Lucast®

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

Composition:

Active substance: montelukast;

1 tablet contains montelukast (as sodium salt) 10 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; Opadry OY-L-1-20419 White (lactose monohydrate; titanium dioxide (E 171); hypromellose; polyethylene glycol); Yellow Sunset FCF (E 110); purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of light orange color, with "PhI" imprinted on one side.

Pharmacotherapeutic group. Other systemic drugs for the treatment of obstructive respiratory diseases. Leukotriene receptor antagonists. Montelukast.

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). The CysLT type 1 receptor (CysLT1) is present in human airways (including airway smooth muscle cells and airway macrophages) as well as on other proinflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLTs are released from nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. According to studies, intranasal administration of CysLT leads to increased nasal airway resistance and enhanced symptoms of nasal congestion.

Montelukast, following oral administration, is an active compound that selectively and with high affinity binds to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits bronchoconstriction induced by inhaled LTD4. Bronchodilation was observed within 2 hours after oral administration, and this effect was additive to bronchodilation caused by β-agonists. Treatment with montelukast suppresses both early and late phases of bronchoconstriction induced by antigen stimulation. Compared to placebo, montelukast reduces the number of eosinophils in peripheral blood in both adult and pediatric patients. In a separate study, montelukast treatment significantly reduced eosinophil counts in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

In clinical trials involving adults, montelukast at a dose of 10 mg once daily, compared to placebo, demonstrated significant improvement in morning forced expiratory volume in 1 second (FEV1) (change from baseline: 10.4% vs. 2.7%, respectively), morning peak expiratory flow rate (PEFR) (change from baseline: 24.5 L/min vs. 3.3 L/min, respectively), and significant reduction in overall use of β-agonists (change from baseline: -26.1% vs. -4.6%, respectively). Improvement in patient-reported daytime and nighttime asthma symptoms was significantly better than placebo.

Studies in adults have demonstrated montelukast's ability to complement the clinical effect of inhaled corticosteroids (change from baseline for inhaled beclomethasone plus montelukast vs. beclomethasone alone, respectively: for FEV1: 5.43% vs. 1.04%; for β-agonist use: -8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, via spacer), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone produced a greater average therapeutic effect (change from baseline for montelukast vs. beclomethasone, respectively: for FEV1: 7.49% vs. 13.3%; for β-agonist use: -28.28% vs. -43.89%). However, compared to beclomethasone, a substantial number of patients receiving montelukast achieved a similar clinical response (i.e., 50% of patients receiving beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, while 42% of patients receiving montelukast achieved a similar response).

A clinical trial was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older who had both asthma and concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets taken once daily demonstrated statistically significant improvement in the daily rhinitis symptom score compared to placebo. The daily rhinitis symptom score is a mean value derived from assessment of daytime nasal symptoms (nasal congestion, rhinorrhea, sneezing, nasal itching) and nighttime symptoms (nasal congestion upon awakening, difficulty falling asleep, frequency of nocturnal awakenings). Significantly better outcomes in overall patient and physician assessment of allergic rhinitis treatment were observed compared to placebo. Evaluation of efficacy for asthma was not a primary objective of this study.

Significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated during a 12-week study in adults (maximum decrease in FEV1: 22.33% for montelukast vs. 32.40% for placebo; time to recovery to within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. The effect was demonstrated with once-daily dosing.

In patients with aspirin sensitivity receiving concomitant therapy with inhaled and/or oral corticosteroids, treatment with montelukast, compared to placebo, resulted in significant improvement in asthma control (change from baseline in FEV1: 8.55% vs. -1.74%; reduction in total β-agonist use from baseline: -27.78% vs. 2.09%).

Pharmacokinetics.

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of the drug (10 mg film-coated tablet) to fasting adults, the mean peak plasma concentration (Cmax) is achieved within 3 hours. The mean oral bioavailability is 64%. A normal meal does not affect bioavailability or Cmax following oral administration. The safety and efficacy of the drug have been established in clinical trials where 10 mg tablets were administered without regard to meal timing.

