Montelukast Sodium Chewable Tablets Instructions

Montelukast Sodium Chewable Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name
Generic Name: Montelukast Sodium Chewable Tablets
English Name: Montelukast Sodium Chewable Tablets
Hanyu Pinyin：Menglusitena Jujuepian
Ingredients
The main ingredient of this product is Montelukast Sodium.
Chemical Name: Sodium [R-(E)]-1-[[[1-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetate
Chemical structure formula.
Molecular formula: C35H35ClNNaO3S
Molecular weight: 608.18
【Properties】.
This product is 4mg as a pink square tablet with rounded corners and “4” engraved on one side; 5mg as a pink oval tablet with “5” engraved on one side.
Indications
This product is indicated for the prevention and long-term treatment of asthma in children between the ages of 2 and 14 years, including the prevention of daytime and nighttime asthma symptoms in patients with aspirin-sensitive asthma and the prevention of exercise-induced bronchoconstriction.
This product is indicated for the relief of symptoms caused by allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis in children aged 2 to 14 years).
Specification
Specification
4mg (as montelukast); 5mg (as montelukast).
Dosage]
Once daily. Asthma patients should take it at bedtime. Patients with allergic rhinitis can take the medication at the desired time according to their condition. Patients with both asthma and allergic rhinitis should take the medication once a night.
Pediatric patients aged 6 to 14 years with asthma and/or allergic rhinitis
One tablet (5 mg) once daily.
Patients aged 2 to 5 years with asthma and/or allergic rhinitis
One tablet (4 mg) once daily.
General Recommendations
The efficacy of treatment is evaluated by the asthma control index and the efficacy of this product appears within one day of dosing. This product may be taken with or in addition to food. Patients should be advised to adhere to it regardless of the stage of asthma control or deterioration.
No dose adjustment is required for patients with renal insufficiency, patients with mild to moderate hepatic impairment, and patients of different genders.
Relationship of Montelukast Sodium Chewable Tablets with other asthma treatment medications
This product may be added to a patient’s existing treatment regimen.
Dose reduction for combined medications.
Bronchodilators
Patients with asthma that is not effectively controlled with bronchodilators alone may have this product added to their regimen and the dose of bronchodilator may be reduced once there is a clinically efficacious response (usually occurring after the first dose), depending on how well tolerated the patient is.
Inhaled glucocorticosteroids
The dose of glucocorticosteroids may be reduced in patients with asthma treated with inhaled glucocorticosteroids according to the patient’s tolerance. The dose should be tapered under the guidance of a physician. In some patients, inhaled glucocorticosteroids may be tapered until they are completely discontinued. However, this product should not be used as an abrupt substitute for inhaled glucocorticosteroids or as prescribed by the physician.
Adverse reactions
This product is generally well tolerated, and adverse reactions are mild and usually do not require discontinuation of therapy. The overall incidence of adverse reactions with the original montelukast sodium chewable tablets was similar to that with placebo.
Pediatric Asthma Patients 6 to 14 Years of Age
Clinical studies have been conducted to evaluate the safety of prodrug montelukast sodium chewable tablets in approximately 475 pediatric patients between the ages of 6 and 14 years. Overall, the safety profile of the original montelukast sodium chewable tablets in pediatric patients was similar to that of adults and was close to that of placebo.
In an 8-week placebo-controlled clinical study, the only drug-related adverse event that occurred >1% more frequently in the prodrug montelukast sodium chewable group than in the placebo group was headache. However, there was no significant difference in the incidence of headache between the two groups.
In clinical studies evaluating the effect on growth rate, the safety profile of the original montelukast sodium chewable tablets for pediatric use was consistent with previous descriptions.
Cumulatively, 263 pediatric patients aged 6 to 14 years have been treated with prodrug montelukast sodium chewable tablets for at least 3 months and 164 patients for 6 months or longer. The incidence of adverse events did not change with increasing duration of treatment with prodrug montelukast sodium chewable tablets.
Children 2 to 5 years of age with asthma
The safety of prodrug montelukast sodium chewable tablets has been evaluated in approximately 573 pediatric patients between the ages of 2 and 5 years. In a placebo-controlled 12-week clinical study, the only drug-related adverse event with an incidence >1% and higher than in the placebo group was thirst in the prodrug montelukast sodium chewable treatment group. However, there was no significant difference in the incidence of thirst between the two groups.
