Date of approval.
Date of revision.
Montelukast Sodium Granules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Montelukast Sodium Oral Granules
English Name: Montelukast Sodium Oral Granules
Hanyu Pinyin：Menglusitena Keli
Ingredients
The main ingredient of this product is Montelukast Sodium, whose chemical name is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid sodium.
Chemical structure formula.
Molecular formula: C35H35ClNNaO3S
Molecular weight: 608.18
【Properties】.
This product is white, coarse granules.
【Indications】.
This product is indicated for the prevention and long-term treatment of asthma in children over 1 year of age, including the prevention of daytime and nighttime asthma symptoms, the treatment of aspirin-sensitive asthma patients 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 5 years).
【Specifications】.
0.5g: 4mg (in montelukast).
Dosage]
Once daily. Asthma patients should take it at bedtime. Patients with allergic rhinitis can take the medication at the time needed according to their condition.
Patients with both asthma and allergic rhinitis should take the medication once a night.
One sachet once a day for children aged 1 to 2 years with asthma.
Children 2 to 5 years of age with asthma and/or 2 to 5 years of age with allergic rhinitis should take one sachet of 4 mg oral granules daily.
Administration of oral granules
This product may be taken directly, mixed with a spoonful of room temperature or cold soft food (e.g. applesauce), or dissolved in a teaspoon of room temperature or cold infant formula or breast milk. The pouch should be opened only at the time of administration. The full dose should be taken immediately after opening the pouch (within 15 minutes). After mixing with food, infant formula or breast milk, this product should not be stored until the next dose. This product should not be dissolved in any liquid other than infant formula or breast milk. However, you may drink water after taking the medication.
General recommendations
The effectiveness of the treatment is evaluated by the asthma control index and the effect of this product appears within one day of administration. This product may be taken with or in addition to food. Patients should be advised to take it consistently whether in the asthma control or worsening phase.
No dose adjustment is required for patients with renal insufficiency, patients with mild to moderate hepatic impairment, and patients of different genders.
Relationship of this product to other asthma treatment medications
This product may be added to a patient’s existing treatment regimen.
Dose reduction of combined medications.
Bronchodilators
In patients with asthma not effectively controlled with bronchodilators alone, this product may be added to the regimen and the dose of bronchodilator may be reduced once there is a clinical response (usually after the first dose), depending on how well tolerated the patient is.
Inhaled glucocorticosteroids
The dose of glucocorticoids may be reduced as tolerated by patients with asthma treated with inhaled glucocorticoids after the addition of this product. 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 for the original product was similar to that of placebo.
In controlled clinical trials of the original product, the most common adverse reactions (incidence ≥ 5% and greater than the placebo group; in descending order of frequency) were: upper respiratory tract infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, and otitis.
Asthma in children aged 2 to 5 years
The safety of the originator product has been evaluated in 573 pediatric patients aged 2 to 5 years. In a placebo-controlled 12-week clinical study, the only drug-related adverse event with an incidence >1% and higher than the placebo group in the original product treatment group was thirst. There was no significant difference in the incidence of thirst between the two groups.
Cumulatively, 426 pediatric patients aged 2 to 5 years had been treated with the investigational product 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 occurrence of adverse events as the duration of treatment with the originator product increased. The following adverse events occurred at a frequency of ≥2% and more frequently than in pediatric patients treated with placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, otalgia, gastroenteritis, eczema, urticaria, chickenpox, pneumonia, dermatitis, and conjunctivitis.
Children aged 6 months to 23 months with asthma
The safety of the originator product has been evaluated in approximately 175 pediatric patients 6 to 23 months of age. The following adverse events occurred at a frequency of ≥2% and more frequently than in pediatric patients treated with placebo: upper respiratory tract infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; rhinitis. The frequency of less common adverse events was comparable between the originator and placebo groups.
