Singlon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SINGLON® (SINGLON®)

Composition:

Active substance: montelukast;

One 4 mg chewable tablet contains 4 mg of montelukast (as montelukast sodium – 4.16 mg);

One 5 mg chewable tablet contains 5 mg of montelukast (as montelukast sodium – 5.2 mg);

Excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, cherry flavor (maltodextrin, modified starch, maltol), aspartame (E 951), iron oxide yellow (E 172), magnesium stearate.

Pharmaceutical form. Chewable tablets.

Main physicochemical properties:

• SINGLON® 4 mg chewable tablets: cream-colored, oval, biconvex chewable tablets with a raised "R 13" imprint on one side; may contain rare specks of darker color; approximately 11 mm in length and 8 mm in width;
• SINGLON® 5 mg chewable tablets: cream-colored, round, biconvex chewable tablets with a raised "R 14" imprint on one side; may contain rare specks of darker color; approximately 10 mm in diameter.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory diseases. Leukotriene receptor antagonists.

ATC code: R03DC03.

Pharmacological Properties

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and cause responses such as bronchoconstriction, mucus secretion, vascular permeability, and increased eosinophil recruitment.

Oral montelukast is an active compound that selectively and with high affinity binds to CysLT1 receptors. Montelukast has been shown to inhibit LTD4-induced bronchoconstriction at a 5 mg dose. Bronchodilation is observed within 2 hours after oral administration; this effect is additive to the bronchodilation caused by β-agonists. Montelukast treatment suppresses both early and late phases of bronchoconstriction induced by antigen challenge. Montelukast reduces peripheral blood eosinophil counts in adult and pediatric patients compared to placebo. It has been demonstrated that montelukast significantly reduces eosinophil counts in the airways (as assessed by sputum analysis) and in peripheral blood, thereby improving clinical control of bronchial asthma.

Treatment with montelukast improves daytime and nighttime asthma symptoms, complements the clinical effect of inhaled corticosteroids, reduces the annual rate of asthma exacerbations, and decreases the need for β-agonist use.

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. Following a 10 mg film-coated tablet dose administered to adults under fasting conditions, the mean peak plasma concentration (Cmax) is achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect the bioavailability or Cmax following oral administration. Safety and efficacy have been confirmed in clinical trials using 10 mg film-coated tablets, administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is reached within 2 hours after oral administration under fasting conditions. The mean oral bioavailability is 73%, decreasing to 63% when taken with a normal meal.

After administration of 4 mg chewable tablets under fasting conditions in children aged 2 to 5 years, Cmax is achieved within 2 hours. The mean Cmax is 66% higher, and the mean Cmin is lower compared to adults after administration of 10 mg tablets.

Distribution

Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution averages between 8 and 11 liters. In rat studies using radiolabeled montelukast, penetration across the blood-brain barrier was minimal. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after dosing were also minimal.

Metabolism

Montelukast undergoes extensive metabolism. In studies using therapeutic doses, metabolites of montelukast are not detectable in plasma (at steady state) in adult and pediatric patients.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, cytochromes CYP3A4 and 2C9 play minor roles. However, itraconazole (a CYP3A4 inhibitor) did not alter the pharmacokinetic profile of montelukast in healthy volunteers receiving 10 mg montelukast daily. In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is considered minimal.

Excretion

The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% of the dose is excreted in feces within 5 days, and less than 0.2% is excreted in urine. These data, combined with information on oral bioavailability, indicate that montelukast and its metabolites are almost entirely eliminated via the biliary route.

Pharmacokinetics in Specific Patient Populations

Dose adjustment is not required in patients with mild to moderate hepatic impairment or in elderly patients. Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are primarily eliminated via the biliary route, dose adjustment in patients with renal impairment is not considered necessary. Pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) are lacking.

When high doses of montelukast (20 and 60 times the recommended adult dose) were administered, a decrease in plasma theophylline concentrations was observed. This effect was not seen with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

Singlon**®**, 4 mg chewable tablets, is indicated for children aged 2 to 5 years.

