How Effective Is Montelukast for Asthma?

Montelukast sodium, a prescription drug, was developed and produced by Merck (known as Merck in the United States and Canada). Shun Erning was officially approved by the State Food and Drug Administration of China in 1999.

Montelukast sodium is an oral leukotriene receptor antagonist that specifically inhibits the cysteyl leukotriene (CysLT1) receptor in the airways, thereby improving airway inflammation and effectively controlling asthma symptoms.

Montelukast sodium is a non-hormonal anti-inflammatory drug, suitable for the prevention and long-term treatment of asthma and allergic rhinitis in adults and children over 1 year old. It has three different specifications. According to the 2008 edition of China's "Guide to Prevention and Treatment of Bronchial Asthma", the leukotriene modulator is the only long-term control drug that can be used alone, in addition to inhaled hormones, and can be used as an alternative treatment for mild asthma and a combination treatment for moderate to severe asthma.

Chinese name: Montelukast sodium tablets
Product name: Shunning

Category: prescription
chemical name: Leukotriene receptor antagonist

Montelukast Sodium Tablets Drug Information

[General name] montelukast sodium tablets, montelukast sodium chewable tablets, montelukast sodium granules

[Product name] Singulair ^®

[English name] Montelukast Sodium Tablets, Montelukast Sodium Chewable Tablets, Montelukast Sodium Oral Granules

[Chinese Pinyin] Menglusitena Pian, Menglusitena Jujuepian, Menglusitena Keli

specification

Montelukast sodium tablets: 10mg (based on montelukast sodium)

Montelukast sodium chewable tablets: 5mg, 4mg (based on Montelukast sodium)

Montelukast sodium granules: 0.5g: 4mg (based on montelukast sodium) ^[1]

Storage

Montelukast Sodium Tablets, Montelukast Sodium Chewable Tablets: Store at 15-30 ° C at room temperature, moisture-proof and shading.

Montelukast sodium granules: sealed, protected from light, stored at room temperature (15-30 ° C).

package

Montelukast sodium tablets: packed in aluminum-plastic board, 5 tablets / box or 7 tablets / box.

Montelukast sodium chewable tablets: packed in aluminum-plastic board, 5 tablets / box or 7 tablets / box.

Montelukast sodium granules: packed in aluminum-plastic composite bag, 5 bags / box, 7 bags / box, 14 bags / box.

[Validity Period]

Montelukast sodium tablets: 36 months

Montelukast sodium chewable tablets: 24 months

Montelukast sodium granules: 24 months

[Executive standards]

Montelukast sodium tablets: import drug registration standard JX20010356

Montelukast Sodium Chewable Tablets : 5mg: Import Drug Registration Standard JX20010357

4mg: Registration Standard for Imported Drugs JX20010106 ^[2]

Montelukast Sodium Granules: Registration Standard for Imported Drugs JX20090135

[Import Drug Registration Certificate Number]

Montelukast sodium tablets: H20120360

manufacturer

Company Name: Merck Sharp & Dohme Australia Pty Ltd

Address: 54-68 Ferndell Street SOUTH GRANVILLE NSW 2142, Australia.

Factory Name: Merck Sharp & Dohme Ltd.

Address: Shotton Lane, Cramlington, Northumberland, NE23 3JU, UK

Packing factory name: Merck Sharp & Dohme Australia Pty Ltd

Address: 54-68 Ferndell Street SOUTH GRANVILLE NSW 2142, Australia ^[2]

[Import Drug Registration Certificate Number]

Montelukast sodium chewable tablets: 5mg: H20120366

4mg: H20120364

manufacturer

Company Name: Merck Sharp & Dohme Australia Pty Ltd

Address: 54-68 Ferndell Street SOUTH GRANVILLE NSW 2142, Australia.

Factory Name: Merck Sharp & Dohme Ltd.

Address: Shotton Lane, Cramlington, Northumberland, NE23 3JU, UK

Packing factory name: Merck Sharp & Dohme (Australia) Pty. Ltd.

Address: 54-68 Ferndell Street SOUTH GRANVILLE NSW 2142, Australia ^[2]

[Import Drug Registration Certificate Number]

Montelukast sodium granules: H20110596, H20110597

manufacturer

Company Name: Merck Sharp & Dohme Australia Pty Ltd

Address: 54-68 Ferndell Street SOUTH GRANVILLE NSW 2142, Australia. Factory Name: Merck Sharp & Dohme Corp.

Factory Address: 770 Sumneytown Pike, West Point, PA 19486, USA Sub-packaging Factory: Merck Sharp & Dohme (Australia) Pty. Ltd.

