INSTRUCTIONS FOR MEDICAL USE
ASTANOL
Trade name of the drug: Astanol
Active substance (INN): Montelukast
Pharmaceutical form: Chewable tablets.
Contents:
1 tablet contains:
The active ingredient:
4 mg chewable tablet: 4.16 mg montelukast sodium (equivalent to 4 mg montelukast).
Chewable tablet 5 mg: 5.20 mg montelukast sodium (equivalent to 5 mg montelukast).
Excipients: mannitol, microcrystalline cellulose, polyvinylpyrrolidone, red iron oxide, croscarmellose sodium, orange flavoring for 4 mg tablets only, sodium saccharin, magnesium stearate.
Description:
4 mg tablets: flat-cylindrical beveled tablets, with a ridge on one side of a light pink to pink-cherry color with flecks of white and dark color with slight marbling.
5 mg tablets: round biconvex tablets from light pink to pinkish-cherry color with spots of white and dark color.
Pharmacotherapeutic group: leukotriene receptor antagonist, agent for treatment of bronchial asthma and allergic rhinitis.
ATX code: R03DC03
Pharmacological action
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are effective inflammatory eicosanoids that are released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotrienes receptors (CysLT) present in the human airways and result in bronchospasm, sputum secretion, changes in vascular permeability, and mobilization of eosinophils.
Montelukast is a drug with oral activity that binds to the CysLTl receptor with a high degree of affinity and selectivity. In clinical studies, montelukast inhibited bronchospasm when LTD4 was inhaled at very low doses (5 mg). Bronchodilation was observed within 2 h after oral administration.
The beta-agonist-induced bronchodilation effect was in addition to the effects of montelukast. The use of montelukast inhibited the early and late phases of bronchospasm induced by antigen administration. Montelukast compared to placebo reduced the number of eosinophils in the peripheral blood of adult patients and children. In a separate study, the use of montelukast significantly reduced the number of eosinophils in the airways (sputum) and in peripheral blood and improved control of the clinical course of bronchial asthma. In adult patients and children aged 2 to 14 years, montelukast reduced peripheral blood eosinophil counts and improved control of the clinical course of the disease compared to placebo. In studies in adult patients, montelukast (10 mg once daily) significantly improved morning FEV1 (forced expiratory volume) (10.4% versus 2.7% for baseline), PEFR (maximum expiratory volume rate) in the morning (24.5 versus 3.3 L/min for baseline) compared with placebo and significantly reduced beta-agonist requirement (-26.1% versus -4.6% at baseline). Improvement of daytime and nighttime bronchial asthma symptoms as assessed by patients was significantly more pronounced in the group of patients receiving the drug compared to the placebo group.
Studies in adult patients demonstrated the ability of montelukast to enhance the clinical impact of inhaled glucocorticosteroids (% change from baseline for inhaled beclomethasone combined with montelukast versus taking beclomethasone alone: FEV1: 5.43% versus 1.04%; beta agonist use: -8.70% versus 2.64%). Compared with inhaled beclomethasone (200 mcg 2 times/day), montelukast demonstrated a faster baseline response, although beclomethasone had a more pronounced therapeutic effect throughout the 12-week study (% change from baseline for montelukast versus beclomethasone respectively for FEV1:7.49% versus 13.3%; beta-agonist use: -28.28%) versus -43.89%). However, when compared with beclomethasone, the proportion of patients taking montelukast who achieved a similar clinical response was quite substantial (for example, 50% of patients in the beclomethasone group achieved an improvement in FEV1 of about 11% or more relative to baseline, whereas about 42% of patients in the montelukast group had the same response).
In a 12-week placebo-controlled study in children aged 2 to 5 years, montelukast 4 mg taken once daily improved bronchial asthma symptom control compared with placebo, despite concomitant anti-asthmatic therapy (inhaled/nebulized glucocorticosteroids or inhaled/nebulized sodium cromoglycate). 60% of patients did not receive concomitant control therapy. Montelukast reduced the severity of daytime (including cough, wheezing, difficulty breathing, and activity limitation) and nighttime bronchial asthma symptoms compared with placebo. Montelukast compared to placebo reduced the need for beta-agonists and glucocorticosteroids used when necessary (for worsening conditions). Patients who received montelukast had a longer remission than patients in the placebo group. The therapeutic effect was noted after the first dose.
