Singlon

Treatment with Singlon improves daytime and nighttime asthma symptoms, complements the clinical effects of inhaled corticosteroids, and reduces the annual frequency of asthma exacerbation episodes and the need for beta-agonist use.

Indications Singlon

Singlon, chewable tablets, 4 mg each is indicated for children 2 to 5 years of age.

Singlon, chewable tablets, 5 mg each is indicated for children 6 to 14 years of age.

Bronchial asthma treatment.

• As adjunctive treatment in bronchial asthma in patients with persistent mild to moderate asthma inadequately controlled by inhaled corticosteroids, as well as in patients with inadequate clinical control of asthma with short-acting β-adrenoreceptor agonists used as needed.
• As an alternative treatment to low-dose inhaled corticosteroids for patients with persistent mild asthma who have not had a recent severe bronchial asthma attack requiring oral corticosteroids and cannot use inhaled corticosteroids see and doses").

Asthma Prevention.

Prevention of asthma, the predominant component of which is exercise-induced bronchospasm, in patients aged 2 years and older.

Relief of symptoms of seasonal and year-round allergic rhinitis.

The risks of neuropsychiatric symptoms in patients with allergic rhinitis may exceed the benefits of Singlon, therefore Singlon should be used as a standby drug in patients with inadequate response or intolerance to alternative therapies.

Release form

1 chewable tablet of 4 mg contains 4 mg of montelukast (in the form of montelukast sodium - 4.16 mg);

1 chewable tablet of 5 mg contains 5 mg of montelukast (in the form of montelukast sodium - 5.2 mg);

other ingredients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, cherry flavoring (maltodextrin, modified starch, maltol), aspartame (E 951), iron oxide yellow (E 172).

Chewable tablets.

Basic physicochemical properties:

• Singlon®, chewable tablets, 4 mg: cream-colored, oval, biconvex, chewable tablets with the relief inscription "R 13" on one side; approximately 11 mm long, approximately 8 mm wide;
• Singlon®, chewable tablets, 5 mg: cream-colored, round, biconvex, chewable tablets, with relief inscription "R 14" on one side; with possible presence of sparse darker colored flecks; approximately 10 mm in diameter.

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent eicosanoids of inflammation secreted by various cells, including mast cells and eosinophils. These important proasthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in the human airways and cause reactions such as bronchospasm, mucus secretion, vascular permeability, and increased eosinophil counts.

Orally administered montelukast is an active compound that binds to CysLT1 receptors with high selectivity and chemical affinity. Montelukast is known to inhibit bronchospasm after inhalation of LTD4 at a dose of 5 mg. Bronchodilation is observed within 2 h after oral administration; this effect is additive to bronchodilation induced by β-agonists.Treatment with montelukast inhibited both the early and late phases of bronchoconstriction caused by antigenic stimulation. Montelukast reduced peripheral blood eosinophil counts in adult patients and children compared with placebo.It is known that administration of montelukast significantly reduced the number of eosinophils in the airways (by sputum analysis) and peripheral blood while improving clinical control of bronchial asthma.

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. After oral administration of 10 mg film-coated tablets in adults on an empty stomach, the mean maximum concentration (C max ) in plasma was reached after 3 h (T max ). The mean oral bioavailability was 64%.Consumption of regular food did not affect bioavailability and Cmax during oral administration of the drug. Safety and efficacy were confirmed during clinical studies conducted with 10 mg film-coated tablets regardless of meal time.

For chewable 5 mg tablets, C max in adults was reached 2 hours after oral administration on an empty stomach. The average bioavailability for oral administration is 73% and decreases to 63% when administered with regular food.

After ingestion of 4 mg chewable tablets on an empty stomach in children from 2 to 5 years of age, the C max value is reached 2 hours after the drug administration. The mean Cmax value is 66% higher and the mean Cmin value is lower than in adults after ingestion of 10 mg tablets.

Distribution

More than 99% of montelukast binds to blood plasma proteins. The volume of distribution of montelukast in the equilibrium state averages 8 to 11 liters. In rat studies using radioactively labeled montelukast, penetration across the blood-brain barrier was minimal. In addition, concentrations of radioisotope-labeled material in all other tissues 24 hours after administration were also minimal.

