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

Excipients: mannitol 161.08 mg, cellulose microcrystalline 52.8 mg, giprolose (hydroxypropyl cellulose) 7.2 mg, iron oxide red 0.36 mg, croscarmellose sodium 7.2 mg, cherry flavoring 3.6 mg, aspartame 1.2 mg, magnesium stearate 2.4 mg.

Description:

Pink, oval, biconvex tablets with an embossed inscription "SINGULAIR" on one side and "MSD 711 "on the other side.

Pharmacotherapeutic group:Anti-inflammatory anti-bronchial asthma, leukotriene receptor blocker

ATX: & nbsp

R.03.D.C.03 Montelukast

Pharmacodynamics:

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are strong mediators inflammation - eicosanoids, which are distinguished by different cells, including mast cells and eosinophils. These important proastmatic mediators bind to cysteinyl leukotriene receptors. Cysteinyl leukotriene type 1 receptors (CysLT₁receptors) are present in the human respiratory tract (including bronchial smooth muscle cells, macrophages) and other pro-inflammatory cells including eosinophils and certain 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 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 a drug that significantly improves the rates of inflammation in bronchial asthma.According to biochemical and pharmacological analysis, a drug with high selectivity and chemical affinity binds to CysLT₁receptors (instead of other pharmacologically important respiratory tract receptors, such as prostaglandin, cholinergic or β-adrenergic receptors).

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

Montelukast inhibits the CysLT receptors of the respiratory epithelium, thus possessing simultaneously the ability to inhibit the bronchospasm caused by the inhalation of LTD4 in patients with bronchial asthma. A dose of 5 mg is sufficient to stop the bronchospasm induced by LTD4.

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

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

Pharmacokinetics:

Suction

Montelukast quickly and almost completely absorbed after ingestion.In adults, when taking fasting tablets coated with 10 mg maximum concentration (Cmah) is achieved after 3 hours (TmOh). The average bioavailability with oral administration is 64%. Eating does not affect Cmah in the blood plasma and bioavailability of the drug.

When taking fasting tablets chewing 5 mg Cmah in adults is achieved after 2 hours. The average bioavailability with oral administration is 73%.

In children aged 2 to 5 years, CmAch is reached in 2 hours after reception on an empty stomach of chewing tablets of 4 mg.

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 performed on rats with radiolabeled Montelukast 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. When studying therapeutic doses in a state of equilibrium concentration in plasma in adults and children, the concentration of metabolites of montelukast is not determined.In vitro studies using human liver microsomes have shown that cytochromes P450, 3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. According to further research conducted in vitro in human liver microsomes, the therapeutic concentration of montelukast in blood plasma does not inhibit cytochrome P450 isoenzymes CYP: 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.

Peculiarities of pharmacokinetics in different patient groups

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 the elderly. Correction of the dose of the drug in the elderly is not required.

Race

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 elimination half-life is -7.4 hours). Changes in the dose of montelukast for patients with mild to moderate hepatic insufficiency are not required. There is no data on the character of the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale).

Renal insufficiency

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

Indications:

- Prophylaxis and long-term treatment of bronchial asthma in children, beginning at the age of 2, control of day and night symptoms of the disease.

- Relief of symptoms of allergic rhinitis (seasonal and year-round) in children, starting from the age of 2 years.

Contraindications:

- Hypersensitivity to any of the components of the drug

- Phenylketonuria

Pregnancy and lactation:

Clinical studies of the preparation SINGULYAR® with the participation of pregnant women were not conducted. The drug SINGULAIR® should be used during pregnancy and during lactation, only if the expected benefit for the mother exceeds the potential risk to the fetus or child. In the course of post-marketing application SINGULAIR® was reported on the development of birth defects limbs in newborns whose mothers took the drug SINGULYAR® during pregnancy.Most of these women also took other medications to treat bronchial asthma during pregnancy. The causal relationship between the ingestion of SINGULYAR® and the development of birth defects in limbs has not been established.

It is not known whether SINGULUAR® is excreted in breast milk. Since many medications are excreted in breast milk, it is necessary to take this into account when prescribing SINGULUAR® with breast-feeding mothers.

Dosing and Administration:

The drug is taken orally once a day, regardless of food intake.

When bronchial asthma: 1 tablet SINGULAR for the night.

With bronchial asthma and allergic rhinitis: 1 tablet SINGULAR for the night.