Sub-packaging factory address: 54-68 Ferndell Street SOUTHGRANVILLE NSW 2142, Australia ^[2]

[Character]

Montelukast sodium tablets: This product is a light yellow shaped film-coated tablet.

Montelukast sodium chewable tablets: 5mg of this product are pink round tablets, 4mg are pink oval tablets.

Montelukast sodium granules: This product is white, rough granules. ^[1]

[Ingredients] The main ingredient of this product is montelukast sodium ^[1]

Chemical name: [R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinoline) vinyl] phenyl] -3- [2- (1-hydroxy 1-methylethyl) phenyl] propyl] sulfur] methyl] cyclopropane sodium acetate.

Molecular formula: C ₃₅ H ₃₅ CINNaO ₃ S

Molecular weight: 608.18

Chemical Structure:

Montelukast sodium tablets indications

Montelukast sodium tablets:

This product is suitable for the prevention and long-term treatment of asthma in adults aged 15 and over, including prevention of asthma symptoms during the day and night, treatment of asthma patients who are sensitive to aspirin, and prevention of exercise-induced bronchoconstriction.

This product is suitable for reducing the symptoms caused by allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis in adults aged 15 years and over).

Montelukast sodium chewable tablets:

This product is suitable for the prevention and long-term treatment of asthma in children aged 2 to 14 years, including prevention of asthma symptoms during the day and night, treatment of asthma patients who are sensitive to aspirin, and prevention of exercise-induced bronchoconstriction.

This product is suitable for reducing the symptoms caused by allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis in children 2 to 14 years old).

Montelukast sodium granules:

This product is suitable for the prevention and long-term treatment of asthma in children over 1 year old, including prevention of asthma symptoms during the day and night, treatment of asthma patients who are sensitive to aspirin, and prevention of exercise-induced bronchoconstriction.

This product is suitable for reducing the symptoms caused by allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis in children 2 to 5 years old). ^[1]

Montelukast sodium tablets dosage

Montelukast sodium tablets:

One tablet (10 mg) once daily. Asthma patients should take it before bedtime. Patients with allergic rhinitis can take it when needed according to their own conditions.

Patients with both asthma and allergic rhinitis should take the drug once a night.

Adult patients aged 15 years and older with asthma and / or allergic rhinitis take the drug once daily at 10 mg each time.

General recommendations

Asthma control indicators were used to evaluate the treatment effect, and the efficacy of this product appeared within one day of administration. This product can be taken with or without food. Patients should be advised to take it regardless of asthma control or exacerbation.

Elderly patients, patients with renal insufficiency, patients with mild to moderate liver damage, and patients of different genders 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 co-administration:

Bronchodilator

Patients with asthma who cannot be effectively controlled by bronchodilator alone can add this product to the treatment plan. Once there is a significant clinical effect (usually after the first dose), bronchodilator can be used according to the patient's tolerance Reduced dose.

Inhaled glucocorticoids

After adding this product to asthma patients receiving inhaled glucocorticoid therapy, the dose of glucocorticoid can be appropriately reduced according to the patient's tolerance. It should be gradually reduced under the guidance of a physician. In some patients, inhaled glucocorticoids can be gradually reduced until complete withdrawal. But this product should not be used as a sudden substitute for inhaled glucocorticoids.

Montelukast sodium chewable tablets:

Once a day. Asthma patients should take it before bedtime. Patients with allergic rhinitis can take medicine when needed according to their own conditions.

Patients with both asthma and allergic rhinitis should take the drug once a night.

6 to 14 year old children with asthma and / or allergic rhinitis

One tablet (5 mg) once daily.

2 to 5 years old children with asthma and / or allergic rhinitis

One tablet (4 mg) once daily.

General recommendations

No dose adjustment is necessary for patients with renal insufficiency, patients with mild to moderate liver damage, and patients of different sexes.

Relationship between this product and other asthma treatment drugs

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

Reduce the dose of concomitant medications:

Bronchodilator

Patients with asthma who cannot be effectively controlled by bronchodilator alone can add this product to the treatment plan. Once there is a clinical treatment response (usually after the first dose), the dose of bronchodilator can be reduced according to the patient's tolerance .

Inhaled glucocorticoids

Montelukast sodium granules:

Once a day. Asthma patients should take it before bedtime. Patients with allergic rhinitis can take medicine when needed according to their own conditions.

Patients with both asthma and allergic rhinitis should take the drug once a night.

Children with asthma from 1 to 2 years old take one sachet per day.