Metabolism

Montelukast is actively metabolized. In studies with therapeutic doses, metabolites of montelukast are not detectable in plasma (in equilibrium) in adults and pediatric children.

Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. In addition, cytochromes CYP ZA4 and 2C9 play a minor role in the metabolism of montelukast, although itraconazole (a CYP ZA4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg of montelukast.According to the results of in vitro studies using human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 ZA4, 2C9, 1A2, 2A6, 2C19 and 2D6. The participation of metabolites in the therapeutic action of montelukast is minimal.

Conclusion

The clearance of montelukast from blood plasma in healthy adult volunteers averages 45 ml/min. After oral administration of isotope-labeled montelukast, 86% of the substance is excreted with feces within 5 days and less than 0.2% with urine. This fact, combined with data on the bioavailability of montelukast when administered orally, indicates that montelukast and its metabolites are almost completely excreted with bile.

Pharmacokinetics in different groups of patients

No dose adjustment is required in patients with mild to moderate hepatic impairment and elderly patients. No studies involving patients with renal impairment have been conducted. Since montelukast and its metabolites are excreted with bile, dose adjustment in patients with renal impairment is not considered necessary. No data on pharmacokinetics of montelukast in patients with severe hepatic impairment (more than 9 points according to Child-Pugh classification) are available.

When taking high doses of montelukast (20 and 60 times the dose recommended for adults), a decrease in plasma theophylline concentration was observed. This effect was not observed when taking the recommended dose of 10 mg once daily.

Dosing and administration

Method of application

For oral administration. Tablets should be chewed before swallowing.

Patients with bronchial asthma and allergic rhinitis (seasonal and year-round) should take 1 chewable tablet of 4 mg once a day. For relief of allergic rhinitis symptoms, the time of administration should be adjusted individually.

Singlon®, 4 mg chewable tablets

The drug should be used in children under adult supervision. Children who have problems using chewable tablets should not be given this medicine.

Singlon, chewable tablets 4 mg, should not be used in children under 2 - x years of age. Safety and efficacy of Singlon, chewable tablets 4 mg, for children under 2 years of age have not been established.

The recommended dose for children 2 to 5 years of age is 4 mg (1 chewable tablet) per day, in the evening. Administration with meals: Singlon, 4 mg chewable tablets, should be administered 1 hour before or 2 hours after meals. There is no need to adjust the dosage for this age group.

Singlon®, 5 mg chewable tablets

Singlon, chewable tablets 5 mg, should not be used in children under 6 years of age. Safety and efficacy of Singlon, chewable tablets 5 mg, in children under 6 years of age have not been established.

The recommended dosage for children 6 to 14 years of age is 5 mg (1 chewable tablet) per day, in the evening. Administration with meals: Singlon, 5 mg chewable tablets, should be used 1 hour before or 2 hours after meals. There is no need to adjust the dosage for this age group.

Film-coated tablets containing 10 mg of montelukast are indicated for adults and adolescents 15 years of age and older.

General advice: The therapeutic effect of Singlon on bronchial asthma control occurs within 1 day. Patients should be advised to continue taking Singlon even if asthma control is achieved and during periods of asthma exacerbation.

Special patient groups : No dose adjustment is necessary in patients with mild to moderate renal impairment or hepatic impairment. No data on patients with severe hepatic impairment are available. The same doses are used for boys and girls.

The use of Singlon as an alternative treatment to low-dose inhaled corticosteroids for persistent mild bronchial asthma. Montelukast is not recommended as monotherapy for patients with persistent moderate asthma.The use of montelukast as an alternative to low-dose inhaled corticosteroids for children with persistent mild bronchial asthma should be considered only for patients who have not had a recent history of severe bronchial asthma attacks that required oral corticosteroids and are not eligible.Persistent mild bronchial asthma is defined as the occurrence of asthma symptoms more than once a week but less than once a day, the occurrence of nocturnal symptoms more than twice a month but less than once a week, and normal lung function in the periods between bronchial asthma episodes.If adequate asthma control is not achieved, the need for additional or different anti-inflammatory therapy should be determined at a later time (usually within 1 month) based on consistent management of bronchial asthma symptoms. Patients should be periodically evaluated for bronchial asthma control.