In a 12-month placebo-controlled study conducted in children aged 2 to 5 years with mild bronchial asthma and episodic exacerbations, montelukast 4 mg when taken once daily significantly (p<0.001) reduced the frequency of bronchial asthma exacerbations (EAs) compared to placebo (1, 60 UU vs. 2.34 UU, respectively) [an exacerbation episode was defined as a period >3 consecutive days with daily bronchial asthma symptoms requiring hospitalization or use of a beta agonist or oral/inhaled glucocorticosteroids]. The reduction in the frequency of bronchial asthma exacerbation episodes was 31.9% with a 95% confidence interval of 16.9 and 44.1. In an 8-week study in children aged 6-14 years, montelukast 5 mg, taken once daily, significantly improved respiratory function compared with placebo (FEV1: 8.71% versus 4.16% relative to baseline; PEFR in the morning: 27.9 versus 17.8 l/min versus baseline) and reduced beta-agonist requirement (-11.7% versus +8.2% relative to baseline). In a 12-month study comparing the effectiveness of montelukast and inhaled fluticasone for bronchial asthma symptom control in children aged 6 to 14 years with mild persistent bronchial asthma, montelukast was as effective as fluticasone in increasing the number of days without asthma symptoms (RFD). On average, over the 12-month treatment period, the percentage of RFD increased from 61.6 to 84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The difference between the groups (mean increase in percent RFD, leveled by least squares) was -2.8 with a 95% confidence interval of -4.7 to -0.9. Montelukast and fluticasone improved control of the following bronchial asthma-related indices during the 12-month treatment period: – FEV1 increased from 1.83 to 2.09 L in the Montelukast group and from 1.85 to 2.14 L in the fluticasone group. The difference between the groups (mean FEV1 increase, aligned by the least-squares method) was -0.02 l with a 95% confidence interval of -0.06 to 0.02. The mean percentage increase in FEV1 relative to baseline was 0.6% for montelukast and 2.7%) for fluticasone. The difference in percentage FEV1 between groups (mean increase, adjusted by least squares method) was – 2.2% with a 95% confidence interval of -3.6 to -0.7; – The number of days with beta-agonists decreased from 38.0% to 15.4% in the montelukast group and from 38.5% to 12.8% in the fluticasone group. The difference in the number of days with beta-agonist use between the groups (mean, adjusted by least squares) was 2.7 with a 95% confidence interval of 0.9 to 4.5; – bronchial asthma attacks (an asthma attack is defined as a period of worsening asthma symptoms during which an oral GCS, an unplanned visit to a doctor/emergency room or hospitalization is required) were reported in 32.2% of patients in the montelukast group and in 25.6% of patients in the fluticasone group the relative risk was 1.38 (with a 95% confidence interval of 1.04 to 1.84); – systemic (predominantly oral) GCS during the study were taken by 17.8% of patients in the montelukast group and 10. 5% of patients in the fluticasone group. The difference in the mean, adjusted by the least squares method, between the groups was 7.3% with a 95% confidence interval of 2.9 to 11.7. Significant attenuation of exercise-induced bronchospasm (EIB) was demonstrated in a 12-week study in adult patients (maximum FEV1 drop of 22.33% for montelukast vs. 32.40% for placebo; time to return FEV1 to baseline ±5%: 44.22 min vs. 60.64 min for placebo). The effect remained unchanged over the entire 12-week period. EIB attenuation was also found in a short-term study in children 6 to 14 years old (maximum FEV1 drop of 18.27%) versus 26.11%; time to return FEV1 to baseline ±5%: 17.76 min versus 27.98 min). The effect in both studies was achieved at the end of the medication interval once a day.
In asthmatic patients sensitive to aspirin (acetylsalicylic acid) and receiving concomitant therapy with inhaled and/or oral glucocorticosteroids, treatment with montelukast versus placebo resulted in a significant improvement in bronchial asthma symptom control (FEV1 8.55% versus -1.74% relative to baseline and a reduction in total beta-agonist requirement of -27.78% versus 2.09% relative to baseline).
Pharmacokinetics
Absorption
Montelukast is rapidly absorbed after oral administration.
Cmax is reached in adult patients 2 hours after their fasting dose. On average, the bioavailability is 73%; it decreases to 63% when the drug is taken after a standard meal.
Distribution
Montelukast is more than 99% bound to plasma proteins. The volume of distribution of montelukast in equilibrium is on average 8-11 liters. Studies with labeled montelukast in rats have demonstrated minimal penetration of the drug through the blood-brain barrier. Concentrations of labeled material 24 hours after administration of the drug were minimal in all other tissues.
Biotransformation
Montelukast undergoes extensive metabolism. In studies with therapeutic doses, stable plasma concentrations of montelukast metabolites were not detected in adults and children.