Cumulatively, 426 pediatric patients aged 2 to 5 years have been treated with prodrug montelukast sodium chewable tablets for at least 3 months, 230 patients for 6 months or longer, and 63 patients for 12 months or longer. There was no change in the incidence of adverse events with longer treatment with prodrug montelukast sodium chewable tablets.
Pediatric patients aged 2 to 14 years with seasonal allergic rhinitis
The safety of prodrug montelukast sodium chewable tablets has been evaluated in a 2-week placebo-controlled clinical study in 280 patients aged 2 to 14 years with seasonal allergic rhinitis. The once-daily evening dose of prodrug montelukast sodium chewable tablets was well tolerated, with an incidence of adverse reactions similar to that of the placebo group. In this study, the incidence of adverse reactions in the treatment group of prodrug montelukast sodium chewable tablets was less than 1%, and no drug-related adverse reactions were found that occurred at a higher rate than in the placebo group.
Combined analysis of clinical practice
A combined analysis of 41 placebo-controlled clinical studies (35 studies in patients aged 15 years and older; 6 studies in pediatric patients aged 6-14 years) was conducted using a validated assessment of suicidal behavior. Of the 9929 patients taking the original montelukast sodium chewable tablets and 7780 patients taking placebo, one patient with suicidal ideation took the original montelukast sodium chewable tablets. There were no completed suicides, suicide attempts, or preparatory actions against suicidal behavior in either group.
An independent combined analysis of 46 placebo-controlled clinical studies (35 studies in patients aged 15 years and older; 11 studies in pediatric patients aged 3 months to 14 years) was conducted to assess behaviorally relevant adverse events. Among 11,673 patients taking the original montelukast sodium chewable tablets and 8,827 patients taking placebo, the incidence of behavior-related adverse events was 2.73% and 2.27%, respectively; the ratio was 1.12 (95% CI [0.93; 1.36]).
The clinical trials included in these combined analyses were not specifically designed to examine suicide rates or behaviorally related adverse events.
Postmarketing experience
The following adverse reactions have been reported after marketing use of the original montelukast sodium chewable tablets.
Infections and infections: upper respiratory tract infections.
Hematologic and lymphatic disorders: increased bleeding tendency, thrombocytopenia.
Immune system disorders: hypersensitivity reactions including allergic reactions, very rare hepatic eosinophil infiltration.
Psychiatric disorders: including aggressive behavior or hostile arousal, anxiety, depression, loss of directional awareness, inattention, abnormal night dreams, hallucinations, insomnia, memory impairment, psychomotor hyperactivity (including irritability, agitation, and tremors), sleepwalking, suicidal thoughts and behavior (suicide), convulsions.
Neurological disorders: vertigo, drowsiness, sensory abnormalities/hypoesthesia and very rare seizures.
Cardiac disorders: palpitations.
Respiratory, thoracic and mediastinal system disorders: epistaxis; pulmonary eosinophilia.
Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting.
Hepatobiliary disorders: elevated ALT and AST, very rare hepatitis (including cholestatic, hepatocellular and mixed liver damage).
Skin and subcutaneous tissue disorders: angioedema, contusions, erythema multiforme, erythema nodosum, pruritus, rash, Stevens-Johnson syndrome/neutrophilic epidermal necrolysis loosening, urticaria.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle spasms.
Renal and urinary disorders: enuresis in children (occasional).
Other disorders and administration site conditions: debilitation/fatigue, edema, fever.
[Contraindications].
Contraindicated in persons with hypersensitivity to any of the ingredients in this product.
Precautions】
The efficacy of oral administration of this product in the treatment of acute asthma attacks has not been established. Therefore, it should not be used to treat acute asthma attacks. Patients should be advised to prepare appropriate resuscitation medication.
Although the combined inhaled glucocorticosteroid dose may be gradually reduced under the direction of a physician, this product should not be used as an abrupt substitute for inhaled or oral glucocorticosteroids.