Pediatric patients aged 2 to 14 years with seasonal allergic rhinitis
The safety of the original product has been evaluated in a 2-week placebo-controlled clinical study in 280 pediatric patients aged 2 to 14 years with seasonal allergic rhinitis. The once-daily evening dose of the original product was well tolerated, with an incidence of adverse reactions similar to that of the placebo group. In this study, no patients taking the original product were observed to have an incidence of ≥1% and a higher incidence of drug-related adverse reactions than in the placebo group. Adverse events with an incidence of ≥2% in the original product treatment group and a greater incidence than in the placebo treatment group were as follows: headache, otitis media, pharyngitis, and upper respiratory tract infection.
Combined analysis of clinical practice
A combined analysis of 41 placebo-controlled clinical studies (35 studies in patients aged 15 years and older and 6 studies in pediatric patients aged 6 to 14 years) was conducted using validated methods for assessing suicidal behavior. Of the 9929 patients taking the original product and 7780 patients taking placebo, one patient with suicidal ideation took the original product. 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 and 11 studies in pediatric patients aged 3 months to 14 years) was conducted to assess behaviorally relevant adverse events. The incidence of behaviorally relevant adverse events was 2.73% and 2.27% in 11,673 patients taking the original product and 8,827 patients taking placebo, 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 were identified during post-approval use of the original product. Because these adverse reactions were voluntarily reported from an indeterminate number of people, frequency cannot always be reliably estimated or a causal relationship with drug exposure established.
The following adverse reactions have been reported following post-marketing use of the original product.
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 perception, inattention, abnormal night dreams, stuttering (stammering), hallucinations, insomnia, memory impairment, obsessive-compulsive symptoms, psychomotor hyperactivity (including irritability, restlessness, and tremors), sleepwalking, suicidal thoughts and behavior (suicidal), 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, 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, Stevens-Johnson syndrome/neutrophilic epidermal necrolysis loosening, rash, 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.
Patients with asthma treated with the originator product may develop systemic eosinophilia and sometimes clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that often requires systemic glucocorticoid therapy. These events sometimes require dose reduction of oral glucocorticoids. Physicians must be alert to the presence of eosinophilia, vasculitic rash, exacerbation of pulmonary symptoms, cardiac complications, and/or neuropathy in patients.
Contraindications]
Contraindicated in patients 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 guidance of a physician, this product should not be used as an abrupt substitute for inhaled or oral glucocorticosteroids.
Patients with known aspirin sensitivity should continue to avoid aspirin or nonsteroidal anti-inflammatory drugs while taking this product. Although this product is effective in improving airway function in aspirin-sensitive asthmatics, studies have not shown that it blocks the bronchoconstrictor response produced by aspirin and other NSAIDs in aspirin-sensitive asthmatics.
Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking the originator product. Post-marketing reports of taking the originator product include euphoria, aggressive behavior or hostility, anxiety, depression, disorientation, attention deficit, dream abnormalities, hallucinations, insomnia, irritability, memory deficits, restlessness, sleepwalking disorder, suicidal ideation and behavior (suicide), convulsions, and tremors. Some clinical details of post-marketing reports about the original product appear to be consistent with drug-induced effects.
Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescribing physician if these changes occur. If such events occur, prescribers should carefully evaluate the risks and benefits of continuing treatment with this product.
In patients receiving antiasthmatic medications including leukotriene receptor antagonists, one or more of the following have occurred in rare cases: eosinophilia, vascular rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy (sometimes diagnosed as ChurgStrauss 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 montelukast sodium is recommended.
For pregnant and lactating women]
Not applicable.
[For Children].
Efficacy and safety studies of the original product have been conducted in children 6 months to 14 years of age (see Dosage and Administration); safety and efficacy in pediatric patients less than 6 months of age have not been studied.
The original study showed that this product does not affect the growth rate of children.
Geriatric Use]
Not applicable.
Drug Interactions]
The investigational product can be used in combination with other drugs routinely used for the prevention and long-term treatment of asthma and the treatment of allergic rhinitis. In drug interaction studies, the recommended doses of the investigational product did not produce clinically significant pharmacokinetic effects on the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory drugs, benzodiazepines, decongestants, and cytochrome P450 (cytochrome P450). and cytochrome P450 (CYP) enzyme inducers.
