[Ingredients]

The main ingredient of this product is montelukast sodium, its chemical name is [R-(E)]-1-[[[1-[3-[2-(7-Chloro-2-quinoline)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfur]methyl] Sodium Cyclopropane Acetate

Chemical Structure:

Molecular formula: C35H35ClNNaO3S

Molecular weight: 608.18

[Properties]

This product is a light yellow special-shaped film-coated tablet.

[Indications]

This product is suitable for the prevention and long-term treatment of asthma in adults aged 15 and over,

including Prevent asthma symptoms during the day and night, treat asthma patients who are sensitive to aspirin, and Prevent exercise-induced bronchoconstriction.

This product is suitable for reducing the symptoms caused by allergic rhinitis (15 years old and older adults

Seasonal allergic rhinitis and perennial allergic rhinitis).

[Specifications]

10mg (based on montelukast).

[Dosage]

Take one tablet (10mg) once a day. Patients with asthma should take it before going to bed. allergy patients with rhinitis can take medicine when needed according to their own conditions.

Patients with both asthma and allergic rhinitis should take the medicine once every night.

Adult patients 15 years and older with asthma and/or allergic rhinitis once a day,

10mg each time.

General advice

Use asthma control indicators to evaluate the therapeutic effect. The efficacy of this product is within one day of medication appear.This product can be taken with food or separately. Patients should be advised to taking it whether they are in asthma control or i at the worsening stage.

Elderly patients, patients with renal insufficiency, patients with mild to moderate liver damage and differences

other patients do not need to adjust the dose.

The relationship between montelukast sodium tablets and other asthma treatment drugs

This product can be added to the patient's existing treatment plan.

Reduce the dose of concomitant drugs:

Bronchodilator

Patients with asthma who cannot be effectively controlled with bronchodilator alone can be included in the treatment plan.After adding this product, once there is an obvious clinical effect response (usually after the first dose),According to the patient's tolerance, the bronchodilator dose can be reduced.

Inhaled corticosteroids

After adding this product to asthma patients receiving inhaled glucocorticoid therapy, the dose of glucocorticoid can be appropriately reduced under the guidance of a physician according to the patient's tolerance.

Some patients can gradually reduce the dose until the inhaled corticosteroid is completely stopped. But this product should not be used to suddenly replace inhaled corticosteroids .

[Adverse reactions]

This product is generally well tolerated, with mild adverse reactions, and usually does not require termination of treatment.

The overall incidence of adverse reactions of this product is similar to that of placebo.

Asthma patients 15 years and older

Clinical studies have been carried out in approximately 2600 adult asthmatic patients aged 15 and over, and the safety of this product has been evaluated. In two similarly designed, placebo-controlled, 12-week clinical studies, the adverse events related to the drug in the product treatment group were ≥1% and higher than the placebo group's adverse events were abdominal pain and headache. However, the incidence of these adverse events was not significantly different between the two groups. There was no significant difference between the groups.

In clinical studies, a total of 544 patients have been treated with this product for at least 6 months, 253 patients have been treated for 1 year, and 21 patients have been treated for 2 years. With the extension of the treatment time with this product, the occurrence of adverse events has not changed

Patients with seasonal allergic rhinitis 15 years and older

linical studies have been carried out in 2199 adult patients with seasonal allergic rhinitis aged 15 and over to evaluate the safety of this product. Taking this product once every morning or night is well tolerated, and the incidence of adverse reactions is similar to taking placebo. In placebo-controlled clinical studies, no drug-related incidence was found in the product treatment group ≥1%, which was higher than the adverse events of the placebo group. In the 4-week placebo-controlled clinical study, the safety profile was consistent with the 2-week clinical study. In all clinical studies, the incidence of sleepiness was similar to that of the placebo group. Perennial allergic rhinitis patients aged 15 years and older

It has been performed in 3235 adult patients with perennial allergic rhinitis aged 15 years and over

