Pharmacological properties
Pharmacodynamics. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids secreted by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CYSLT) found in the human airways and cause reactions such as bronchospasm, sputum production, increased vascular permeability and increased eosinophil numbers.
Montelukast is an active compound that binds with high selectivity and chemical affinity to CysLT 1 receptors. Montelukast causes significant blockade of airway cysteine leukotriene receptors, which was confirmed by its ability to inhibit bronchoconstriction in patients with bronchial asthma induced by inhalation of LTD 4. Even a low dose of 5 mg causes significant blockade of LTD 4-induced bronchoconstriction. Montelukast causes bronchodilation within 2 hours after oral administration; this effect was additive to the bronchodilation caused by agonists and β-blockers.
In adult patients and children aged 2-14 years, montelukast reduces peripheral blood eosinophil counts and improves clinical control of asthma compared with placebo.
In studies in adults, montelukast 10 mg once daily demonstrated significant improvements in morning forced expiratory volume, morning peak expiratory flow, and a significant reduction in total β-agonist use compared with placebo. Patient-reported reductions in daytime and nighttime asthma symptoms were significantly greater than placebo.
Studies in adults have demonstrated the ability of montelukast to add to the clinical effects of inhaled corticosteroids. Compared with inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast demonstrated a more rapid initial response, although beclomethasone resulted in a greater mean therapeutic effect over the 12-week study. However, a greater number of patients treated with montelukast achieved a similar clinical response compared with beclomethasone.
Montelukast and fluticasone also improved asthma control on secondary variables assessed over the 12-month treatment period.
A significant reduction in exercise-induced bronchospasm (EIB) was demonstrated in a 12-week study in adults. This effect was observed throughout the 12-week study period. A reduction in EIB was also demonstrated in a short-term study in children aged 6-14 years. The effect in both studies was demonstrated at the end of the once-daily dosing interval.
Treatment with montelukast suppresses both early and late-stage bronchospasm by reducing the response to antigens. Montelukast, compared with placebo, reduces peripheral blood eosinophil counts in adult and pediatric patients. In a separate study, montelukast significantly reduced airway (sputum) and peripheral blood eosinophil counts, which improved clinical control of asthma.
Pharmacokinetics
Absorption: After oral administration, montelukast is rapidly and almost completely absorbed.
After taking the drug in the form of chewable tablets at a dose of 5 mg on an empty stomach, C max is reached after 2 hours. The average bioavailability is 73% and decreases to 63% after eating.
After taking the drug in the form of chewable tablets at a dose of 4 mg on an empty stomach, C max in children aged 2-5 years is reached after 2 hours. C max is 66% higher, and C min is lower compared to the values obtained for adults when taking 10 mg tablets.
After taking the drug in the form of tablets, 10 mg, C max in blood plasma is reached after 3 hours (Tmax). The average bioavailability is 64%. Taking a regular meal does not affect C max in blood plasma and bioavailability. Safety and efficacy have been demonstrated in clinical studies in groups where film-coated tablets, 10 mg, were taken regardless of food intake.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 L. In animal studies, the passage of radiolabeled montelukast across the blood-brain barrier was minimal. In all other tissues, the concentration of radiolabeled material was also minimal 24 hours after dosing.
Metabolism: Montelukast is extensively metabolized. Steady-state plasma concentrations of montelukast metabolites have not been determined in studies with therapeutic doses in adults and pediatric patients.
Elimination: The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% is excreted in the feces within 5 days and less than 0.2% in the urine. This, together with the oral bioavailability of montelukast, indicates that its metabolites are almost entirely excreted in the bile.
Pharmacokinetics in different patient groups. No dose adjustment is required for elderly patients and patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are excreted in the bile, dose adjustment is not considered necessary for patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).
At high doses (20 and 60 times the recommended adult dose), montelukast decreased plasma theophylline concentrations. This effect was not observed at the recommended dose of 10 mg once daily.
Indication
Montelukast-Teva 4 mg chewable tablets are recommended for children aged 2-5 years; Montelukast-Teva 5 mg chewable tablets are recommended for children aged 6-14 years:
as an additional treatment for bronchial asthma in patients with persistent mild to moderate asthma, which is not adequately controlled by inhaled corticosteroids, as well as in cases of insufficient clinical control of asthma with short-acting β-adrenoceptor agonists used as needed; as an alternative treatment to low doses of inhaled corticosteroids in patients with persistent mild asthma, who have not recently had serious asthma attacks requiring oral corticosteroids, as well as for those patients who are intolerant to inhaled corticosteroids; prophylactically before physical exertion to prevent an asthma attack.