Use of Singlon®, chewable tablets 4 mg for the prevention of bronchial asthma in patients aged 2 to 5 years, in whom the main component of bronchial asthma is exercise-induced bronchospasm.Singlon® is recommended in patients aged 2 to 5 years for the prevention of exercise-induced bronchospasm, which may be a major manifestation of persistent bronchial asthma requiring inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with montelukast. If an adequate response is not achieved, additional or different therapy should be considered.

Treatment with Singlon in dependence on other treatments for bronchial asthma. If Singlon is used as an adjunctive treatment to inhaled corticosteroids, Singlon should not dramatically replace inhaled corticosteroids (see "Administration details").

Kids.

The drug Singlon, chewable tablets, is not recommended for use in children under 2 years of age, as safety and efficacy have not been established.

The drug Singlon, chewable tablets of 4 mg, to use in children aged 2 to 5 years.

The drug Singlon, chewable tablets of 5 mg, to use in children aged 6 to 14 years.

Use Singlon during pregnancy

Pregnancy: Animal studies show no harmful effects on pregnancy or embryonic/fetal development.

Available data from published prospective and retrospective cohort studies involving the use of montelukast by pregnant women evaluating for significant congenital malformations in children have not established a risk associated with the use of the drug. The available studies have methodological limitations, including small sample sizes, in some cases retrospective data collection, and incompatible comparison groups.

The drug Singlon should be used during pregnancy only if clearly necessary.

Breastfeeding. Studies in rats have demonstrated that montelukast passes into milk. It is not known whether montelukast is excreted with breast milk in women.

Singlon may be used during breastfeeding only if it is considered absolutely necessary.

Contraindications

• Hypersensitivity to montelukast or any of the excipients of the drug.
• Children under 2 years of age.

Side effects Singlon

Table of frequency of adverse reactions

Class of organ systems	Adverse Reactions	Frequency*
Infections and infestations	Upper respiratory tractinfections	Very frequent
Blood and lymphatic system disorders	Increased tendency to bleed	Singles
	Thrombocytopenia	Rare
Immune system	Hypersensitivity reactions, including anaphylaxis	Infrequent
	Eosinophilic infiltration of the liver	Rare
On the mental side	Sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation, including aggressive behavior or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor )	Infrequent
	Attention deficit disorder, memory impairment, tics.	Singles
	Hallucinations, disorientation, suicidal thoughts and behavior (suicidality), obsessive-compulsive disorder, dysphemia	Rare
Nervous system	Headache	Frequent
	Dizziness, drowsiness, paresthesia/hypoesthesia, seizures	Infrequent
On the heart side	Heart palpitations	Singles
Respiratory system, chest and mediastinal organs.	Nosebleed	Infrequent
	Churg-Strauss syndrome (see section "Specifics of use")	Rare
	Pulmonary eosinophilia	Rare
Gastrointestinal side	Diarrhea , nausea , vomiting , abdominal pain.	Frequent
	Dry mouth, dyspepsia.	Infrequent
Hepatobiliary system	Elevated serum transaminases SGPT(ALT), SGOT(AST).	Frequent
	Hepatitis (including cholestatic, hepatocellular and mixed liver disease)	Rare
Skin and subcutaneous tissues	Rash ‡	Frequent
	Tendency to bruising, hives, itching	Infrequent
	Angioedema	Singles
	Nodular erythema, erythema multiforme	Rare
Musculoskeletal and connective tissue disorders	Arthralgia, myalgia, including muscle spasms	Infrequent
Kidney and urinary tract disorders	Enuresis in children	Infrequent
General disorders and adverse reactions caused by taking the drug	Hyperthermia ‡, thirst	Frequent
	Asthenia/increased fatigue, malaise, edema	Infrequent

*Frequency was defined according to the frequency of reports in the clinical trials database: very frequent (≥1/10), frequent (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), single (≥1/10000 to <1/1000), rare (<1/10000).

†This adverse reaction was reported with a frequency of "very common" in patients using montelukast and in patients receiving placebo during clinical trials.

‡This adverse reaction was reported with a frequency of "frequent" in patients using montelukast as well as in patients receiving placebo during clinical trials.

§Frequency of "singular".

Overdose

There is no specific information on overdose of Singlon. In studies of chronic bronchial asthma, montelukast was administered at doses up to 200 mg/day to adult patients for 22 weeks and in short-term studies at doses up to 900 mg/day for approximately 1 week; these doses did not cause any clinically important adverse reactions.