Children with asthma from 2 to 5 years and / or allergic rhinitis from 2 to 5 years.

A bag of 4 mg oral granules should be taken daily.

Taking Granules Orally

This product can be taken directly, mixed with a spoonful of room temperature or cold soft food (such as applesauce), or dissolved in a teaspoon of room temperature or cold infant formula or breast milk. Do not open the packaging until you take it. Take the full dose (within 15 minutes) immediately after opening the package. This product mixed with food, infant formula or breast milk cannot be stored until the next time you take it. This product should not be dissolved in liquids other than infant formula or breast milk. But you can drink water after taking the medicine.

General recommendations

No dose adjustment is necessary for patients with renal insufficiency, patients with mild to moderate liver damage, and patients of different sexes.

Relationship between this product and other asthma treatment drugs

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

Reduce the dose of concomitant medications:

Bronchodilator

Inhaled glucocorticoids

Montelukast sodium tablets adverse reactions

Montelukast sodium tablets:

This product is generally well tolerated, with minor adverse reactions, and usually does not require termination of treatment. The overall incidence of adverse effects of this product is similar to placebo.

15 years old and older

Clinical studies have been performed on approximately 2600 adult asthma patients aged 15 years and older to evaluate the safety of this product. In two similarly designed, placebo-controlled, 12-week clinical studies, drug-related incidences in the treatment group of this product were 1% and higher than those in the placebo group were abdominal pain and headache. However, the incidence of these adverse events was not significantly different between the two 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.

15 years and older with seasonal allergic rhinitis

Clinical studies have been performed in 2,199 adults with seasonal allergic rhinitis aged 15 years and over to evaluate the safety of this product. Taking this product 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 treatment group of this product 1%, which was higher than the adverse events in the placebo group. In the 4-week placebo-controlled clinical study, the safety profile was consistent with the 2-week clinical study. The incidence of drowsiness was similar in all clinical studies to the placebo group.

15 years and older patients with perennial allergic rhinitis

Two 6-week placebo-controlled clinical studies have been performed on 3235 adult perennial allergic rhinitis patients aged 15 years and older to evaluate the safety of this product. Taking this product once a day is well tolerated, 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 both clinical studies, the incidence of adverse events in the treatment group was less than 1%, and no drug-related incidents were found, and the incidence was higher than in the placebo group. The incidence of drowsiness was similar to that in the placebo group.

Consolidated analysis of clinical practice

A pooled analysis of 41 placebo-controlled clinical studies (35 studies for patients aged 15 years and older; 6 studies for children aged 6-14 years) was performed using an effective method of suicide assessment. Among 9929 patients taking this product and 7780 patients taking placebo, one patient with suicidal ideation took this product. No group has completed suicide, attempted suicide, or preparedness for suicide.

An independent pooled analysis of 46 placebo-controlled clinical studies (35 studies for patients 15 years and older; 11 studies for pediatric patients aged 3 months to 14 years) evaluated behavioral-related adverse events. Among 11,673 patients taking this product and 8827 patients taking placebo, the incidence of behavioral-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 examine suicide rates or behavior-related adverse events.

Montelukast sodium chewable tablets:

6 to 14 year old children with asthma

Clinical studies have been performed in approximately 475 children aged 6 to 14 years to evaluate the safety of this product. In general, pediatric patients use this product similarly to adults and close to placebo.

In a placebo-controlled 8-week clinical study, the only adverse event associated with the drug in the treatment group was> 1% and the only adverse event was higher than the placebo group was headache. However, the incidence of headache was not significantly different between the two groups.

In clinical studies evaluating the effect on growth rate, the safety characteristics of this product for children are consistent with previous descriptions.

A total of 263 children aged 6 to 14 years have been treated with this product for at least 3 months, and 164 patients have been treated for 6 months or longer. With the extension of the treatment time with this product, the occurrence of adverse events has not changed.

2 to 5 year old children with asthma

The safety of this product has been evaluated in approximately 573 children aged 2 to 5 years. In a placebo-controlled 12-week clinical study, the only adverse event with a drug-related incidence of> 1% and a higher incidence in the treatment group than in the placebo group was thirst. However, the incidence of thirst was not significantly different between the two groups.

A total of 426 children aged 2 to 5 years have been treated with this product for at least 3 months, 230 patients have been treated for 6 months or longer, and 63 patients have been treated for 12 months or longer. With the extension of the treatment time with this product, the occurrence of adverse events has not changed.