Montelukast-Teva, tablets 10 mg. Additional treatment of persistent mild to moderate asthma, which is not adequately controlled by inhaled corticosteroids, as well as with insufficient clinical control of asthma with short-acting β-adrenergic agonists used as needed.
Symptomatic treatment of seasonal allergic rhinitis in patients with bronchial asthma.
For the prevention of asthma attacks caused by physical exertion.
Application
Montelukast-Teva, chewable tablets, 4 or 5 mg. The drug should be used in children under adult supervision.
Children aged 2-5 years. The recommended dose is 1 chewable tablet of 4 mg/day, in the evening. Montelukast-Teva is taken 1 hour before or 2 hours after a meal. Individual dose adjustment is not required for patients in this group.
Children aged 6-14 years. The recommended dose is 1 chewable tablet of 5 mg/day, in the evening. Montelukast-Teva is taken 1 hour before or 2 hours after a meal. Individual dose adjustment is not required for patients in this group.
For patients over 15 years of age, Montelukast-Teva, film-coated tablets, 10 mg, is recommended.
Montelukast-Teva, film-coated tablets, 10 mg. Montelukast-Teva can be taken with or without food.
The recommended dose for patients aged 15 years and older is 1 tablet of 10 mg/day, in the evening.
General recommendations. The therapeutic effect of Montelukast-Teva on asthma control indicators is manifested within 1 day. Patients are advised to continue using Montelukast-Teva, even if asthma is under control, as well as during its exacerbation.
It is not recommended to use Montelukast-Teva simultaneously with other drugs that contain the same active ingredient - montelukast.
No dose adjustment is required in patients with renal insufficiency or mild to moderate hepatic impairment. There are no data on the use of the drug in patients with severe hepatic impairment.
The dosage is the same for men and women.
Alternative therapy with low-dose inhaled corticosteroids in patients with mild persistent asthma. Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment with low-dose inhaled corticosteroids in children with mild persistent asthma is recommended only for patients who have not had a recent serious asthma attack requiring oral corticosteroids and who are intolerant to inhaled corticosteroids. Mild persistent asthma is asthma with symptoms more than once a week, but less than once a day, nocturnal attacks more than 2 attacks per month, but less than 1 time per week, between attacks - normal lung function is preserved.
Prevention of exercise-induced asthma. In children, exercise-induced bronchospasm may be a dominant feature of persistent asthma and requires treatment with inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with Montelukast. If a satisfactory response to therapy is not achieved, additional therapy should be considered.
Montelukast-Teva treatment in relation to other methods of treatment of asthma. Montelukast-Teva therapy can be added to the patient's existing treatment regimen. Montelukast-Teva treatment can be used as an adjunct when other drugs, such as inhaled corticosteroids used as needed, do not provide adequate clinical control of asthma. When montelukast treatment is an adjunct therapy to inhaled corticosteroids, Montelukast-Teva should not be abruptly replaced by inhaled corticosteroids.
Children: The chewable tablet form is not recommended for use in children under 2 years of age. The 10 mg film-coated tablet form is not recommended for use in children under 15 years of age.
Contraindication
Hypersensitivity to montelukast or to any component of the drug.
Montelukast-Teva, chewable tablets, 4 or 5 mg: children up to 2 years of age.
Montelukast-Teva, film-coated tablets, 10 mg: children up to 15 years of age.
Side effects
Adverse reactions reported during clinical trials
Central nervous system: headache.
General: feeling thirsty.
On the part of the digestive system: abdominal pain.
The following adverse reactions have been reported in the post-marketing period:
Infections and infestations: upper respiratory tract infections.
From the hematopoietic system: increased tendency to bleeding.
Immune system disorders: hypersensitivity, including anaphylaxis, eosinophilic infiltration of the liver.
Psychiatric disorders: sleep disorders including nightmares, hallucinations, disorientation, insomnia, somnambulism, psychomotor hyperactivity (irritability, restlessness, agitation including aggressive behavior or hostility, tremor), depression, suicidal thoughts and behavior (suicide attempts).
From the side of the central nervous system: lethargy and dizziness, drowsiness, paresthesia / hypoesthesia, convulsions.
Cardiovascular system: palpitations.
Respiratory system: epistaxis.
On the part of the digestive system: diarrhea, dry mouth, dyspepsia, nausea, vomiting.