Acute overdose of montelukast has been reported during post-registration use and during clinical trials. These included administration of the drug in adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory findings were consistent with the safety profile in adult patients and children.No adverse reactions were reported in most cases of overdose. The most frequently observed adverse reactions consistent with the safety profile of montelukast included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is not known whether montelukast is excreted by peritoneal dialysis or hemodialysis.

Interactions with other drugs

Singlon can be administered together with other drugs commonly used for the prophylaxis or long-term treatment of bronchial asthma. In drug-drug interaction studies, the clinical dose of montelukast had no important clinical effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.

In patients concomitantly taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Because montelukast is metabolized by CYP ZA4, 2C8 and 2C9, caution should be exercised, especially in children, if montelukast is administered concomitantly with CYP ZA4, 2C8 and 2C9 inducers, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug interaction study involving montelukast and rosiglitazone (marker substrate; drug metabolized by CYP 2C8) showed that montelukast is not an inhibitor of CYP 2C8 in vivo.Thus, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

During in vitro studies it was found that montelukast is a substrate of CYP 2C8 and to a lesser extent 2C9 and ZA4. During clinical drug interaction study with montelukast and gemfibrozil (CYP 2C8 and 2C9 inhibitor) gemfibrozil increased the systemic effect of montelukast by 4.4 times.In case of concomitant use with gemfibrozil or other potent CYP 2C8 inhibitors, dose adjustment of montelukast is not required, but the physician should take into account the increased risk of adverse reactions.

Based on the results of in vitro studies, clinically important interactions with less potent CYP 2C8 inhibitors (e.g. Trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a potent CYP ZA4 inhibitor, did not significantly increase the systemic exposure of montelukast.

Storage conditions

Store at a temperature not exceeding 25 C in the original packaging to protect from light and moisture.

Keep out of reach of children.

Special instructions

Patients should be warned that Singlon for oral use should never be used for the treatment of acute attacks of bronchial asthma and that they should always carry an appropriate emergency medication. In case of an acute attack, inhaled short-acting β-agonists should be used. Patients should consult their physician as soon as possible if they require more short-acting β-agonist than usual.

Therapy with inhaled or oral corticosteroids should not be abruptly substituted for montelukast.

There are no data to support that the dose of oral corticosteroids can be reduced with concomitant use of montelukast.

In isolated cases, systemic eosinophilia, sometimes accompanied by clinical manifestations of vasculitis (so-called Churg-Strauss syndrome) treated with systemic corticosteroid therapy, may be observed in patients receiving antiasthmatics, including montelukast. Such cases have usually (but not always) been associated with dose reduction or discontinuation of oral corticosteroid medication.The possible relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be refuted or confirmed. Clinicians should be aware of the possibility of patients experiencing eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and/or neuropathy. Patients who experience such symptoms should be re-examined and their treatment regimen should be reviewed.

Treatment with montelukast does not allow patients with acetylsalicylic acid-sensitive bronchial asthma to use acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Neuropsychiatric reactions have been reported in adults, children and adolescents taking Singlon (see section "Adverse Reactions"). Physicians and patients should be aware of the possibility of neuropsychiatric reactions.Patients and/or observers should be instructed to inform their physician if such changes occur. Physicians should carefully evaluate the risks and benefits of continuing treatment with Singlon if such reactions develop.

Singlon, 4 mg chewable tablets, contains 1.2 mg of aspartame in each tablet, equivalent to 0.674 mg of phenylalanine per dose.

Singlon, 5 mg chewable tablets, contains 1.5 mg of aspartame in each tablet, equivalent to 0.842 mg of phenylalanine per dose.

Aspartame is hydrolyzed in the gastrointestinal tract when taken orally. One of the major products of hydrolysis is phenylalanine, which may be harmful to patients with phenylketonuria.

These medications contain less than 1 mmol (23 mg) per chewable tablet of sodium, meaning they are virtually sodium free.

Ability to affect reaction speed when driving motor transport or other mechanisms.

No effect of montelukast on the ability to drive a car or other mechanisms is expected. However, drowsiness and dizziness may occur in individual patients, such patients should refrain from driving a car or other mechanisms while taking the drug Singlon.

Shelf life

2 years.