In patients receiving anti-asthmatic medications including leukotriene receptor antagonists, one or more of the following have occurred in rare cases: eosinophilia, vascular rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy (sometimes diagnosed as Churg-Strauss syndrome – a systemic eosinophilic vasculitis). These conditions are sometimes associated with the reduction or discontinuation of oral glucocorticoid therapy. Although a causal relationship between these conditions and leukotriene receptor antagonists has not been established, caution and appropriate clinical monitoring of patients taking this product is recommended.
Patients with phenylketonuria should be advised that the 4 mg and 5 mg chewable tablets contain 0.674 and 0.842 mg phenylalanine (a component of aspartame), respectively.
Montelukast may have no effect or a minor effect on the ability to drive and operate machinery. However, there have been isolated reports of drowsiness and dizziness.
Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking prodrug montelukast sodium chewable tablets. Post-marketing reports with prodrug montelukast sodium chewable tablets include euphoria, aggressive behavior or hostility, anxiety, depression, disorientation, attention disorders, dream abnormalities, hallucinations, insomnia, irritability, memory deficits, restlessness, sleepwalking disorder, suicidal thoughts and behaviors (including suicide), seizures, and tremors. Some of the clinical details reported post-marketing about the original montelukast sodium chewable tablets appear to be consistent with drug-induced effects.
Psychoneurological events have been reported in patients taking prodrug montelukast sodium chewable tablets (see Adverse Reactions). Because other factors may also contribute to these events, it is not possible to confirm whether they are related to prodrug montelukast sodium chewable tablets. Physicians should discuss these adverse events with their patients and/or caregivers. Patients and/or caregivers should be advised to notify their physician if these occur.
Patients with known aspirin sensitivity should continue to avoid aspirin or nonsteroidal anti-inflammatory drugs while taking this product.
[For pregnant and lactating women].
There are no studies in pregnant women and this product should be avoided in pregnant women unless clearly required.
Global post-marketing experience has shown that there have been rare reports of congenital limb defects in newborns following the use of the original montelukast sodium chewable tablets during pregnancy. The vast majority of these women also used other asthma treatment medications during pregnancy. A causal relationship between the use of this product and these events has not been established.
It is not clear whether this product can be secreted from breast milk. Because many drugs can be secreted from breast milk, this product should be used with caution in nursing women.
Pediatric Use]
Safety and efficacy studies have been conducted in children 6 months to 14 years of age; safety and efficacy in pediatric patients under 6 months of age have not been studied.
Studies have shown that montelukast sodium chewable tablets do not affect the growth rate of children.
[Geriatric Use].
Not applicable.
Drug Interactions]
This product may be used in combination with other drugs routinely used for the prevention and long-term treatment of asthma and for the treatment of allergic rhinitis. In drug interaction studies, the recommended dose of this product did not produce clinically significant pharmacokinetic effects on the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/ethinyl estradiol 35/1), terfenadine, digoxin, and warfarin.
Thyroid hormones, sedative hypnotics, NSAIDs, benzodiazepines and decongestants: Although no additional specific interaction studies were conducted, there was no evidence of clinical adverse interactions when the original montelukast sodium chewable tablets were combined with common prescription drugs widely used in clinical studies. These medications include thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory drugs, benzodiazepines, and decongestants.
The area under the plasma concentration-time curve (AUC) of montelukast was reduced by approximately 40% in patients who were combined with phenobarbital. Because montelukast is metabolized by CYP 3A4, 2C8, and 2C9, montelukast should be taken with caution with CYP, 3A4, 2C8, and 2C9 inducers (e.g., phenytoin sodium, phenobarbital, rifampin), especially in children. However, dose adjustment of this product is not recommended.
In vitro trials have shown that montelukast is an inhibitor of CYP2C8. However, data from a clinical study of the drug interaction between montelukast and rosiglitazone, a typical probe substrate metabolized primarily by CYP2C8, showed that montelukast did not inhibit CYP2C8 in vivo. Therefore, it is believed that montelukast does not affect drugs that are metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, repaglinide).