The area under the plasma concentration-time curve (AUC) of montelukast was reduced by approximately 40% in patients on combined phenobarbital. 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, indicate that montelukast does 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 2C9, demonstrated that gemfibezil increased systemic exposure levels of montelukast by 4.4-fold. 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 up to 900 mg/day given to patients for approximately 1 consecutive week) in which no clinically meaningful adverse events were observed, 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 is no specific information on overdose of the original 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, routine supportive measures are reasonable; for example, removal of unabsorbed material from the gastrointestinal tract, clinical monitoring, and, if needed, supportive therapy.
Acute post-marketing overdoses and clinical studies using the original product have been reported. These include reports of doses up to 1000 mg in adults and children. Both clinical and laboratory findings have consistently demonstrated safety in adult and pediatric patients. In the majority of overdose reports, there were no adverse events. The most frequent 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 inflammatory mediators that are released by a variety of cells, including mast cells and eosinophils. These important pre-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. Type I cysteinyl leukotriene (CysLTl) receptors are distributed in the human airways (including airway smooth muscle cells and airway macrophages) and other proinflammatory 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, CysLTs associated with allergic rhinitis symptoms are released from the nasal mucosa in both tachyphylaxis and late phase responses following allergen exposure. intranasal CysLTs excitation increases nasal airway resistance and symptoms of nasal obstruction.
Montelukast improves indicators of asthma inflammation. Montelukast has a high affinity and selectivity for the CysLT1 receptor and effectively inhibits the physiological effects of LTC4, LTD4 and LTE4 binding to the CysLT1 receptor without any receptor agonist activity. The current study concluded that montelukast does not antagonize the CysLT2 receptor.
Children 2-5 years old
In a 12-month, placebo-controlled study in children aged 2 to 5 years with mild intermittent asthma and exacerbations induced by viral infection (referred to as PREVIA, Prevention of Virus-Induced Asthma with Montelukast), once-daily dosing of montelukast 4 mg significantly reduced the frequency of asthma exacerbation episodes compared to placebo.
Toxicology
Acute toxicity
In mice and rats, no mortality occurred at single oral doses of montelukast sodium up to 5000 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 > 5000 mg/kg) and corresponds 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 a wide range of safe doses were used. When montelukast sodium was administered to any animal in the trial at least 125 times the recommended dose for humans, no effects on toxicological parameters were observed*. No inability to use therapeutic doses of montelukast sodium was 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 an in vitro rat hepatocyte base elution assay and a chromosomal aberration assay in Chinese hamster ovary cells 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*.
Developmental Toxicity
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.
Tests conducted in adults on an empty stomach demonstrated bioequivalence between 4 mg oral pellets and 4 mg chewable tablets. There was no clinically significant effect on the pharmacokinetics of montelukast by AUC for concomitant administration of applesauce or a standard diet (AUC 1 225.7 and 1 223.1 ng-hr/ml for concomitant administration of applesauce and 1191.8 and 1148.5 ng-hr/ml for concomitant administration of a standard meal). A high-fat breakfast did not affect the AUC of montelukast oral pellets; however, the meal reduced Cmax by 35% and prolonged Tmax from 2.3 ± 1.0 to 6.4 ± 2.9 hours.
Distribution
More than 99% of montelukast sodium was bound to plasma proteins. The steady-state volume of distribution of montelukast averaged 8 to 11 liters. Studies with isotopically labeled montelukast in rats showed that only a very small amount of montelukast crossed 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 stools collected over the following 5 days, and the amount measured in urine was <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 is no clinical information on the use of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).
Storage】Store under shade and seal.
Package】Packaged in aluminum-plastic composite bag, 7 bags/box.
Expiration date】24 months
【Execution standard
Approval number】
Marketing authorization holder
Marketing authorization holder: Jiangsu Zhengda Fenghai Pharmaceutical Co.
Address of the listed license holder: No. 103, Health East Road, Dafeng District, Yancheng City, Jiangsu Province
Manufacturer
Company Name: Jiangsu Zhengda Fenghai Pharmaceutical Co.
Production Address: No. 103, Health East Road, Dafeng District, Yancheng City, Jiangsu Province
Postal Code: 224100
Telephone number: 0515-83514661
Fax number: 0515-83516010
Web address: www.ctfh.com.cn