients aged 15 years and older; 11 studies involving patients aged 3 months to 14 years) to assess adverse behavioral effects (NPE). Among the 1,163 patients who took the Singular® in these studies and 8827 patients taking placebo, the percentage of patients with at least one NPE was 2.73% among those taking Singular® and 2.27% in the placebo-treated 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 infection;

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

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

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

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

violations of the heart: cardiopalmus;

disorders of the respiratory system, chest and mediastinum: nasal bleeding, pulmonary eosinophilia;

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

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

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

disorders of 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 site of administration: asthenia (weakness) / fatigue, swelling, pyrexia.

Overdose:

There is no specific information on the treatment of an overdose of Singular®. Symptoms of an overdose of ns were observed in clinical studies of long-term (22 weeks) treatment of adults with bronchial asthma with daily doses of the preparation Singul® to 200 mg, or during short (about 1 week) clinical studies with daily doses of up to 900 mg.

There have been cases of acute overdose (ingestion of at least 1000 mg per day) with Singular® during the post-registration period and during clinical trials in adults and children. Clinical and laboratory data indicated the comparability of the safety profile of the Singular® preparation 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 the Singular® preparation.

Treatment for acute overdose is symptomatic.

Data on the effectiveness of peritoneal dialysis or hemodialysis Montelukast no.

Interaction:

The Singular® preparation can be administered together with other drugs that are commonly used to prevent and prolong treatment of bronchial asthma and / or treat allergic rhinitis. The recommended therapeutic dose of montelukast had no clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol / norethisterone 35/1), terfenadine, digoxin and warfarin.

Value AUC Montelukast decreases with simultaneous intake of phenobarbital by about 40%. but this does not require a change in the dosage regimen of the Singular® preparation.

In studies in vitro determined that montelukast inhibits isoenzyme CYP2C8 system of cytochrome P450, however, in the study of drug interactions in vivo Montelukast and rosiglitazone (metabolized with the participation of isoenzyme CYP2C8 system of cytochrome P450) it was shown that montelukast did not inhibit isoenzyme CYP 2C8. Thus, the effect of Montelukast on CYP 2C8-mediated metabolism of medications (eg, paclitaxel, rosiglitazone, repaglinide). Research in vitro showed that montelukast is a substrate of isoenzymes CYP2C8, 2C9 and 3A4. Data from the clinical trial of drug interaction for montelukast and gemfibrozil (an inhibitor of both CYP 2C8, and 2C9) demonstrate that gemfibrozil increases the effect of systemic exposure of Montelukast 4.4 times. Joint use of itraconazole, a potent inhibitor CYP 3A4, together with gemfibrozil and montelukast did not lead to an additional increase in the effect of systemic exposure to montelukast. The effect of gemfibrozil on the systemic effect of montelukast can not be considered clinically significant on the basis of safety data when administered at doses exceeding the approved dose of 10 mg for adult patients (eg, when administered 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, with a co-administration with gemfibrozilom adjustment of the dose of montelukast is not required.Based on research results in vitro no clinically significant drug interactions with other known inhibitors CYP 2C8 (for example, with trimethoprim). In addition, the joint administration of montelukast with itraconazole alone did not result in a significant increase in the effect of systemic exposure to montelukast.

Combined treatment with bronchodilators

A drug Singular® is a valid 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 preparation of Singular® it is possible to start a gradual decrease in the dosage of bronchodilators.

Combined treatment with inhaled glucocorticosteroids

Treatment with the preparation Singular® provides an additional therapeutic effect to patients using inhaled glucocorticosteroids. Once the stabilization of the condition is achieved, a gradual decrease in the dose of the glucocorticosteroid can be started under the supervision of the physician. In some cases, complete cancellation of inhaled glucocorticosteroids is permissible, but a sharp substitution of inhaled glucocorticosteroids for the preparation of Singular® is not recommended.

Special instructions:

The effectiveness of the Singular® preparation for oral administration for the treatment of acute attacks of bronchial asthma has been established, so the preparation of Singular® in tablets is not recommended for the treatment of acute attacks of bronchial asthma. Patients should be instructed to always have emergency medication to relieve asthma attacks (short-acting inhaled short-acting 2-agonists).

You should not stop taking Singular® during the period of asthma exacerbation and the need to use emergency drugs to stop 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 Singular®, since the Singular® preparation, improving respiratory function in patients with allergic bronchial asthma, nevertheless can not completely prevent the evoked them NSAIDs bronchoconstriction.

The dose of inhaled glucocorticosteroids used concurrently with the preparation of Singular®,can be gradually reduced under the supervision of a physician, however, a sharp substitution of inhaled or oral glucocorticosteroids with Singular® can not be carried out. Psychoneurological disorders have been described in patients taking Singulary ® (see the side effect section). Given that these symptoms may have been caused by other factors, it is not known whether they are associated with taking Singular®. The physician should discuss the AE data with patients and / or their parents / guardians. Patients and / or their parents / guardians should explain that in case of such symptoms it is necessary to inform the attending physician about it.

In rare cases, patients receiving antiasthmatic drugs, including leukotriene receptor antagonists, experienced one or more AEs from below listed: eosinophilia, rash, worsening of pulmonary symptoms, cardiac complications and / or neuropathy, sometimes diagnosed as Chardz-Strauss syndrome, systemic eosinophilic vasculitis. These cases have sometimes been associated with a reduction in the dose or withdrawal of oral glucocorticosteroid therapy.Although the causal relationship of these AEs to therapy with leukotriene receptor antagonists has not been established, patients taking the preparation of Singular® should be careful: in such patients, appropriate clinical observation is necessary.

The preparation Singular® tablets chewing 5 mg contains aspartame - A source of phenylalanine. Patients with phenylketonuria should be informed that each chewable tablet of 5 mg contains aspartame in an amount equivalent to 0.842 mg of phenylalanine, and the preparation Singular® 5 mg chewing tablets is not recommended for use in patients with phenylketonuria.

Application in elderly patients

Differences in the efficacy and safety profile of the Singulary® preparation, associated with the age of patients, have not been identified.

Effect on the ability to drive transp. cf. and fur:

It is not expected that the use of Singular® will affect the ability to drive vehicles and work with mechanisms. Nevertheless, individual reactions to the drug may be different. Some side effects (such as dizziness and drowsiness) that have been reported to occur very rarely with the use of the Singular® preparation,may affect the ability of some patients to drive vehicles and work with mechanisms.

Form release / dosage:

Tablets are chewable, 5 mg.

Packaging:

7 tablets per blister of PBX/ aluminum foil. 1, 2 or 4 blisters in a cardboard box with instructions for use.

Storage conditions:

Store at a temperature of no higher than 30 ° C in a place protected from moisture and light. Keep out of the reach of children.

Shelf life:

Shelf life - 2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N016104 / 02

Date of registration:30.03.2010 / 15.07.2014

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

MERCK SHARP & DOHME, Ltd. United Kingdom

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp25.03.2016

Illustrated instructions

Instructions

Singular® (Singulair®)