Children with seasonal allergic rhinitis from 2 to 14 years

In a two-week placebo-controlled clinical study, the safety of this product has been evaluated in 280 patients with seasonal allergic rhinitis from 2 to 14 years of age. Taking this product once a night is well tolerated, and the incidence of adverse reactions is similar to that of the placebo group. In this study, the incidence of adverse reactions in the treatment group was less than 1%, and no drug-related adverse reactions were found, and the incidence was higher than that in the placebo group.

Consolidated analysis of clinical practice

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

Montelukast sodium granules:

2 to 5 year old children with asthma

The safety of this product has been evaluated in 573 children aged 2 to 5 years. In a placebo-controlled 12-week clinical study, the only adverse event associated with the drug in the treatment group was> 1% and the only adverse event was higher than the placebo group was thirst. There was no significant difference in the incidence of thirst between the two groups.

A total of 426 children aged 2 to 5 years have been treated with this product for at least 3 months, 230 patients have been treated for 6 months or more, and 63 patients have been treated for 12 months or more. With the extension of the treatment time of this product, the occurrence of adverse events has not changed.

6 months to 2 years old children with asthma

The safety of this product has been evaluated in approximately 175 children between 6 months and 2 years of age. In a placebo-controlled, 6-week clinical study, drug-related adverse events in the treatment group of this product were> 1% and higher than those in the placebo group. rash. However, the incidence of these adverse reactions was not significantly different between the two groups.

Children with seasonal allergic rhinitis from 2 to 14 years

In a 2-week placebo-controlled clinical study, the safety of this product has been evaluated in 280 children with seasonal allergic rhinitis from 2 to 14 years of age. Taking this product once a night is well tolerated, and the incidence of adverse reactions is similar to that of the placebo group. In this study, the incidence of adverse reactions in the treatment group was less than 1%, and no drug-related adverse reactions were found, and the incidence was higher than that in the placebo group.

Consolidated analysis of clinical practice

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

[Post-marketing experience]

The following adverse reactions have been reported after using this product:

Infections and infections: upper respiratory infections

Blood and lymphatic disorders: increased tendency to bleed.

Immune system disorders: including hypersensitivity reactions to allergic reactions, very rare infiltration of eosinophils in the liver.

Mental disorders: Includes aggressive behavior or hostile excitement, anxiety, depression, loss of direction perception, inattention, abnormal nightmares, hallucinations, impaired memory, impotence, including irritability, irritability, and tremor ), Sleepwalking, suicidal thoughts and actions (suicide).

Neurological disorders: dizziness, drowsiness, paresthesia / hypertensiveness, and very rare seizures.

Heart disorders: palpitations.

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

Gastrointestinal disorders: diarrhea, indigestion, nausea, vomiting.

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

Disorders of skin and subcutaneous tissue: angioedema, contusion, erythema polymorpha, nodular erythema, pruritus, rash, urticaria.

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

Other disorders and site conditions: weakness / fatigue, edema, fever. ^[1]

Those who are allergic to any ingredient in the drug are prohibited. ^[1]

Precautions for montelukast sodium tablets

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

Patients should be advised to prepare appropriate rescue medication.

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

Patients taking this product have reported neurological events (see Adverse Reactions). Since other factors may also cause these events, we cannot confirm whether it is related to this product. The doctor should discuss these adverse events with the patient and / or caregiver. Patients and / or caregivers should be informed and their doctors should be notified if these occur.

Patients receiving anti-asthma medications, including leukotriene receptor antagonists, rarely have one or more of the following cases: eosinophilia, vascular rash, worsening pulmonary symptoms, and cardiac complications And / or neuropathy (sometimes diagnosed with Churg-Strauss syndrome-a systemic eosinophilic vasculitis). These conditions are sometimes associated with reducing or discontinuing oral glucocorticoid therapy. Although the causal relationship between these conditions and leukotriene receptor antagonists has not yet been determined, it is recommended that patients taking shunning be given careful clinical monitoring.

[ Medication for pregnant and lactating women ]

Montelukast sodium tablets, Montelukast sodium chewable tablets:

There are no research data on pregnant women, and pregnant women should avoid taking this product unless they explicitly require medication.

Post-marketing experience worldwide has shown that there are rare reports of congenital limb defects in newborns after using this product during pregnancy. The vast majority of these women also used other asthma medications during pregnancy. The causal relationship between the use of this product and these events has not yet been established.

It is not clear whether this product can be secreted from milk. Because many drugs can be secreted from breast milk, lactating women should use this product with caution.

Montelukast sodium granules: Not applicable.