At an allergic rhinitis: 1 tablet of SINGULAIR per day in an individual mode, depending on time of the greatest aggravation of signs.

Children aged 2 to 5 years with bronchial asthma and / or allergic rhinitis Dosage for children 2-5 years is one chewing tablet of 4 mg per day.

The therapeutic effect of SINGULAIR with changes in the parameters of the course of bronchial asthma develops within 24 hours.Chewable tablets can be taken regardless of food intake.

For children, the elderly, patients with renal insufficiency and a patient with mild / moderate impairment of liver function, no special dose selection is required.

Side effects:

In general, the preparation SINGULAIR® 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 SINGULYAR®, 573 patients aged from 2 to 5 years took part. In a 12-week, placebo-controlled clinical trial, the only adverse event (AE) estimated to be associated with drug intake was observed in> 1% of patients taking the SINGULAR® preparation and More often than in the group of patients taking placebo, there was thirst. Differences in the frequency of this AE between the two treatment groups were statistically insignificant.

In total, 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 profile of AE did not change.

Children aged 2 to 14 years with seasonal allergic rhinitis

In a 2-week placebo-controlled clinical trial with the use of the preparation SINGULYAR®, 280 patients aged from 2 to 14 years took part in the treatment of seasonal allergic rhinitis. The preparation SINGULAIR® 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 that were considered to be associated with drug administration were not observed, would be observed in ≥ 1% of patients taking the SINGULAIR® preparation 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-week, placebo-controlled clinical trial, a single AE, estimated to be associated with drug intake,> 1% of patients taking the SINGULAIR® drug, and more often than in the placebo group, was headache. The frequency difference between the two treatment groups was statistically insignificant.

In studies evaluating the rate of growth, the safety profile of patients in this age group was consistent with the previously described safety profile of the SINGULAIR® 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 studies with a similar design are the only ones that are undesirable (AE) events evaluated as related to drug intake observed in ≥ 1% of patients taking the SINGULAIR® preparation, and more often than in the placebo group, there was abdominal pain and 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 preparation SINGULAIR® was taken by patients once 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 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. In a 4-week, placebo-controlled clinical study, 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 SINGULAIR® was taken patients once a day and 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 the SINGULAIR® drug were more likely than in the placebo group. The incidence of drowsiness when taking the drug was the same as when taking a placebo.

Generalized analysis of the results of clinical trials

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 the preparation of SINGULAIR® and 7780 patients taking placebo in these studies, one patient with suicidal tendencies was identified in the group of patients taking the preparation of SINGULAIR®. In none of the treatment groups were any suicide, suicide attempt or other preparatory actions that indicated suicidal behavior. Separately, a generalized analysis of 46 placebo-controlled clinical trials (35 studies involving patients aged 15 years and older, 11 studies involving patients aged 3 months to 14 years) was conducted to assess adverse behavioral effects (NPEs). Among the 11673 patients who took the SINGULAIR® in these studies and 8827 patients taking placebo, the percentage of patients with at least one NPE was 2.73% among patients taking SINGULAIR® and 2.27% among those taking placebo; the odds ratio was 1.12 (95% confidence interval [0.93, 1.36]).

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;

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 disorders, psychomotor activity (including irritability, anxiety and tremor), somnambulism, suicidal ideation and behavior (suicidality);

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 ALT activity and ACT in the blood, very rarely (<1/10000) hepatitis (including cholestatic, hepatocellular and mixed liver damage);

disorders of the skin and subcutaneous tissues: angioedema, a tendency to form hematomas, erythema nodosum, erythema multiforme, itching, rashes, hives;

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:

Symptoms of overdose after a long (22 weeks) treatment of patients with bronchial asthma daily doses of SINGULAIR over 200 mg in, or after treatment with daily doses of 900 mg for 1 week, were not observed.

There have been cases of acute overdose (reception of at least 1000 mg per day) of montelukast in the postmarketing period and in clinical studies in adults and children. Clinical and laboratory data indicated the comparability of the safety profiles of SINGULAIR in children, adults and elderly patients.The most common side effects were thirst, drowsiness, vomiting, psychomotor agitation, headache and abdominal pain.

Treatment for acute overdose is symptomatic.

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

Interaction:

The drug SINGULAIR can be prescribed together with other drugs that 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 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 reception of phenobarbital by about 40%, but this does not require changes in the dosage regimen of the preparation SINGULAR.