On the part of the hepatobiliary system: increased levels of blood plasma transaminases (ALT, AST), hepatitis (including cholestatic, hepatocellular and mixed liver damage).
Skin and subcutaneous tissue disorders: angioedema, hematoma, urticaria, pruritus, rash, erythema, erythema multiforme.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, including muscle cramps.
General: asthenia/fatigue, fever, malaise, edema.
During treatment with montelukast in patients with asthma, the occurrence of Churg-Strauss syndrome has been described.
Special instructions
Patients should be advised that montelukast should not be used for the relief of acute attacks of BA. It is recommended that treatment with the usual appropriate medication for the relief of attacks be continued. In the event of an acute attack, a short-acting inhaled β-agonist should be used. Patients should consult their doctor as soon as possible if they require more inhalations of a short-acting β-agonist than usual.
Montelukast therapy should not be abruptly replaced with inhaled or oral corticosteroids.
There is no evidence to suggest that oral corticosteroids can be reduced with concomitant use of montelukast.
Neuropsychiatric events have been reported in patients taking Montelukast (see Adverse Reactions). Because these events may be influenced by other factors, it is not known whether they are related to Montelukast. Physicians should discuss these adverse events with their patients and/or caregivers. Patients and/or caregivers should be instructed to report any such changes to their physician.
In rare cases, patients receiving anti-asthma drugs, including montelukast, may experience systemic eosinophilia, sometimes with clinical manifestations of vasculitis, the so-called Churg-Strauss syndrome (granulomatous allergic angiitis), which is treated with systemic corticosteroids. Such cases are usually (but not always) associated with a dose reduction or discontinuation of GCS therapy. The possibility that leukotriene receptor antagonists may be associated with the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed, so physicians should be alerted to the possibility of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and/or neuropathy in patients. Patients who develop the above symptoms should be re-examined and their treatment regimen should be reviewed.
Treatment with montelukast does not allow patients with aspirin-dependent asthma to use acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.
Monetukast-Teva in the form of film-coated tablets, 10 mg, should not be used in patients with rare hereditary diseases: galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy: Animal studies have not shown adverse effects on pregnancy or fetal development.
Limited data from global marketing experience have not revealed a causal relationship between isolated cases of congenital limb defects in children whose mothers took montelukast during pregnancy and taking the drug.
Montelukast-Teva can be taken during pregnancy only if, in the opinion of the doctor, the expected benefit to the mother outweighs the possible risk to the fetus.
Breastfeeding: Animal studies have shown that montelukast is excreted in human milk. It is not known whether montelukast is excreted in human milk.
Therefore, Montelukast-Teva can be taken during breastfeeding when, in the opinion of the doctor, the expected benefit to the mother outweighs the possible risk to the child.
Ability to influence the speed of reactions when driving vehicles or using other mechanisms. Montelukast is not expected to affect the ability to drive vehicles or operate other mechanisms. However, in very rare cases, dizziness or drowsiness may occur in individual patients.
Interactions
Montelukast-Teva can be prescribed together with other drugs for the prevention or long-term treatment of BA. In drug interaction studies, the recommended dose of montelukast had no clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol / norethindrone 35/1), terfenadine, digoxin, and warfarin.
In patients receiving concomitant phenobarbital, the AUC of montelukast was decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution should be exercised, especially in children, when montelukast is 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, data from a clinical drug interaction study involving montelukast and rosiglitazone (a drug metabolized by CYP 2C8) have shown 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 shown that montelukast is a substrate of CYP 2C8 and, to a lesser extent, 2C9 and 3A4. In a clinical drug interaction study with montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No dose adjustment of montelukast is required when gemfibrozil or other potent inhibitors of CYP 2C8 are administered, but the physician should consider the increased risk of adverse reactions.
Based on in vitro studies, no clinically significant 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.
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, with no clinically significant adverse reactions.
Acute overdose of montelukast has been reported in post-marketing experience and in clinical trials. These data include doses in excess of 1000 mg (approximately 61 mg/kg, 42-month-old child) in adults and children. The clinical and laboratory data obtained were consistent with the safety profile in adults and children.
In most reports of overdose, no adverse effects were observed. The most frequently reported adverse effects were consistent with the safety profile of the drug and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.
It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis. Treatment is symptomatic.
Storage conditions
Montelukast-Teva, chewable tablets, 4 or 5 mg: at a temperature not exceeding 30 °C in the original packaging to protect from light.
Montelukast-Teva, film-coated tablets, 10 mg: does not require any special storage conditions.