Distribution

Over 99% of montelukast is bound to plasma proteins. The volume of distribution at steady state is 8 to 11 L. Animal studies using radiolabeled montelukast indicate minimal penetration across the blood-brain barrier. Additionally, concentrations of radiolabeled material 24 hours after administration were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, plasma concentrations of montelukast metabolites in adults and pediatric patients at steady state are undetectable.

Cytochrome P450 2C8 is the primary enzyme involved in the metabolism of montelukast. Additionally, CYP 3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetic parameters 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 minimal.

Excretion

The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% is excreted in feces over 5 days and less than 0.2% in urine. Together with the oral bioavailability of montelukast, this indicates that montelukast and its metabolites are almost entirely eliminated via bile.

Pharmacokinetics in Specific Patient Populations

Dose adjustment is not required for elderly patients or for patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) was associated with decreased plasma theophylline concentrations. This effect was not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

Adjunctive treatment of bronchial asthma in patients with persistent asthma of mild to moderate severity, which is not adequately controlled by inhaled corticosteroids, as well as in cases of inadequate clinical control of asthma with short-acting beta-agonists used as needed. Symptomatic treatment of seasonal allergic rhinitis in patients with bronchial asthma.

Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Children under 15 years of age.

Interaction with other medicinal products and other forms of interactions.

Montelukast may be administered together with other drugs commonly used for the prevention or long-term treatment of bronchial asthma. The recommended clinical dose of montelukast has no significant clinical effect on the pharmacokinetics of drugs such as 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 by CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is used concomitantly with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

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

In vitro studies have established that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4 times. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dosage adjustment of montelukast is not required; however, physicians should consider the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with weaker inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with weaker inhibitors of CYP 3A4 did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Lukast® must not be used to relieve acute asthma attacks, and that they should always have a suitable emergency relief medication available. In the event of an acute attack, short-acting beta-agonist inhalers should be used. Patients should seek medical advice as soon as possible if they find they need a greater than usual number of inhalations of short-acting beta-agonists.

Montelukast must not be used to abruptly replace inhaled or oral corticosteroids.

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

Cases of neuropsychiatric events have been reported in adults, adolescents, and children taking montelukast (see section "Adverse reactions"). Patients and physicians should be aware of the possibility of such events occurring. Furthermore, patients and/or their caregivers should be instructed to inform their physician if such events occur. Physicians should carefully evaluate the risks and benefits of continuing montelukast therapy if neuropsychiatric events occur.

In rare cases, systemic eosinophilia, sometimes manifesting with clinical features of vasculitis (Churg-Strauss syndrome), has been observed in patients receiving anti-asthma treatments, including montelukast. This syndrome is typically treated with systemic corticosteroid therapy. These cases have sometimes been associated with reduction or withdrawal of corticosteroid therapy. Leukotriene receptor antagonists may possibly be linked to the occurrence of Churg-Strauss syndrome. Physicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in such patients. Patients who develop the aforementioned symptoms should be re-evaluated and their treatment regimen reviewed.

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

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Since the product contains the dye E 110 (Ponceau 4R) as an excipient, it should be noted that this may cause allergic reactions.

Patients with known sugar intolerances should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

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

Limited data available from pregnancy registries do not indicate a causal relationship between montelukast use and malformations (such as limb defects) that have been rarely reported during post-marketing use.

Lukast® should be used during pregnancy only if clearly necessary.

Breastfeeding

Animal studies have shown that montelukast passes into milk. However, it is unknown whether montelukast or its metabolites are excreted in human breast milk.

Lukast® should be used during breastfeeding only if clearly necessary.

Effect on ability to drive or operate machinery

Lukast® has no or negligible influence on the ability to drive or operate machinery. However, somnolence and dizziness have been reported.

Dosage and Administration.

The recommended dose for patients (aged 15 years and older) with asthma or with asthma and concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening.

General recommendations. The therapeutic effect of the medicinal product Lukast® on asthma control parameters develops within 1 day. The drug may be taken regardless of food intake. Patients should be advised to continue taking Lukast® even when asthma is well controlled, as well as during periods of exacerbation. The drug should not be used simultaneously with other medicinal products containing the same active substance – montelukast.