[Child medication]

Montelukast sodium tablets:

Safety and effectiveness studies have been performed in children between 6 months and 14 years of age. For patients aged 2 to 14 years, see the [ Dosage and Administration] of montelukast sodium chewable tablets. The safety and effectiveness of children under 6 months have not been studied.

Studies have shown that this product does not affect children's growth rate.

Montelukast sodium chewable tablets:

Safety and effectiveness studies have been conducted in children between 6 months and 14 years of age. The safety and effectiveness of children under 6 months have not been studied.

Studies have shown that this product does not affect children's growth rate.

Montelukast sodium granules:

Studies on the effectiveness and safety of this product have been conducted in children between 6 months and 14 years of age (see Dosage and Administration). The safety and effectiveness of children under 6 months have not been studied.

Studies have shown that this product does not affect children's growth rate.

[Medicine for the elderly]

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

Montelukast Sodium Chewable Tablets and Montelukast Sodium Granules: Not applicable. ^[1]

This product can be used in combination with other drugs commonly used in the prevention and long-term treatment of asthma and allergic rhinitis. In drug interaction studies, the recommended dose of this product does not have a clinically significant pharmacokinetic effect on: 35/1), terfenadine, digoxin and warfarin.

In patients with concomitant use of phenobarbital, the area under the plasma concentration-time curve (AUC) of montelukast sodium was reduced by approximately 40%. However, it is not recommended to adjust the dosage of this product.

In vitro tests have shown that montelukast sodium is an inhibitor of CYP2C8. However, data from a clinical study of drug interactions between montelukast sodium and rosiglitazone, a typical probe substrate that is primarily metabolized by CYP2C8, suggest that montelukast sodium does not inhibit CYP2C8 in vivo. Therefore, montelukast sodium is not expected to affect drugs metabolized by this enzyme (for example: paclitaxel, rosiglitazone, regitaline).

In vitro studies have shown that montelukast sodium is a substrate for CYP 2C8, 2C9 and 3A4. A clinical study involving drug interactions between montelukast and gemfibrezil (inhibitors of CYP 2C8 and 2C9) demonstrated that gemfibril increased systemic exposure levels of montelukast sodium by 4.4 times. Itraconazole, a potent inhibitor of CYP 3A4, does not further increase systemic exposure of montelukast sodium when administered concurrently with gemfibrozil and montelukast sodium. In clinical safety studies, doses greater than 10 mg approved in adults were used (for example, a dose of 200 mg / day given to adult patients for 22 consecutive weeks, and a maximum dose of 900 mg / day given to patients for about 1 week), No clinically significant adverse events were observed, and based on such data, the effect of gemfibrozil on montelukast sodium systemic exposure levels was considered to be of no clinical significance. Therefore, simultaneous administration of gemfibrozil does not require adjustment of the montelukast sodium dose. Based on in vitro data, no clinically significant drug interactions are expected between montelukast sodium and other known CYP 2C8 inhibitors, such as trimethoprim. In addition, co-administration of montelukast sodium and itraconazole alone did not significantly increase the systemic exposure level of the former. ^[1]

In most reports of overdose, there were no adverse events. The most common adverse events were consistent with safety characteristics and included abdominal pain, lethargy, thirst, headache, vomiting, and psychomotor activity.

It is unclear whether this product can be removed via peritoneal or hemodialysis. ^[1]

1.Pharmacology

Montelukast sodium tablets:

Cysteinyl leukotriene (LTC ₄ , LTD ₄ , LTE ₄ ) is a potent inflammatory mediator and is released by a variety of cells including mast cells and eosinophils. These important pre-asthmatic mediators bind to cysteine leukotriene (CysLT) receptors. Type I cysteyl 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 pathophysiology 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 related to the symptoms of allergic rhinitis in the rapid phase and late phase reactions after allergen exposure. Intranasal CysLTs stimulation can increase symptoms of nasal airway resistance and nasal obstruction.

Montelukast sodium chewable tablets:

This product is a powerful oral preparation that can significantly improve asthma inflammation indicators. Biochemical and pharmacological bioassays show that montelukast sodium has a high affinity and selectivity for CysLT1 receptors (with other pharmacologically important airway receptors such as prostaglandin, cholinergic and -adrenergic receptors). Montelukast sodium can effectively inhibit the physiological effects of LTC ₄ , LTD ₄ and LTE ₄ binding to CysLT1 receptor without any receptor agonistic activity. Current studies suggest that montelukast sodium does not antagonize the CysLT2 receptor. Children 6 to 14 years of age: In a 12-month study conducted in children with mild persistent asthma aged 6 to 14 years (MOSAIC, montelukast sodium in children with asthma), a comparison was made Efficacy of montelukast sodium and fluticasone inhalation in controlling asthma. Montelukast sodium was not worse than fluticasone in increasing the percentage of asthma-free days (averages were 83.6% and 86.4%, respectively). Both montelukast sodium and fluticasone are effective in controlling asthma: including an increase in forced expiratory volume for one second (FEV1, 0.27L and 0.30L, respectively, compared with baseline, P = 0.232) and a reduction in the number of days of beta-agonist (22.7% and 25.4% lower than baseline, respectively. P = 0.003 between groups).

