Singlon®

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

Composition:

Active ingredient: montelukast;

One film-coated tablet contains 10 mg of montelukast (as montelukast sodium – 10.4 mg);

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated, round, biconvex tablets, yellow in color, with a relief inscription "R 15" on one side, approximately 8 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 key 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 binds selectively and with high affinity 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 bronchodilation induced by β-agonists. Montelukast treatment suppresses both early and late phases of bronchoconstriction provoked 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 eosinophils 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 frequency 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) was achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. A standard meal does not affect the bioavailability or Cmax of the drug following oral administration. Safety and efficacy have been confirmed in clinical trials using 10 mg film-coated tablets, regardless of the time of administration relative to food intake.

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

Distribution

Over 99% of montelukast is bound to plasma proteins. The mean volume of distribution at steady state is 8 to 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 found to be 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. Cytochromes CYP3A4 and 2C9 also play minor roles. However, itraconazole (a CYP3A4 inhibitor) did not alter the pharmacokinetic profile of montelukast in healthy volunteers receiving 10 mg 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 negligible.

Excretion

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After administration of radiolabeled montelukast orally, 86% of the dose was excreted in feces within 5 days and less than 0.2% in urine. These data, together 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 for patients with mild to moderate hepatic impairment or elderly patients. Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are excreted via bile, 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 10 mg once-daily dose.

Clinical characteristics.

Indications.

Singlon® film-coated tablets, 10 mg, are indicated for adults and adolescents aged 15 years and older.

• Treatment of bronchial asthma:
  • as add-on therapy in patients with mild to moderate persistent asthma whose symptoms are not adequately controlled with inhaled corticosteroids, and in patients who require additional clinical control beyond as-needed use of short-acting β-agonists. In patients with asthma, Singlon® also helps relieve symptoms of seasonal allergic rhinitis.
• Prevention of asthma with exercise-induced bronchospasm as the predominant component.
• 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.
• Pediatric use under 15 years of age (for the 10 mg dosage).

Interaction with other medicinal products and other forms of interaction.

Singlon® can be administered 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 did not have a clinically significant 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 received 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 demonstrated that montelukast is a potent inhibitor of CYP2C8. However, clinical drug interaction studies involving montelukast and rosiglitazone (a marker substrate metabolized by CYP2C8) have shown 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 shown that montelukast is a substrate of CYP2C8 and, to a lesser extent, of CYP2C9 and 3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When co-administered 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 data, clinically significant interactions are not expected with weaker inhibitors of CYP2C8 (e.g., trimethoprim). 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 warned that Singlon® for oral use should never be used to treat acute attacks of bronchial asthma, and that they must always have a suitable emergency medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they find they need a greater amount of short-acting β-agonist than usual.

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

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

In isolated cases, systemic eosinophilia has been observed in patients receiving anti-asthma medications, including montelukast, sometimes accompanied by clinical features of vasculitis (so-called Churg-Strauss syndrome), which 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 treatment. A possible association between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Physicians should be aware of the potential for the development of 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 bronchial asthma to use acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

One film-coated tablet of Singlon® 10 mg contains 89.3 mg of lactose monohydrate.

This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol (23 mg) of sodium per film-coated 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 the medicinal product. The available studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

Singlon**®** may be used during pregnancy only if clearly necessary.

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

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

Ability to influence reaction rate while driving or operating machinery.

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

Method of Administration and Dosage.

The recommended dose for patients (aged 15 and older) with bronchial asthma or bronchial asthma associated with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening, regardless of food intake. To alleviate symptoms of allergic rhinitis, the timing of drug administration should be individually adjusted.

General Recommendations

• The therapeutic effect of Singlon**®** on bronchial asthma control parameters lasts for 24 hours. Patients should be advised to continue taking Singlon**®** even after achieving control of asthma symptoms, as well as during asthma exacerbations;
• Singlon**®** should not be used concomitantly with other medicinal products containing the same active substance – montelukast;
• Elderly patients, patients with renal impairment, or those with mild to moderate hepatic impairment do not require dose adjustment. Data in patients with severe hepatic impairment are lacking. Dosage is the same for men and women.

Treatment with Singlon® in relation to other methods of bronchial asthma management.

• Singlon**®** may be added to an existing treatment regimen.

• Inhaled corticosteroids: Singlon**®** can be used as an add-on therapy in patients who do not achieve adequate clinical control of disease with inhaled corticosteroids in combination with short-acting β-agonists used as needed.

• Singlon**®** should not abruptly replace inhaled corticosteroids.

Children.

Singlon**®, 10 mg film-coated tablets, is indicated for use in patients aged 15 years and older. Safety and efficacy of Singlon®**, 10 mg film-coated tablets, have not been established in children and adolescents under 15 years of age.

Chewable 5 mg tablets are indicated for children aged 6 to 14 years.

Chewable 4 mg tablets are indicated for children aged 2 to 5 years.

Singlon**®** should not be used in children under 2 years of age. Safety and efficacy have not been established in children under 2 years of age.

Overdose.

Specific information regarding overdose with Singlon**®** is limited. In clinical trials of chronic bronchial asthma, montelukast was administered at doses up to 200 mg/day in adult patients for 22 weeks and up to 900 mg/day in short-term studies for approximately 1 week; these doses did not cause any clinically significant adverse reactions.

During post-marketing use and clinical trials, cases of acute Singlon**®** overdose have been reported, including ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The observed clinical and laboratory findings were consistent with the safety profile of Singlon**®** in adults and children. Most overdose cases were not associated with adverse reactions. The most commonly reported adverse reactions were consistent with the known safety profile of Singlon**®** and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

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

Adverse reactions.

Table of frequency of adverse reactions

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via 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, in the original packaging to protect from light and moisture. Keep out of reach of children.

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

Prescription status. Prescription only.

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

Manufacturer's address and place of business:

5 Józefa Poniatowskiego Street, Grójec, 05−825, Poland.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address and place of business:

19−21 Demblé Street, Budapest, H−1103, Hungary.

Marketing Authorization Holder.

Gedeon Richter Plc., Hungary.

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

19−21 Demblé Street, Budapest, H−1103, Hungary.