In studies in vitro determined that montelukast inhibits isoenzyme CYP 2C8 of the cytochrome P450 system, however, in the study of the drug interaction in vivo Montelukast and rosiglitazone (metabolized with the participation of isoenzyme CYP 2C8 of the cytochrome system), no confirmation of the inhibition by Montelukast of the isoenzyme CYP 2C8. Therefore, in clinical practice, no influence of montelukast on CYP 2C8-mediated metabolism of a number of medications, including paclitaxel, rosiglitazone, repaglinide, etc. Studies in vitro showed that montelukast is a substrate CYP 2C8, 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 systemic exposure to 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,200 mg / day for adult patients for 22 weeks and up to 900 mg / day for patients taking the drug for about one week there were no clinically significant adverse effects). Thus, with co-administration with gemfibrozilom adjustment dose montelukast is not required. According to the results of in vitro studies, clinically significant drug interactions with other known inhibitors of CYP 2C8 (for example, with trimethoprim) are not expected. 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

The drug SINGULAIR is a justified addition to monotherapy with bronchodilators if the latter do not provide adequate control of bronchial asthma. After achieving the therapeutic effect of treatment with the drug SINGULAIR, you can start a gradual reduction in the dose of bronchodilators.

Combined treatment with inhaled glucocorticosteroids

Treatment with SINGULAR provides an additional therapeutic effect to patients who use inhaled glucocorticosteroids. Once the state stabilizes, you can start gradual decrease in the dose of glucocorticosteroid under the supervision of a doctor. In some cases, full cancellation is permissible inhaled glucocorticosteroids, However, a sharp substitution of inhaled corticosteroids for the preparation of SINGULAR does not recommended.

Special instructions:

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

Do not stop taking SINGULUAR® during the period of asthma exacerbation and the need for relief of attacks of emergency drugs (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 the SINGULAIR® preparation, since the preparation of Singular®,improving respiratory function in patients with allergic bronchial asthma, nevertheless, can not completely prevent the bronchoconstriction caused by their NSAIDs.

The dose of inhaled glucocorticosteroids used concomitantly with the preparation of SINGULYAR® can be gradually reduced under the supervision of a physician, however, a sharp substitution of inhaled or oral glucocorticosteroids with SINGULYAR® can not be performed.

In patients who took the drug SINGULYAR®, psychoneurological disorders were described (see the "Side effect" section). Given that these symptoms may have been caused by other factors, it is not known whether they are related to taking SINGULAIR®. The physician should discuss these adverse events with patients and / or their parents / guardians. Patients and / or their caregivers need to explain that in the case of the appearance of such symptoms it is necessary to report this the attending physician.

In rare cases, patients receiving antiasthmatic drugs, including leukotriene receptor antagonists, experienced one or more of the following adverse events: 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 adverse events with therapy with leukotriene receptor antagonists has not been established, care should be taken in patients taking the preparation of SINGULAIR® and appropriate clinical observation should be conducted.

The preparation SINGULAIR® tablets chewing 4 mg contains aspartame - A source of phenylalanine. Patients with phenylketonuria should be informed that each chewable tablet of 4 mg contains aspartame in an amount equivalent to 0,674 mg of phenylalanine, and the preparation SINGULYAR® chewable tablets of 4 mg is not recommended for use in patients with phenylketonuria.

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

This section does not apply to the preparation of Singular® chewing tablets of 4 mg, since it is intended for treatment of children from 2 to 5 years of age. Thus, the information presented below refers to the active substance of the preparation montelukastu.

It is not expected that the use of Singular® will affect the ability to drive and move vehicles. However, 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® drug may affect the ability of some patients to drive and drive vehicles.

Form release / dosage:Tablets chewing 4 mg.

Packaging:

For 7 chewable tablets of 4 mg per blister of PVC-A1 foil.

1, 2 or 4 blisters in a cardboard box with instructions for use.

Storage conditions:

At a temperature of 15-30 ° C in a dry, protected from light place.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005945/09

Date of registration:21.07.2009 / 17.07.2014

Expiration Date:Unlimited

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

Manufacturer: & nbsp

MERCK SHARP & DOHME, B.V. Netherlands

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp07.07.2016

Illustrated instructions

Instructions

Singular® (Singulair®)