Instructions for Milukant film-coated tablets 10 mg No. 28
Composition
active ingredient: montelukast sodium;
1 tablet contains montelukast sodium 10.4 mg equivalent to montelukast 10 mg;
excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, disodium edetate, magnesium stearate; coating: Opadry® Yellow 20A82938 (hypromellose 6 cp, hydroxypropylcellulose, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: beige, round, biconvex tablets, film-coated.
Pharmacotherapeutic group
Antiasthmatics. Selective and orally active leukotriene receptor blockers. ATC code R03D C03.
Pharmacological properties
Pharmacodynamics.
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLTs) present in the human airways and are responsible for bronchoconstriction, sputum production, vascular permeability, and eosinophil recruitment. CysLTs have been implicated in the pathophysiology of asthma and allergic rhinitis. In allergic rhinitis, cysteinyl leukotrienes are released from the nasal mucosa after allergen exposure during the early and late phases of the reaction and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is an intranasal active compound that binds to CysLT1 receptors with high affinity and selectivity. Montelukast causes significant blockade of airway cysteinyl leukotriene receptors, which was confirmed by its ability to inhibit bronchoconstriction in patients with bronchial asthma induced by inhalation of LTD4.
Montelukast inhibits bronchoconstriction, due to inhaled LTD4 even at a dose of up to 5 mg. Bronchodilation is observed within 2 hours after oral administration. The bronchodilating effect caused by the β-agonist is additive to that caused by montelukast. Treatment with montelukast inhibited the early and late phases of bronchoconstriction due to the effect on antigens. Montelukast reduces peripheral blood eosinophils. Treatment with montelukast significantly reduces the number of eosinophils in the airways (when measured in sputum) and in the peripheral blood, while improving clinical control of asthma.
In studies in adults, montelukast 10 mg demonstrated significant improvements in morning FEV1, morning peak expiratory flow rate, and a significant reduction in total β-agonist use. Improvement in patient-reported daytime and night-time asthma symptoms was significantly greater.
Pharmacokinetics.
Absorption.
Montelukast is rapidly absorbed after oral administration. For 10 mg film-coated tablets taken on an empty stomach, mean peak plasma concentrations (Cmax) are achieved 3 hours (Tmax) after administration in adults under fasted conditions. Mean bioavailability is 64% with a standard meal. Mean bioavailability and Cmax are independent of a standard meal. The efficacy and safety of this dosage form have been demonstrated in clinical studies in which 10 mg film-coated tablets were administered without regard to food intake.
Distribution.
More than 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 L. Studies with radiolabeled montelukast have shown minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled montelukast 24 hours after administration were minimal in all other tissues.
Biotransformation.
Montelukast is almost completely metabolized. In studies of therapeutic doses, steady-state plasma concentrations of montelukast metabolites in adults and children could not be determined.
In vitro studies using human liver microsomes have shown that cytochromes P450 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Further in vitro results using human liver microsomes have shown that therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Breeding.
The plasma clearance of montelukast averages 45 mL/min in healthy adult subjects.
After oral administration, 86% of radiolabeled montelukast is excreted in the feces within 5 days, less than 0.2% is excreted in the urine. Taking into account the bioavailability and elimination characteristics, it can be concluded that montelukast and its metabolites are almost completely excreted in the bile.
No dose adjustment is required for elderly patients or patients with mild to moderate hepatic impairment. Since montelukast and its metabolites are almost completely eliminated in the bile, no dose adjustment is required for patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment.
At high doses of montelukast (20-60 times the therapeutic dose), a decrease in theophylline plasma concentrations was observed. This effect was not observed at therapeutic doses.
Indication
· As an additional treatment for bronchial asthma in patients with mild to moderate persistent asthma inadequately controlled with inhaled corticosteroids, and in patients whose asthma is not adequately controlled with short-acting β-adrenergic agonists used as needed. In patients with asthma taking Milukant, this drug also relieves symptoms of seasonal allergic rhinitis.
· Prevention of asthma, the dominant component of which is exercise-induced bronchospasm.
· Relief of symptoms of seasonal and perennial allergic rhinitis.
Contraindication
Hypersensitivity to the active substance of the drug or any excipient.
Interaction with other medicinal products and other types of interactions
Montelukast can be used with other drugs for the prevention and chronic treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no clinically important effect on the pharmacokinetics of the following drugs: theophylline, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.
The area under the concentration-time curve (AUC) for montelukast decreased by approximately
40% in subjects taking phenobarbital concomitantly. Montelukast is metabolized by CYP 3A4, 2C8, and 2C9, therefore caution should be exercised, especially in children, when administered 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 with montelukast and rosiglitazone (a marker substrate representing drugs primarily metabolized by CYP 2C8) have shown that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not expected to significantly alter 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 CYP 2C8 and, to a lesser extent, 2C9 and 3A4. In a clinical drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9), gemfibrozil increased the systemic exposure of montelukast in
4.4 times. Usually, dose adjustment of montelukast is not required when used simultaneously with gemfibrozil or other potent CYP 2C8 inhibitors, but in this case, the physician should take into account the possibility of increased adverse reactions.
Based on in vitro studies, no clinically significant drug interactions are expected with less potent CYP 2C8 inhibitors (e.g., trimethoprim). Coadministration of montelukast with itraconazole, a potent CYP 3A4 inhibitor, did not result in a significant increase in systemic exposure to montelukast.
Application features
Patients should be advised never to use Milukant for the treatment of acute asthma attacks and to keep their usual first aid preparations ready for these cases. If an acute attack occurs, a short-acting inhaled β-agonist should be used. Patients should consult their doctor as soon as possible if they require more inhalations of short-acting β-agonists than usual.