Singlon**®**, 5 mg chewable tablets, is indicated for children aged 6 to 14 years.

• Treatment of bronchial asthma.
  • As add-on therapy in patients with mild to moderate persistent asthma, whose condition is not adequately controlled by inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenergic agonists on an as-needed basis.
  • As an alternative treatment to low-dose inhaled corticosteroids in patients with mild persistent asthma who have not experienced severe asthma attacks requiring oral corticosteroids in recent history and who are unable to use inhaled corticosteroids (see section "Dosage and administration").
• Prevention of asthma.

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

• Relief of symptoms of seasonal and perennial allergic rhinitis.

The risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefits of Singlon**®. Therefore, Singlon®** should be used as a reserve medication in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

• Hypersensitivity to montelukast or to any of the excipients of the medicinal product.
• Age under 2 years.

Interaction with other medicinal products and other forms of interaction.

Singlon**®** may be prescribed concomitantly with other medications commonly used for the prevention or long-term treatment of bronchial asthma. In drug interaction studies, the clinical dose of montelukast had no significant clinical effect on the pharmacokinetics of the following agents: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who concurrently took phenobarbital, the area under the concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized via CYP3A4, 2C8, and 2C9, caution should be exercised, especially in children, when montelukast is co-administered with inducers of CYP3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP2C8. However, clinical drug interaction studies involving montelukast and rosiglitazone (a marker substrate metabolized by CYP2C8) demonstrated that montelukast is not an inhibitor of CYP2C8 in vivo. Therefore, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have established that montelukast is a substrate of CYP2C8 and, to a lesser extent, of CYP2C9 and CYP3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP2C8 and CYP2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When used concomitantly with gemfibrozil or other potent inhibitors of CYP2C8, dose adjustment of montelukast is not required; however, physicians should be aware of the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with weaker inhibitors of CYP2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a potent inhibitor of CYP3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Singlon**®** for oral use must never be used for the treatment of acute asthma attacks, and that they should always have a suitable rescue medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they find they need to use a short-acting β-agonist more frequently than usual.

Montelukast should not be used to abruptly discontinue inhaled or oral corticosteroid therapy.

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is administered concomitantly.

In rare cases, systemic eosinophilia, sometimes accompanied by clinical features of vasculitis (so-called Churg-Strauss syndrome), has been observed in patients receiving anti-asthma medications, including montelukast. This condition is treated with systemic corticosteroid therapy. These cases have usually (but not always) been associated with a reduction in dose or discontinuation of oral corticosteroid therapy. A possible association between leukotriene receptor antagonists and the emergence of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Physicians should be aware of the possibility of developing eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

Treatment with montelukast does not permit patients with aspirin-sensitive asthma to take acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

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

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

Aspartame is hydrolyzed in the gastrointestinal tract following oral administration. One of the main hydrolysis products is phenylalanine, which may be harmful to patients with phenylketonuria.

These medicinal products contain less than 1 mmol (23 mg) of sodium per chewable tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any harmful effects on pregnancy or embryonal/fetal development.

Available data from published prospective and retrospective cohort studies on montelukast use in pregnant women assessing major congenital malformations in children have not established a risk associated with the use of this medicinal product. However, the available studies have methodological limitations, including small sample sizes, retrospective data collection in some cases, and non-comparable control groups.

Singlon**®** should be used during pregnancy only if clearly needed.

Breastfeeding. Studies in rats have shown that montelukast is excreted into milk. It is unknown whether montelukast is excreted in human breast milk.

Singlon**®** may be used during breastfeeding only if considered absolutely necessary.

Ability to affect reaction speed when driving or operating machinery.

Montelukast is not expected to influence the ability to drive or operate machinery. However, in individual patients, somnolence and/or dizziness may occur. Such patients should refrain from driving or operating machinery while taking Singlon**®**.

Dosage and Administration

Route of Administration

For oral use. Tablets should be chewed before swallowing.

Patients with asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet of 4 mg once daily. The time of administration should be individually adjusted to best relieve symptoms of allergic rhinitis.