In vitro studies have shown that montelukast is a substrate for CYP2C8, 2C9 and 3A4. A clinical study involving drug-drug interactions between montelukast and gemfibezil, an inhibitor of CYP2C8 and 2C8, demonstrated that gemfibezil increased systemic exposure levels of montelukast by 4.4-fold and that itraconazole, a potent inhibitor of CYP3A4, when administered concomitantly with gemfibezil and montelukast did not further increase the systemic exposure level of montelukast. Based on data from clinical safety studies using doses greater than the 10 mg approved in adults (e.g., 200 mg/day given to adult patients for 22 consecutive weeks and 900 mg/day given to patients for approximately 1 consecutive week), no clinically meaningful adverse events were observed and the effect of gemfibezil on systemic exposure levels to montelukast is not considered to be clinically meaningful. Therefore, no dose adjustment of montelukast is required for concomitant administration with gemfibezil. Based on in vitro data, clinically meaningful drug interactions between montelukast and other known CYP2C8 inhibitors (e.g., meperidine) are not expected to occur. In addition, concomitant administration of montelukast with itraconazole alone does not significantly increase systemic exposure levels of the former.
[Drug Overdose].
There are no specific data on overdose of this product in clinical treatment. In studies for the treatment of chronic asthma, no clinically significant adverse events were observed in adult patients using doses up to 200 mg per day for 22 weeks and in short-term studies using doses up to 900 mg per day for approximately 1 week. In the event of an overdose, it is reasonable to take routine supportive measures; for example, removing unabsorbed material from the gastrointestinal tract, implementing clinical monitoring, and, if needed, supportive therapy. Post-marketing acute overdoses have been reported and clinical studies using the original montelukast sodium chewable tablets. These include reports of doses up to 1000 mg in adults and children. Both clinical and laboratory findings have consistently demonstrated safety in both adult and pediatric patients. In the majority of overdose reports, there were no adverse events. The most frequently occurring adverse events consistent with the safety profile included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor overload.
It is not known whether this product can be cleared by peritoneal or hemodialysis.
Pharmacology and Toxicology
Pharmacology
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory mediators that are released by a variety of cells including mast cells and eosinophils. These important asthma pro-mediators bind to cysteinyl leukotriene (CysLT) receptors. type I cysteinyl leukotriene (CysLT1) receptors are distributed in the human airways (including airway smooth muscle cells and airway macrophages) and other pro-inflammatory cells (including eosinophils and certain bone marrow stem cells). cysLTs are associated with the pathophysiological processes of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a range of airway responses, such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil aggregation. In allergic rhinitis, the nasal mucosa releases CysLTs associated with allergic rhinitis symptoms in both the tachyphylaxis and late phase responses following allergen exposure. intranasal CysLTs excitation increases nasal airway resistance and symptoms of nasal obstruction.
This product is a potent oral formulation that significantly improves the inflammatory markers of asthma. Biochemical and pharmacological bioassays show that montelukast has a high affinity and selectivity for CysLT1 receptors (compared to other pharmacologically important airway receptors such as prostaglandin-like, cholinergic and beta-adrenergic receptors). Montelukast effectively inhibits the physiological effects of LTC4, LTD4 and LTE4 binding to CysLT1 receptors without any receptor agonist activity. Current studies suggest that montelukast does not antagonize the CysLT2 receptor.
Toxicology
Acute toxicity
In mice and rats, no mortality occurred at single oral doses of montelukast sodium up to 5,000 mg/kg (15,000 mg/m2 and 29,500 mg/m2 in mice and rats, respectively). This dose is the maximum tested dose (oral LD50> 5,000 mg/kg), which is equivalent to 25,000 times the recommended daily dose for adults*.
Long-term toxicity
Tests were conducted in monkeys and rats for up to 53 weeks, and in young monkeys and mice for up to 14 weeks. The results of the trials showed that montelukast sodium was well tolerated and that a wide range of safe doses were used. When montelukast sodium was administered to any test animal at least 125 times the recommended human dose, no effects on toxicological indices were observed*. No inability to use therapeutic doses of montelukast sodium has been observed in either adult or pediatric patients.
Carcinogenicity
Montelukast sodium was not found to be carcinogenic in studies in rats at oral doses up to 200 mg/kg/day for 106 weeks and in mice at oral doses up to 100 mg/kg/day for 92 weeks. These doses correspond to 1000 and 500 times the recommended adult dose*.
