Montelukast genheim

INSTRUCTIONS for medical use of the medicinal product Montelukast Geneym (Montelukast Geneym)

Composition:

Active substance: montelukast;

One film-coated tablet contains montelukast sodium 10.4 mg, equivalent to montelukast 10 mg;

Excipients: microcellulose 100, including lactose monohydrate; microcrystalline cellulose; low-substituted hydroxypropylcellulose LH-11; sodium croscarmellose; magnesium stearate;

Tablet coating: hydroxypropylcellulose LF, hypromellose 6 cps, titanium dioxide (E 171), polyethylene glycol 6000, iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: 7.9 x 7.9 mm, beige square tablets with rounded edges, film-coated, biconvex with imprint «M10» on one side and flat on the other side.

Pharmacotherapeutic group. Drugs for systemic use in obstructive airway 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). The CysLT type 1 receptor (CysLT1) is present in human airways (including airway smooth muscle cells and airway macrophages) as well as on other pro-inflammatory 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, CysLT protein is released from the nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. Studies have shown that intranasal administration of CysLT increases nasal airway resistance and exacerbates nasal congestion symptoms.

Orally administered montelukast is an active compound that binds selectively and with high affinity to CysLT1 receptors. Clinical studies have demonstrated that montelukast at a dose of 5 mg inhibits LTD4-induced bronchoconstriction. Bronchodilation is observed within 2 hours after oral administration, and this effect is 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 peripheral blood eosinophils in adult and pediatric patients. In one study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

In studies involving adults, montelukast 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 a 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 with 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 for FEV1: 5.43% vs. 1.04%; β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, via spacer device), 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 for FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a greater proportion 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, compared to 42% of patients receiving montelukast who achieved the same response).

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

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily significantly improved respiratory function compared to placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline: –11.7% vs. +8.2%).

A 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 within 5% of baseline FEV1: 44.22 minutes vs. 60.64 minutes). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 minutes vs. 27.98 minutes). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In patients with aspirin sensitivity receiving ongoing 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%; change from baseline in overall β-agonist use: –27.78% vs. 2.09%).

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets on an empty stomach in adults, the mean peak plasma concentration (Cmax) is achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect the bioavailability or Cmax of montelukast after oral administration. Safety and efficacy have been confirmed in clinical studies with the administration of 10 mg film-coated tablets regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is achieved within 2 hours after administration on an empty stomach. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

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. Furthermore, concentrations of radiolabeled material in all other tissues 24 hours after dose administration were also minimal.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and pediatric patients are not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, cytochromes CYP 3A4 and 2C9 play a minor role in its metabolism, although itraconazole (a CYP3A4 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 cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 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 within 5 days and less than 0.2% in urine. Combined with the oral bioavailability of montelukast, this indicates 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. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are eliminated via the biliary route, 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 is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As an add-on therapy in patients with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, and in patients with inadequate clinical control of asthma requiring short-acting β-adrenergic agonists on an as-needed basis. In patients with bronchial asthma, it also alleviates symptoms of seasonal allergic rhinitis.

Prophylaxis of asthma in which exercise-induced bronchospasm is 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 benefit of montelukast; therefore, Montelukast Genheim should be used as a reserve agent in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product. Pediatric age under 15 years (for the 10 mg dose).

Interaction with other medicinal products and other forms of interactions.

Montelukast may be administered concomitantly with other medicinal products commonly used for the prophylaxis or long-term treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no clinically significant effect on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients concurrently taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is administered concomitantly with inducers of CYP 3A4, 2C8, and 2C9 (e.g., phenytoin, phenobarbital, and rifampicin).

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, clinical drug interaction data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) demonstrated that montelukast is not an inhibitor of CYP 2C8 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 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-fold. When montelukast is coadministered with gemfibrozil or other potent inhibitors of CYP 2C8, dosage adjustment of montelukast is not required; however, the physician should consider the increased risk of adverse reactions.

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

Special precautions for use.