Two six-week placebo-controlled clinical studies have been conducted in 3235 adult patients with perennial allergic rhinitis aged 15 years and over to evaluate the safety of this product. Taking this product once a day is well tolerated, and the incidence of adverse reactions is similar to that of the placebo group, and is consistent with the clinical research results of seasonal allergic rhinitis. In these two clinical studies, the incidence of adverse events in the treatment group was less than 1%, and no drug-related events were found, and the incidence was higher than that in the placebo group. The incidence of sleepiness was similar to that of the placebo group. Consolidated analysis of clinical practice

A combined analysis of 41 placebo-controlled clinical studies (35 studies for patients 15 years and older; 6 studies for children 6-14 years old) using effective suicidal behavior assessment methods. Among 9929 patients taking this product and 7780 patients taking placebo, one patient with suicidal ideation took this product. There was no completion of suicide, suicide attempt, or preparatory action for suicidal behavior in any group.

An independent pooled analysis was conducted for 46 placebo-controlled clinical studies (35 studies for patients 15 years and older; 11 studies for children aged 3 months to 14 years) to evaluate behavior-related adverse events. Among 11,673 patients taking this product and 8827 patients taking placebo, the incidence of behavior-related adverse events was 2.73% and 2.27%, respectively; the odds ratio was 1.12 (95% CI [0.93; 1.36]).

The clinical trials included in these pooled analyses did not specifically design tests for suicide rates or behavior-related adverse events.

Post-IPO experience

The following adverse reaction reports have been reported after this product has been used on the market:

Infections and infections: upper respiratory tract infections.

Disorders of blood and lymphatic system: increased bleeding tendency.

Immune system disorders: including hypersensitivity reactions of allergic reactions, very rare liver eosinophil infiltration.

Mental system disorders: including aggressive behavior or hostile excitement, anxiety, depression, loss of perception of orientation, inattention, abnormal night dreams, hallucinations, insomnia, memory impairment, psychomotor hyperactivity (including irritability, irritability and restlessness) Tremors), sleepwalking, suicidal thoughts and behaviors (suicide).

Nervous system disorders: dizziness, drowsiness, paresthesia/dyssensation and very rare seizures.

Heart disorders: palpitations.

Respiratory, thoracic and mediastinal system disorders: epistaxis; pulmonary eosinophilia.

Gastrointestinal disorders: diarrhea, indigestion, nausea, vomiting.

Hepatobiliary disorders: elevated ALT and AST, very rare hepatitis (including cholestatic, liver cell and mixed liver damage).

Skin and subcutaneous tissue disorders: angioedema, contusion, erythema multiforme, erythema nodosa, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: joint pain, myalgia including muscle spasms.

Kidney and urinary system disorders: childhood enuresis (occasionally).

Other disorders and administration site conditions: weakness/fatigue, edema, fever.

[Taboo]

Those who are allergic to any ingredient in this product should not be used.

[Precautions]

The efficacy of oral administration of this product in the treatment of acute asthma attacks has not been determined. Therefore, it should not be used

Treat acute asthma attacks. Patients should be informed to prepare appropriate rescue medication.

Although the combined dose of inhaled corticosteroids can be gradually reduced under the guidance of a physician, this product should not be used to suddenly replace inhaled or oral corticosteroids.

Patients taking this product have reports of neuropsychiatric events (see Adverse Reactions). Since other factors may also cause these events, it cannot be confirmed whether it is related to this product. The doctor should discuss these adverse events with the patient and/or nursing staff. The patient and/or caregiver should be informed and the doctor should be notified if these conditions occur.

In patients receiving anti-asthma medications including leukotriene receptor antagonists, very few cases have one or more of the following conditions: eosinophilia, vascular skin rash, worsening pulmonary symptoms, cardiac complications and/or neuropathy (sometimes diagnosed as ChurgStrauss syndrome-a systemic eosinophilic vasculitis). These conditions are sometimes related to the reduction or discontinuation of oral glucocorticoid therapy. Although these conditions are affected by leukotrienes

The causality of antagonists has not been determined, but it is recommended to pay attention to patients taking Shun Erning and make proper clinical monitoring.