Dose adjustment is not required in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data available regarding patients with severe hepatic impairment. Dosage is the same for men and women.

Treatment with Lukast® in relation to other asthma therapies.

Lukast® may be prescribed as an add-on to the patient's existing therapy.

Inhaled corticosteroids. Lukast® may be used as add-on therapy when inhaled corticosteroids in combination with short-acting beta-agonists taken as needed do not provide adequate clinical control of the disease.

Lukast® must not be used as a sudden substitute for inhaled corticosteroids (see section "Special precautions").

Children.

This pharmaceutical form is indicated for use in patients aged 15 years and older. Children under 15 years of age should receive montelukast in the form of chewable tablets.

Overdose.

In clinical studies, montelukast was administered at doses up to 200 mg/day in adult patients with chronic asthma for 22 weeks, and up to 900 mg/day in short-term studies for approximately 1 week, without causing clinically significant adverse reactions.

During post-marketing use and clinical trials, cases of acute overdose of the medicinal product Lukast® have been reported. These involved ingestion of the drug by adults and children at a dose of 1000 mg (approximately 61 mg/kg in a 42-month-old child). The observed clinical and laboratory findings were consistent with the known safety profile in adults and children. In most reported cases of overdose, no adverse events were observed. The most commonly reported adverse effects were consistent with the known safety profile of Lukast®, including abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

There is no specific antidote or treatment recommendations for Lukast® overdose. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse Reactions

During clinical studies, the following adverse reactions were reported frequently (from ≥ 1/100 to < 1/10) and more frequently than in patients receiving placebo:

Nervous system disorders: headache.

Gastrointestinal disorders: abdominal pain.

In long-term treatment clinical trials with a limited number of patients (up to 2 years in adults), the safety profile remained unchanged.

Adverse reactions reported during the post-marketing period:

Infections and infestations: very common – upper respiratory tract infections*.

Blood and lymphatic system disorders: uncommon – tendency to increased bleeding; very rare – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions, including anaphylaxis; very rare – hepatic eosinophilic infiltration.

Psychiatric disorders: uncommon – sleep disorders, including nightmares, insomnia, somnambulism, anxiety (agitation, including aggressive behavior or hostility), depression, psychomotor hyperactivity (including irritability, restlessness, tremor§); rare – attention disorders, memory impairment, tic; very rare – hallucinations, disorientation, suicidal ideation and behavior (suicidality), dysphemia, obsessive-compulsive disorders.

Nervous system disorders: uncommon – dizziness, somnolence, paraesthesia/hypoaesthesia, seizures.

Cardiac disorders: rare – palpitations.

Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis; very rare – Churg-Strauss syndrome (see section "Special Warnings and Precautions for Use"), pulmonary eosinophilia.

Gastrointestinal disorders: common – diarrhea**, nausea**, vomiting**; uncommon – dry mouth, dyspepsia.

Hepatobiliary disorders: common – increased serum transaminase levels (alanine aminotransferase, aspartate aminotransferase); very rare – hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

Renal and urinary disorders: uncommon – enuresis in children.

Skin and subcutaneous tissue disorders: common – rash**; uncommon – bruising, urticaria, pruritus; rare – angioneurotic edema; very rare – nodular erythema, erythema multiforme.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia, including muscle cramps.

General disorders: common – pyrexia**; uncommon – asthenia/fatigue, malaise, swelling.

Frequency categories: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

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

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

§ Frequency category: rare.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical 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: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children.

Store at a temperature not exceeding 30 °C.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder.

Pharma International Company.

Manufacturer's address and place of business.

Al Kastal area, Airport Road, P.O. Box 334, Jubaiha 11941, Amman – Jordan.

Marketing Authorization Holder's address.

P.O. Box 334, Al-Jubaiha 11941, Amman, Jordan.

Contact details of the manufacturer's/marketing authorization holder's representative in Ukraine – LLC "Megakom":

195-B Klovkivska Street, Kharkiv, 61145; phone: +38 (057) 701 37 55.