Mutagenicity
Montelukast sodium was not found to be genotoxic or mutagenic. In an in vitro microbial mutation assay and in a V-79 mammalian cell mutation assay, montelukast sodium was negative with or without metabolic activity. No genotoxic effects were observed in the in vitro rat hepatocyte base elution assay and the Chinese hamster ovary cell chromosome aberration assay with or without microsomal enzyme activity system. Similarly, no induction of chromosomal abnormalities in bone marrow cells was observed when montelukast sodium was administered orally to male or female mice at up to 1200 mg/kg (3600 mg/m2) (6000 times the recommended daily adult dose*).
Reproductive toxicity
No effects on fertility or reproduction were observed in studies in male rats given oral doses of montelukast sodium up to 800 mg/kg/day and in female rats given oral doses up to 100 mg/kg/day. These doses were 4000 and 500 times higher than the recommended adult dose, respectively*.
In developmental toxicity studies, no treatment-related adverse effects were observed when montelukast sodium was administered to rats at doses up to 400 mg/kg/day and to rabbits at doses up to 100 mg/kg/day. Fetal exposure to montelukast sodium did occur in rats and rabbits, and montelukast sodium was significantly detected in the milk of lactating rats.
[Pharmacokinetics].
Absorption
Montelukast is rapidly and completely absorbed orally. After taking 5mg chewable tablets on an empty stomach in adults, the plasma drug concentration reached peak concentration (Cmax) in 2 hours. The mean bioavailability was 73%. Food has no clinically important effect on the long-term use of montelukast sodium.
Cmax was reached at 2 hours after administration of 4 mg chewable tablets on an empty stomach in pediatric patients aged 2 to 5 years.
Distribution
More than 99% of montelukast sodium is bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. Studies with isotopically labeled montelukast in rats have shown that only a very small amount of montelukast crosses the blood-brain barrier. Also, the amount of radiolabeled material in all other tissues was minimal at 24 hours post-dosing.
Metabolism
Montelukast is almost completely metabolized. In studies using therapeutic doses, no metabolites of montelukast were measured in plasma under steady-state conditions in adults and children.
In vitro studies using human liver microsomes have shown that cytochrome P450 3A4 and 2C9 are associated with the metabolism of montelukast. Based on the results of further studies with human liver microsomes in vitro, plasma concentrations of montelukast at therapeutic doses did not inhibit cytochrome P450 3A4, 2C9, 1A2, 2Ad6, 2C19 or 2D6.
Excretion
The mean plasma clearance of montelukast in healthy adults was 45 mL/min. Following oral administration of isotopically labeled montelukast, 86% of the radioactivity was detected in stool collected over the following 5 days, and the amount measured in urine <0.2%. Considered in conjunction with the oral bioavailability of montelukast, montelukast and its metabolites are almost entirely excreted via the bile.
Numerous studies in healthy young adults have shown a mean plasma half-life of 2.7 to 5.5 hours for montelukast. The pharmacokinetics of montelukast were approximately linear over the range of oral doses up to 50 mg. No differences were found in the pharmacokinetics of early morning and nighttime administration of montelukast. Only a very small amount of prodrug accumulation (~14%) in plasma was observed with a single daily dose of 10 mg of montelukast.
Special Patients
No dose adjustment is required in the elderly, in patients with renal insufficiency, or in patients with mild to moderate hepatic insufficiency. There are no clinical data on the use of montelukast in patients with severe hepatic insufficiency (Child-Pugh score > 9).
* Based on adult weight of 50kg
Storage
Storage
Keep under 25℃ and sealed away from light.
Package
Package
Double aluminum packaging, 5 tablets/box.
Expiration date
24 months.
Execution Standard
Approval number】
【Drug marketing license holder】
Company Name: Shanghai Anbisson Pharmaceutical Technology Co.
Location
Address: Unit E, 7/F, Building 4, No. 889 Yishan Road, Xuhui District, Shanghai
Postal Code: 200233
Tel: 021-54973497
Fax number: 021-54973497-8013
Web
Address: http://www.anbison.com/cn
[Entrusted manufacturer]
Company name: Hangzhou Minsheng Binjiang Pharmaceutical Co.
Address
Address: Building 2, No. 658, Binan Road, Binjiang District, Hangzhou City, Zhejiang Province
Postal Code: 310051
Tel: 0571-89976059
Fax number: 0571-89976050
Web
Address: www.msbinjiangpharma.com