Children 2 to 5 years of age: a placebo-controlled study (PREVIA, montelukast sodium prevention) in a 12-month period in children with mild intermittent asthma 2 to 5 years of age and exacerbation of viral infection Viral-induced asthma studies), compared with placebo, taking montelukast sodium 4mg once a day can significantly reduce the frequency of exacerbations of asthma.

Montelukast sodium granules:

Cysteinyl leukotriene (LTC ₄ , LTD ₄ , LTE ₄ ) is an inflammatory mediator and is released by a variety of cells including mast cells and eosinophils. These important pre-asthmatic mediators bind to cysteine leukotriene (CysLT) receptors. Type I cysteyl 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 pathophysiology 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 related to the symptoms of allergic rhinitis in the rapid phase and late phase reactions after allergen exposure. Intranasal CysLTs stimulation can increase symptoms of nasal airway resistance and nasal obstruction.

This product can improve the indicators of asthma inflammation. This product has a high affinity and selectivity for CysLT1 receptor, and can effectively inhibit the physiological effects of LTC ₄ , LTD ₄ and LTE ₄ binding to CysLT1 receptor without any receptor agonistic activity. Current studies suggest that montelukast sodium does not antagonize the CysLT2 receptor.

2-5 years old

A 12-month, placebo-controlled study (PREVIA, montelukast sodium to prevent virus-induced asthma) in children with mild intermittent asthma 2 to 5 years of age and exacerbation of viral infection ), Compared with placebo, taking montelukast sodium 4mg once a day can significantly reduce the frequency of exacerbations of asthma.

2. Toxicology

Acute toxicity

In mice and rats, death did not occur when the single oral montelukast sodium dose was as high as 5000 mg / kg (dose for mice and rats were 15000 mg / m ² and 29500 mg / m ^{2, respectively} ). This dose is the maximum test dose (oral LD50 5000mg / kg), which is equivalent to 25,000 times the recommended daily dose for adults.

Long-term toxicity

Tests in monkeys and rats lasted up to 53 weeks, and in young monkeys and mice up to 14 weeks. The test results show that montelukast sodium is well tolerated and the dosage used has a large safety range. No effect of toxicological indicators was found when all montelukast sodium was used at least 125 times the recommended human dose for all animals in the trial. The use of montelukast sodium at therapeutic doses was not found in either adult or pediatric patients.

Carcinogenicity

In studies of oral doses of up to 200 mg / kg / day in rats and 106 weeks of medication, and studies of oral doses of up to 100 mg / kg / day in mice and 92 weeks of medication, montelukast sodium was not found to be carcinogenic. These doses are equivalent to 1000 and 500 times the recommended adult dose.

Mutagenicity

Montelukast sodium was not found to be genotoxic and mutagenic. In the in vitro microbial mutation test and V-79 mammalian cell mutation test, montelukast sodium was negative regardless of the presence or absence of metabolic activity. In the rat liver cell alkali elution test and the Chinese hamster ovary cell chromosome aberration test performed in vitro, there was no genotoxic effect with or without the microsomal enzyme activity system. Similarly, when male or female mice took oral montelukast sodium up to 1200 mg / kg (3600 mg / m ² ) (6,000 times the recommended daily dose for adults), no effect was found to induce chromosomal abnormalities in bone marrow cells.

Reproductive toxicity

In studies on the oral montelukast sodium doses of up to 800 mg / kg / day in male rats and up to 100 mg / kg / day in female rats, no effect on fertility and reproduction was found. These doses are 4000 and 500 times higher than the adult recommended dose, respectively.