Singlon®, 4 mg chewable tablets

The medication must be used in children under adult supervision. This medicinal product should not be given to children who have difficulty chewing chewable tablets.

Singlon**®, 4 mg chewable tablets, must not be used in children under 2 years of age. The safety and efficacy of Singlon®**, 4 mg chewable tablets, have not been established in children under 2 years of age.

The recommended dose for children aged 2 to 5 years is 4 mg (1 chewable tablet) once daily in the evening. With regard to food intake: Singlon**®**, 4 mg chewable tablets, should be taken 1 hour before or 2 hours after food. Dose adjustment in this age group is not required.

Singlon®, 5 mg chewable tablets

Singlon**®, 5 mg chewable tablets, must not be used in children under 6 years of age. The safety and efficacy of Singlon®**, 5 mg chewable tablets, have not been established in children under 6 years of age.

The recommended dose for children aged 6 to 14 years is 5 mg (1 chewable tablet) once daily in the evening. With regard to food intake: Singlon**®**, 5 mg chewable tablets, should be taken 1 hour before or 2 hours after food. Dose adjustment in this age group is not required.

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

General recommendations. The therapeutic effect of Singlon**®** on asthma control parameters begins within 1 day. Patients should be advised to continue taking Singlon**®** even after asthma is well controlled, as well as during asthma exacerbations.

Special patient groups. Dose adjustment is not required in patients with renal impairment or mild to moderate hepatic impairment. Data in patients with severe hepatic impairment are lacking. The same doses are used for boys and girls.

Use of Singlon® as an alternative treatment instead of low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The use of montelukast as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma should be considered only for patients who have not had severe asthma attacks requiring oral corticosteroids in the recent past and who are unable to use inhaled corticosteroids. Mild persistent asthma is defined as asthma symptoms occurring more than once per week but less than once per day, nocturnal symptoms occurring more than twice per month but less than once per week, and normal lung function between asthma episodes. If adequate asthma control is not achieved, the need for additional or alternative anti-inflammatory therapy should be evaluated subsequently (usually within 1 month), based on a stepwise approach to asthma symptom management. Patients should be periodically assessed for asthma control.

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

Treatment with Singlon**®** in relation to other asthma therapies. When Singlon**®** is used as an add-on to inhaled corticosteroids, Singlon**®** must not abruptly replace inhaled corticosteroids (see section "Special precautions for use").

Children.

Singlon®, chewable tablets, are not recommended for children under 2 years of age, as safety and efficacy have not been established.

Singlon®, 4 mg chewable tablets, should be used in children aged 2 to 5 years.

Singlon**®**, 5 mg chewable tablets, should be used in children aged 6 to 14 years.

Overdose.

Specific information on Singlon**®** overdose is lacking. In clinical trials of chronic asthma, montelukast was administered at doses up to 200 mg/day in adults 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 significant adverse reactions.

During post-marketing use and clinical trials, reports of acute montelukast overdose have been received. These included ingestion by 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 observed in adult and pediatric patients. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse reactions.

Table of frequency of adverse reactions

*Frequency determined according to the frequency of reports in the clinical trial database: very common (≥ 1/10), common (from ≥ 1/100 to <1/10), uncommon (from ≥ 1/1000 to <1/100), rare (from ≥ 1/10000 to <1/1000), very rare (<1/10000).

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

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

§Frequency "rare".

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging. 14 (7×2), 28 (7×4), or 56 (7×8) tablets in blisters, in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Gedeon Richter Polska Sp. z o.o.

Manufacturer's address and place of business.

ul. Księdza Józefa Poniatowskiego 5, Grodzisk Mazowiecki, 05-825, Poland.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address and place of business.

H-1103 Budapest, Demrédi út 19-21, Hungary.

Marketing Authorization Holder.

Gedeon Richter Plc., Hungary.

Address of the Marketing Authorization Holder and/or its representative.

H-1103 Budapest, Demrédi út 19-21, Hungary.