 [Medication for pregnant women and lactating women]

There is no research data for pregnant women. Pregnant women should avoid taking this product unless it is clearly necessary to take the drug.

Global post-marketing experience has shown that there are rare cases of neonates after using this product during pregnancy.

Reports of natural limb defects. The vast majority of these women also used it during pregnancy

He has asthma medication. The 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 divided from breast milk

Women in lactation and lactation should use this product with caution.

[Children's Medication]

Safety and efficacy studies have been conducted in children between 6 months and 14 years of age. For medication for children between 2 and 14 years old, please refer to the [Usage and Dosage] of Montelukast Sodium Chewable Tablets. The safety and effectiveness of children under 6 months of age have not been studied.

Studies have shown that this product will not affect the growth rate of children.

[ Geriatric medication]

In clinical studies, there is no age difference in the effectiveness and safety of this product.

[medicine interactions]

This product can be combined with other drugs that are routinely used for the prevention and long-term treatment of asthma and the treatment of allergic rhinitis. In drug interaction studies, the recommended dose of this product does not have clinically significant pharmacokinetic effects on the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin. In patients with combined use of phenobarbital, the area under the plasma concentration-time curve (AUC) of montelukast was reduced by approximately 40%. However, it is not recommended to adjust the dosage of this product.

In vitro experiments show that montelukast is an inhibitor of CYP2C8. However, data from a clinical study on the drug interaction between montelukast and rosiglitazone (a typical detection substrate mainly metabolized by CYP2C8) showed that montelukast has no inhibitory effect on CYP2C8 in vivo. Therefore, it is believed that montelukast will not affect drugs metabolized by this enzyme (such as paclitaxel, rosiglitazone, repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9 and 3A4. A clinical study involving the drug interaction between montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9) proved that gemfibrozil can increase the systemic exposure level of montelukast by 4.4 times. (Itraconazole, a potent inhibitor of CYP and 3A, will not further increase the systemic exposure level of montelukast after simultaneous administration of gemfibrozil and montelukast. In clinical safety studies , Using a dose greater than the 10 mg approved in adults (for example, a dose of 200 mg/day given to adult patients for 22 consecutive weeks, and a dose of up to 900 mg/day given to patients for approximately 1 week), no clinical Significant adverse events. Based on such data, the effect of gemfibrozil on the systemic exposure level of montelukast is considered to be of no clinical significance. Therefore, simultaneous administration with gemfibrozil does not require adjustment of montelukast According to in vitro data, no clinically significant drug interactions between montelukast and other known CYP 2C8 inhibitors (such as trimethoprim) are expected. In addition, only montelukast and i Simultaneous administration of Traconazole will not significantly increase the former's systemic exposure.

[Drug overdose]

There is no specific data on the overdose of this product in clinical treatment. In studies on the treatment of chronic asthma, adult patients used doses as high as 200 mg per day, 22 weeks of continuous medication, and doses as high as 900 mg per day in short-term studies, for about 1 week of continuous medication, and there were no clinically significant adverse events.

There have been reports of acute drug overdose after marketing and clinical studies using this product. These include reports of adults and children using doses up to 1000 mg. Both clinical and laboratory findings consistently show its safety in adult and pediatric patients. In most reports of drug overdose, there were no adverse events. The most frequently occurring adverse events are consistent with safety characteristics, including abdominal pain, drowsiness, thirst, headache, vomiting, and hyperpsychiatric hyperactivity.

It is not clear whether this product can be cleared by peritoneal or hemodialysis

[Pharmacology and Toxicology]

Pharmacology

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are powerful mediators of inflammation, released by a variety of cells including mast cells and eosinophils. These important pre-asthma mediators cysteyl leukotriene (CysLT) receptor binding. Type I cysteyl leukotriene (CysLT1) receptors are distributed in the human airway (including airway smooth muscle cells and airway macrophages) and other pro-inflammatory cells (including eosinophils and certain bone marrow stem cells) . CysLTs are related to the pathophysiological process of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a series of airway reactions, such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil accumulation. In allergic rhinitis, both the immediate and delayed phase reactions after allergen exposure, the nasal mucosa will release CysLTs related to the symptoms of allergic rhinitis. Intranasal CysLTs stimulation can increase nasal airway resistance and symptoms of nasal obstruction.