In vitro studies on human liver microsomes demonstrated that cytochromes P450 ZA4, 2A6, and 2C9 are involved in the metabolism of montelukast. Subsequent in vitro studies on human liver microsomes found that therapeutic plasma concentrations of montelukast did not inhibit cytochromes P450 WA4, 2C9, 1A2, 2A6, 2C19 and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Excretion
Plasma clearance of montelukast in healthy adults averages 45 ml/minute. After ingestion of labeled montelukast, 86%> of the drug was excreted within 5 days by the intestine and <0.2% by the kidneys. Together with the calculated bioavailability of montelukast after oral administration, these results indicate that the drug and its metabolites are excreted primarily with the bile.
Pharmacokinetics in special patient groups
Elderly patients
No dose adjustment is required for elderly patients.
Patients with impaired renal function
Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are excreted with bile, no dose adjustment is required for patients with renal impairment.
Patients with impaired liver function
No dose adjustment is required for patients with mild to moderate hepatic impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score > 9).
Indications for use
- as adjunctive therapy for persistent mild to moderate bronchial asthma in patients whose disease is not controlled by inhaled glucocorticosteroids and whose short-acting beta agonists, if necessary, fail to produce the desired clinical effect;
- alternative therapy with low-dose inhaled glucocorticosteroids for patients with mild-to-moderate persistent bronchial asthma without a history of severe attacks that require oral glucocorticosteroids;
- For patients unable to use inhaled glucocorticosteroids;
- prevention of bronchial asthma, the predominant component of which is bronchospasm that occurs against the background of physical activity.
Dosage and administration
Dose for children aged 2-5 years:
1 chewable tablet 4 mg daily in the evening, 1 h before or 2 h after a meal.
No dose adjustment is required within this age group.
Dose for children aged 6-14 years:
1 chewable tablet 5 mg daily in the evening 1 h before or 2 h after a meal.
No dose adjustment is required within this age group.
General Recommendations:
The therapeutic effect of the drug on the symptoms associated with bronchial asthma is apparent within one day. The patient should continue taking the drug both in periods of controlled bronchial asthma course and in periods of worsening of the disease course. The dose of the drug is the same for female and male patients.
Montelukast as an alternative therapy to low-dose inhaled glucocorticosteroids in mild persistent bronchial asthma: the drug is not recommended for monotherapy in patients with moderately severe persistent bronchial asthma. The use of the drug in the form of chewable tablets in children with mild-to-moderate persistent bronchial asthma as an alternative therapy to low-dose inhaled glucocorticosteroids should be considered only for those patients who in the recent past have not had serious asthma attacks that require taking oral glucocorticosteroids, or those patients who are unable to use inhaled glucocorticosteroids. Persistent bronchial asthma of mild severity refers to bronchial asthma symptoms that occur more frequently than once a week but less frequently than once a day; symptoms that occur at night more frequently than twice a month but less frequently than once a week with normal lung function between events. If satisfactory control of bronchial asthma symptoms is not achieved during the physician’s follow-up period (usually one month), consideration should be given to the need for additional or other anti-inflammatory treatment based on stepwise bronchial asthma therapy. Patients are followed up periodically to monitor bronchial asthma symptoms.
Therapy with montelukast in combination with other drugs for the treatment of bronchial asthma:
If the drug is prescribed against the background of taking inhaled glucocorticosteroids, montelukast should not be abruptly replaced with inhaled glucocorticosteroids.
Use in patients with impaired renal function.
No dose adjustment is required in patients with renal impairment.
Administration in patients with hepatic dysfunction
No dose adjustment is required in patients with mild to moderate hepatic impairment. No data is available for patients with severe hepatic impairment.
Administration in children and adolescents
For children aged 6 to 14 years old chewable tablets of 5 mg are used.
For children aged 6 to 14 years old the drug is indicated in form of chewable tablets 5 mg,
For children aged 2 to 5 years old – in form of chewable tablets 4 mg.
Safety and efficacy of the preparation in form of chewable tablets 4 mg for children under 2 years of age has not been established.
Side effects
The following adverse reactions have been described in clinical studies, which were commonly (>1/100, <1/10) observed in patients with bronchial asthma who received montelukast with a higher frequency of occurrence compared to patients in the placebo group:
| Organs and systems | Adult patients 15 years of age and older (two 12-week studies; n=795) | Pediatric patients aged 6-14 years (one 8-week follow-up; n=201) (two 56-week follow-ups; n=615) | Pediatric patients aged 2-5 years (one 12-week study; n=461) (one 48-week study; n=278) |
| Nervous system disorders | Headache | Headache | |
| Gastrointestinal disorders | Abdominal pain | Organs and systems |
There was no change in the safety profile of the drug during long-term treatment in clinical trials with a limited number of patients (up to 2 years for adults and up to 6 months for patients aged 6-14 years).