Developmental toxicity

In developmental toxicity studies, no adverse effects related to treatment occurred when rats were administered montelukast sodium at doses up to 400 mg / kg / day and rabbits at doses up to 100 mg / kg / day. Montelukast sodium did occur in rats and rabbits, and montelukast sodium was clearly detected in the milk of lactating rats. ^[1]

Pharmacokinetics of montelukast sodium tablets

Montelukast sodium tablets:

absorb

Montelukast sodium is quickly and completely absorbed orally. After taking 10 mg film-coated tablets on an empty stomach in adults, the plasma drug concentration reached a peak concentration (Cmax) at 3 hours (Tmax). The average oral bioavailability was 64%. The normal diet had no effect on oral bioavailability and Cmax. Clinical studies have shown that taking montelukast sodium 10 mg film-coated tablets at any time after eating is safe and effective.

distributed

More than 99% of montelukast sodium binds to plasma proteins. The average distribution volume of montelukast sodium is 8-11 liters. Studies of isotopically labeled montelukast sodium in rats have shown that only very small amounts of montelukast sodium cross the blood-brain barrier. Furthermore, the amount of radiolabels in all other tissues was minimal 24 hours after administration.

metabolism

Montelukast sodium is almost completely metabolized. In studies using therapeutic doses, montelukast metabolites were not detected in plasma under steady-state conditions in adults and children.

Studies in vitro using human liver microsomes have shown that cytochrome P450 3A4 and 2C9 are involved in the metabolism of montelukast sodium. According to the results of further studies of human liver microsomes in vitro, the plasma concentration of montelukast sodium does not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.

excretion

The mean plasma clearance of montelukast sodium in healthy adults was 45 mL / min. After oral isotope-labeled montelukast sodium, 86% of radioactivity was detected in stool collected during the following 5 days, and the amount measured in urine was <0.2%. Considering the oral bioavailability of montelukast sodium, montelukast and its metabolites are almost exclusively excreted via bile.

Many studies in healthy young people have shown that montelukast sodium has an average plasma half-life of 2.7 to 5.5 hours. The pharmacokinetics of montelukast sodium are approximately linear in the range of oral doses up to 50 mg. No difference in the pharmacokinetics of montelukast sodium in the morning and night was found. Taking 10 mg montelukast sodium once a day, only a very small amount of the original drug was accumulated in the plasma (~ 14%).

Special patient

No dosage adjustment is required for elderly, patients with renal insufficiency, or patients with mild to moderate liver insufficiency. There are no clinical data on the use of montelukast sodium in patients with severe liver dysfunction (Child-Pugh score> 9 points).

Montelukast sodium chewable tablets:

Absorption: Montelukast sodium is quickly and completely absorbed orally. Adults reach Cmax in 2 hours after taking 5 mg chewable tablets on an empty stomach. The average bioavailability was 73%. Food has no significant clinical impact on the long-term use of montelukast sodium. Children 2 to 5 years old reached Cmax within 2 hours after taking 4 mg chewable tablets on an empty stomach.

Distribution: More than 99% of montelukast sodium binds to plasma proteins. The average distribution volume of montelukast sodium is 8-11 liters. Studies of isotopically labeled montelukast sodium in rats have shown that only very small amounts of montelukast sodium cross the blood-brain barrier. Furthermore, the amount of radiolabels in all other tissues was minimal 24 hours after administration.

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

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

Special patients: No dosage adjustment is required for the elderly, patients with renal insufficiency, or patients with mild to moderate liver insufficiency. There are no clinical data on the use of montelukast sodium in patients with severe liver dysfunction (Child-Pugh score> 9 points).

Montelukast sodium granules:

absorb

Montelukast sodium is quickly and completely absorbed orally.

Tests performed on fasting adults showed that 4 mg oral granules were bioequivalent to 4 mg chewable tablets. According to AUC calculation, taking applesauce or standard diet at the same time has no clinically significant effect on the pharmacokinetics of montelukast.AUC1191.81148.5 ng·hr/ml

99%81124

metabolism

P450 3A42C9P450 3A42C91A22A62C192D6

excretion

45mL/586%<0.2%

2.75.550mg

10mg14%

Child-Pugh>9 ^[1]

^[3]

4502002~20075601500

7090

801989

Hard work pays off. 1991

At the Merck East Foster Institute on the outskirts of Montreal, Quebec, Canada, a 18-year team of researchers working on the development of leukotriene receptor antagonists has named this new anti-asthma drug. It was eventually called "Montelukast" in memory of its birthplace, Montreal. In February 1998, Montelukast (trade name: Shunning) was listed and approved for adults and children aged 6-14. In June 2000, Shun Erning was further approved by the US Food and Drug Administration for infants with asthma over 1 year old.

Thanks to the use of new anti-asthma drugs such as Shunning, today's treatments can better control the symptoms of nearly 80% of asthma patients, leaving their lives and work hardly affected. The World Health Organization sets the first Tuesday of May each year as World Asthma Day, which aims to remind the public of the disease and improve the level of prevention and treatment of asthma.