This product is a powerful oral preparation that can significantly improve the inflammation indicators of asthma. Biochemical and pharmacological bioassays show that montelukast has a high affinity and selectivity for CysLT1 receptors (with other pharmacologically important airway receptors such as prostaglandins, cholinergic and β -Compared with adrenergic receptors). Montelukast can effectively inhibit LTC4, LTD4, LTE4 and ysLT1

The physiological effect of receptor binding without any receptor agonistic activity. Current research suggests that montelukast does not antagonize the CysLT2 receptor.

toxicology

Acute toxicity

In mice and rats, when a single oral dose of montelukast sodium was as high as 5000 mg/kg (the doses for mice and rats were 15,000 mg/m 2 and 29,500 mg/m 2 respectively), there was no death. This dose is the maximum tested dose (oral LD50>5000mg/kg), which is equivalent to 25,000 times the recommended daily dose for adults.

Long-term toxicity

The test in monkeys and rats was up to 53 weeks, and in young monkeys and mice it was up to 14 weeks. The test results show that montelukast sodium is well tolerated and the dose used has a wide range of safety. When using montelukast sodium at least 125 times the recommended dose for humans to any experimental animal, no effect on toxicological indicators was found*. Neither adult nor pediatric patients were found to be unable to use the therapeutic dose of montelukast sodium..

Mutagenicity

Montelukast sodium has not been found to have genotoxic and mutagenic effects. In the in vitro microbial mutation test and the V-79 mammalian cell mutation test, montelukast sodium was negative regardless of its metabolic activity. In the in vitro alkaline elution test of rat liver cells and the chromosomal aberration test of Chinese hamster ovary cells, there was no genotoxic effect with or without the microsomal enzyme activity system. Similarly, when male or female mice oral administration of up to 1200mg/kg (3600mg/m2) (6000 times the recommended daily dose for adults*) of montelukast sodium, no effect was found to induce chromosomal abnormalities in bone marrow cells. [Pharmacokinetics]

absorb

Montelukast is quickly and completely absorbed orally. After adults take 10 mg film-coated tablets on an empty stomach, the plasma drug concentration reaches the peak concentration (Cmax) at 3 hours (Tmax). The average oral bioavailability is 64%. Ordinary diet has no effect on oral bioavailability and Cmax. Clinical studies have shown that it is safe and effective to take 10 mg film-coated Montelukast sodium at any time after eating.

metabolism

Montelukast is almost completely metabolized. In studies using therapeutic doses, montelukast metabolites were not detected in the plasma of adults and children under steady-state conditions. In vitro studies using human liver microsomes have shown that cytochrome P450 3A4 and 2C9 are involved in the metabolism of montelukast. According to the results of further studies on human liver microsomes in vitro, the plasma concentration of montelukast at therapeutic doses does not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.

excretion

The average plasma clearance rate of montelukast in healthy adults is 45 mL/min. After oral administration of isotope-labeled montelukast, 86% of radioactivity was detected in stool collected for the next 5 days, and the amount measured in urine was <0.2%. Considering the oral bioavailability of montelukast, montelukast and its metabolites are almost exclusively excreted via bile. Many studies conducted in healthy young people have shown that the average plasma half-life of montelukast is 2.7 to 5.5 hours. In the range of oral doses up to 50 mg, the pharmacokinetics of montelukast is approximately linear. No difference in the pharmacokinetics of montelukast was found in the morning and night. Taking 10 mg montelukast once a day, only a very small amount of the original drug (~14%) accumulates in the plasma.Special patient

There is no need to adjust the dose for the elderly, patients with renal insufficiency, or patients with mild to moderate hepatic insufficiency. There is no clinical data on the use of montelukast in patients with severe hepatic insufficiency (Child-Pugh score>9).

[Storage]

Store at 15-30°C at room temperature, protected from moisture and light.