Montelukast should not be abruptly substituted for inhaled or oral corticosteroids. There is no evidence to suggest that oral corticosteroids can be reduced while taking montelukast.
In rare cases, patients treated with anti-asthma drugs, including montelukast, may develop systemic eosinophilia, sometimes accompanied by clinical features of vasculitis, consistent with Churg-Strauss syndrome, a condition often treated with systemic corticosteroid therapy. These events are usually, but not always, associated with reduction or discontinuation of oral corticosteroid therapy. It cannot be excluded or established that leukotriene receptor antagonists may be associated with the development of Churg-Strauss syndrome. Therefore, physicians should be alerted to the possibility of eosinophilia, vasculitic rashes, worsening pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop these symptoms should be reevaluated and their treatment regimen should be reevaluated.
Treatment with montelukast does not change the need to avoid aspirin and other nonsteroidal anti-inflammatory drugs in patients with aspirin-sensitive asthma.
Milukant, 10 mg film-coated tablets, contain lactose, therefore patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take it.
Use during pregnancy or breastfeeding
Pregnancy.
Animal studies have not shown any harmful effects of montelukast on pregnancy or embryonal/fetal development.
Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (such as limb defects), which have been rarely reported in postmarketing surveillance worldwide. Most of these women were also taking other asthma medications. A causal relationship between these cases and montelukast has not been established.
When prescribing Milukant to pregnant women, the benefit/risk ratio must be considered.
Breast-feeding.
Studies in rats have shown that montelukast passes into breast milk.
There is no data on the penetration of Milukant into breast milk of breastfeeding women, therefore, it is necessary to consider the benefit/risk ratio when prescribing Milukant during breastfeeding.
Fertility.
In animal studies, montelukast did not affect fertility or reproductive function at systemic exposures that exceeded the clinical systemic exposure by more than 100%.
24 times.
Ability to influence reaction speed when driving vehicles or other mechanisms
Milukant usually does not affect the ability to drive or use machines, but in very rare cases drowsiness or dizziness have been reported in patients taking the drug, so you should refrain from driving or using other machinery while taking the drug.
Method of administration and doses
The dose for patients (aged 15 years and over) with asthma or with asthma and concomitant seasonal allergic rhinitis is 10 mg (1 tablet) per day, in the evening. The time of administration should be selected individually to relieve the symptoms of allergic rhinitis.
No dose adjustment is required for patients with mild or moderate hepatic impairment. No data are available for dose adjustment in patients with severe hepatic impairment. No dose adjustment is required for elderly patients.
General recommendations
The therapeutic effect of Milukant on asthma control parameters is observed for
1 day. The drug can be used without regard to meals. Patients should be advised to continue taking the drug even if their asthma is under control, as well as during periods of worsening asthma.
Milukant should not be used at the same time as other medications that contain the same active ingredient, montelukast.
No dose adjustment is required for elderly patients. No dose adjustment is required for patients with renal insufficiency, mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. The dosage for male and female patients is identical.
Treatment with Milukant compared to other asthma treatments
Milukant can be added to a patient's existing treatment regimen.
Inhaled corticosteroids
Treatment with Milukant can be used as add-on therapy for patients when inhaled corticosteroids together with short-acting β-agonists as needed do not provide adequate clinical control of asthma.
Inhaled corticosteroids should not be abruptly replaced with Milukant.
Children.
Milukant, 10 mg film-coated tablets, should be used in children aged from
15 years. For children under 15 years of age, use 4 mg and 5 mg chewable tablets according to the child's age.
Overdose
There is no specific information on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies, up to 900 mg/day for approximately 1 week, without clinically significant adverse reactions.
In post-marketing use and during clinical studies, there have been reports of acute overdose, including reports of adults and children taking the drug in doses exceeding 1000 mg (approximately 61 mg/kg in children aged 42 months). In most reports of overdose, no adverse events were observed. The most common manifestations of side effects were consistent with the safety profile of the drug and included: abdominal pain, drowsiness, thirst, headache, vomiting and psychomotor hyperactivity. Treatment is symptomatic. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
Adverse reactions
Milukant is generally well tolerated. In clinical studies, long-term treatment in different age groups demonstrates a consistent safety profile.
Infections and infestations: upper respiratory tract infections.
From the circulatory and lymphatic systems: tendency to increase bleeding.
Immune system disorders: hypersensitivity reactions, including anaphylaxis, eosinophilic infiltration of the liver.
Nervous system: dizziness and lethargy, drowsiness, paresthesia/hypoesthesia, seizures, headache.
Cardiovascular system: palpitations.
Respiratory, thoracic and mediastinal disorders: epistaxis, Churg-Strauss syndrome (CSS).
Gastrointestinal: diarrhea, dry mouth, dyspepsia, nausea, vomiting, abdominal pain.
On the part of the hepatobiliary system: increased serum transaminase levels (ALT, AST), hepatitis, including cholestatic, hepatocellular and mixed type, liver damage.
Skin and subcutaneous tissue disorders: angioedema, hematoma, urticaria, pruritus, rash, erythema nodosum, erythema multiforme.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, including muscle cramps.
General disorders and administration site conditions: fever, asthenia/fatigue, malaise, edema, thirst.
Expiration date
2 years.
Storage conditions
Store in original packaging out of the reach of children.
Packaging
7 tablets in a blister. 4 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Pabianice Pharmaceutical Plant Polfa A.T.
Location of the manufacturer and its business address
St. Marsh. J. Pilsudskiego 5, 95-200, Pabianice, Poland.