Patients should be advised that montelukast 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 acute attacks, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they find they need to use their short-acting β-agonist more frequently 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, sometimes manifesting with clinical features of vasculitis, namely Churg-Strauss syndrome, has been observed in patients receiving anti-asthmatic agents, including montelukast. This condition is usually treated with systemic corticosteroid therapy. These cases have typically (but not always) been associated with a reduction in dose or discontinuation of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the development of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Physicians should be aware of the potential for eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients presenting with such symptoms should be re-evaluated and their treatment regimen reconsidered.

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

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

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not demonstrated any harmful effects on pregnancy or embryonal/foetal development.

Available data from published prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing major congenital malformations in offspring, 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.

Montelukast may be used during pregnancy only if considered absolutely necessary.

Breastfeeding period. Animal studies have demonstrated that montelukast is excreted into milk. It is unknown whether montelukast is excreted into human breast milk.

Montelukast Genehm may be used during breastfeeding only if considered absolutely necessary.

Ability to influence reaction speed when driving or operating machinery.

Montelukast is not expected to affect a patient's ability to drive or operate machinery. However, very rare cases of somnolence or 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. To relieve symptoms of allergic rhinitis, the timing of administration should be individually adjusted.

General recommendations

The therapeutic effect of montelukast on asthma control parameters begins within 1 day. The medicinal product can be administered regardless of food intake. Patients should be advised to continue taking Montelukast Genehm even when asthma is well controlled, as well as during asthma exacerbations. Montelukast Genehm should not be used concomitantly with medicinal products containing montelukast as the active ingredient.

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

Use of Montelukast Genehm in relation to other asthma treatments

Montelukast Genehm may be added to an existing asthma treatment regimen.

Inhaled corticosteroids

Montelukast Genehm can be used as add-on therapy in patients in whom inhaled corticosteroids together with short-acting β-agonists used as needed do not provide adequate clinical control of the disease.

Montelukast Genehm should not be used to abruptly displace inhaled corticosteroids (see section "Special precautions").

Children
For use in children aged 15 years and older. Children under 15 years of age should be administered the medicinal product in the form of chewable tablets.

Overdose

There is no specific information on the treatment of montelukast overdose. In chronic asthma studies, montelukast was administered at doses up to 200 mg/day in adult patients for 22 weeks, and in short-term studies at doses up to 900 mg/day for approximately one week, without clinically significant adverse reactions.

During post-marketing surveillance and clinical trials, acute montelukast overdoses have been reported. These included 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 montelukast in adults and children. 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, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

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

Adverse Reactions

During clinical studies, the following adverse reactions were frequently reported (≥ 1/100 to < 1/10) in patients aged 15 years and older receiving montelukast treatment, and more frequently than in patients receiving placebo.

Nervous system disorders: Headache.

Gastrointestinal disorders: Abdominal pain.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed according to system organ classes.

Frequency is defined according to the frequency of reporting in the clinical study database: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

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

Blood and lymphatic system disorders: rare – 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, tics; very rare – hallucinations, disorientation, suicidal thoughts and behavior (suicidality), obsessive-compulsive disorders, dysphemia.

Nervous system disorders: uncommon – dizziness, drowsiness, paraesthesia/hypoaesthesia, convulsions.

Cardiac disorders: rare – palpitations.

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

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

Hepatobiliary disorders: common – elevated serum transaminases (ALT, AST); very rare – hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

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

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

Renal and urinary disorders: uncommon – enuresis in children.

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

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

**Rare.

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

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: http://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Store in the original packaging to protect from light and moisture.

Keep out of the reach of children.

Packaging.

14 tablets in a blister pack. 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare Polska Sp. z o.o./Accord Healthcare Polska Sp. z o.o.

Inquiries regarding substandard quality of the medicinal product; questions concerning safety of use, improper use of the medicinal product, or complaints are accepted 24/7 by phone: +380993100335 or by email at: [email protected].

Address of the Marketing Authorization Holder. 7 Tasmowa St., Warsaw, 02-677, Poland.