The following adverse reactions were identified during the post-marketing study:
Blood and lymphatic system disorders: increased susceptibility to bleeding.
Immune system disorders: hypersensitivity reactions, including anaphylaxis; eosinophilic liver infiltrates.
Mental disorders: sleep disorders, including nightmares, hallucinations, psychomotor hyperactivity (including irritability, restlessness, agitation, including aggressive behavior, and tremor), depression and insomnia.
Nervous system disorders: drowsiness, dizziness, paresthesia/hyperesthesia, seizures.
Cardiovascular system disorders: palpitations.
Gastrointestinal disorders: diarrhea, dry mouth, dyspepsia, nausea and vomiting.
Hepatobiliary system disorders: increased serum transaminases (alanine aminotransferase, aspartate aminotransferase), cholestatic hepatitis.
Skin disorders: angioedema, ecchymosis, urticaria, itching, rash.
Musculoskeletal system disorders: arthralgia, myalgia, including muscle spasms.
In very rare cases, against the background of taking Montelukast, patients suffering from bronchial asthma develop Churg-Strauss syndrome.
Contraindications
Hypersensitivity to the active or excipients. Childhood under 2 years of age.
Drug interaction
Montelukast can be used together with other drugs traditionally prescribed for the prevention and long-term treatment of bronchial asthma. In the studies to identify interactions, montelukast in recommended doses had no clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin and warfarin. The plasma AUC of montelukast was decreased by approximately 40% in patients who were taking montelukast and phenobarbital. Since CYP3A4 is involved in metabolism of montelukast, caution should be exercised, especially in children, when using montelukast with such CYP3A4 inducers as phenytoin, phenobarbital and rifampicin. In in vitro studies it was found that montelukast is a potent inhibitor of CYP2C8. However, the results of clinical interaction studies of montelukast and rosiglitazone (an example of marker substrates for drugs whose main metabolism is carried out by the CYP2C8 enzyme) have not shown an inhibitory effect of montelukast on CYP2C8 in vivo. Therefore, it is expected that montelukast will not significantly alter the conversions of drugs that are metabolized with participation of this enzyme (e.g., paclitaxel, rosiglitazone and repaglinide).
Special Indications
Patients should not take the drug to relieve acute attacks of bronchial asthma; a suitable promptly effective, readily available antiasthmatic agent should be available for this purpose. Inhaled beta-agonists are recommended when an attack occurs. If the need for short-acting beta-agonists increases, patients should see their physician as soon as possible. Inhaled or oral glucocorticosteroids should not be abruptly replaced with a drug in the form of chewable tablets. Inhaled or oral glucocorticosteroids should not be abruptly replaced with a drug in tablet form. There is no evidence to suggest that the dose of oral glucocorticosteroids may be reduced with concomitant use of the drug. In rare cases, systemic eosinophilia may occur in patients taking bronchial asthma drugs, including montelukast, sometimes accompanied by clinical manifestations of vasculitis and Churg-Strauss syndrome; in this case systemic glucocorticosteroids are used. Such cases are usually, but not always, associated with dose reduction or withdrawal of oral glucocorticosteroids. The possibility that taking leukotriene receptor antagonists may be associated with the occurrence of Churg-Strauss syndrome cannot be excluded or confirmed. Physicians should be aware of the possibility of eosinophilia, vasculitic rash, increased pulmonary symptoms, cardiac complications, and/or neuropathy in their patients. Patients with the above symptoms should be reevaluated and their treatment regimens should be reviewed.
It is assumed that the drug does not affect the ability of patients to drive or operate other mechanisms. However, caution should be exercised, since during treatment in very rare cases drowsiness has been noted in patients.
Indications during pregnancy and lactation
Pregnancy
Limited information in pregnancy databases does not suggest a causal relationship between montelukast and birth defects (e.g., limb defects), which are rarely identified in global post-marketing studies. The drug should only be used in pregnancy if absolutely necessary. There are no data on excretion of montelukast with breast milk.
Lactation
During breast-feeding the drug may be used only in case of extreme necessity.
Overdose
Symptoms: abdominal pain, drowsiness, thirst, headache, vomiting, psychomotor hyperactivity.
Treatment: symptomatic. There are no data on the possibility of Montelukast excretion by peritoneal dialysis or hemodialysis.
Form of production
Chewable tablets 4 mg and 5 mg in carton packs.
Storage conditions
Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!
Shelf life
3 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies
Released by a doctor’s prescription.