Montelukast sodium tablet guide recommendation

Guidelines for the prevention and treatment of bronchial asthma in the asthma group of the Chinese Medical Association Respiratory Branch ^[4]

National and international guidelines consistently recommend leukotriene receptor antagonists as first-line control agents for mild persistent asthma in children ^[5]

The EAACI / AAAAI PRACTALL Pediatric Consensus Report (2008) states:

Preventive treatment for children with asthma over 2 years of age.

Guidelines for the diagnosis and prevention of bronchial asthma in Chinese children ( 2008 ) states : ^[6]

"LTRA can be used alone for the treatment of mild persistent asthma, especially for children who are unable or unwilling to use ICS, or with allergic rhinitis."

Combined with ICS to treat children with moderate to severe persistent asthma can reduce the dose of glucocorticoids and improve the efficacy of ICS "

Study on clinical data of montelukast sodium tablets

Study on Shunning® combination treatment of adult asthma

IMPACT Study - Study on Montelukast Sodium-Assisted Combination Therapy

The study compared the compliance of montelukast sodium with salmeterol in combination with fluticasone.

The proportion of patients without acute attacks of asthma was similar in both groups, and the cumulative proportion of acute attacks was similar.

Conclusion: A 52-week randomized, double-blind, double-simulation, parallel group, and multicenter study involving 1490 patients showed that montelukast sodium combined with fluticasone significantly reduced eosinophils in sputum. In a subgroup analysis of 41 patients, montelukast sodium significantly reduced markers of airway inflammation. ^[7]

COMPACT Study - Subgroup analysis of montelukast sodium in patients with asthma complicated by allergic rhinitis

1, montelukast sodium + budesonide treatment for 12 weeks, significantly improved the highest morning expiratory flow rate.

2. Subgroup analysis of asthma with variant rhinitis. Montelukast sodium + budesonide improves morning PEFR better than double-dose budesonide.

3. In the subgroup analysis of asthma with variant rhinitis, montelukast + budesonide improved morning PEFR in patients with asthma and allergic rhinitis better than double-dose budesonide.

CONCLUSION: In the COMPACT study, montelukast sodium combined with budesonide in the subgroup of asthma with allergic rhinitis can better improve lung function and is significantly better than doubling the budesonide dose. (P <0.05) ^[8]

ELEVATE study - effectiveness of montelukast sodium in the treatment of asthma in the real world

The full name is Evaluation of Asthma Therapies and for health Economics.

MONICA study - efficacy of montelukast sodium in asthmatic patients with poorly controlled ICS or ICS + LABA

1) The use of montelukast sodium improves the ACT score:

After adding montelukast sodium to ICS or ICS + LABA (14.6 ± 4.6) treatment, the average ACT score at the 6th month (19.4 ± 4.4) and the 12th month (20.3 ± 4.2) (as shown in the brackets (Write) were significantly improved from the baseline period (both time nodes P <0.0001).

2) In the ICS and ICS + LABA subgroups, the use of montelukast sodium improves the ACT score

In the ICS group and the ICS + LABA group, the mean square ACT score increased by 6.6 and 5.4, respectively, from baseline to 12 months after montelukast sodium was added.

3) In the subgroup with / without allergic rhinitis, the use of montelukast sodium improves the ACT score

In the AR and non-AR groups, the mean square ACT score increased by 6.4 and 4.7 from the time of addition of montelukast sodium to the 12th month at baseline.

4) Improvement of MiniAQLQ by adding montelukast sodium

5) In the ICS and ICS + LABA subgroups, the use of montelukast sodium MiniAQLQ scores improved

6) In the subgroup with or without allergic rhinitis, the use of montelukast sodium MiniAQLQ score improved

Shun Erning (granular, chewable tablet type) study for children with asthma aged 1 to 14 years

1) A placebo-controlled study (PREVIA, montelukast sodium for the prevention of virus-induced asthma) in a 12-month-old child with mild intermittent asthma 2 to 5 years of age and exacerbation of viral infection Study), compared with placebo, taking montelukast sodium 4mg once a day can significantly reduce the frequency of exacerbations of asthma.

2) A 12-month clinical study of children with mild persistent asthma aged 4-16 years (N = 994) showed:

Montelukast sodium is effective in controlling asthma in children and is no less effective than fluticasone in increasing the number of days without first aid.

Merge Atlas (2 photos)

3) A 12-month clinical study of children with intermittent asthma aged 2-5 years (N = 549) showed:

The incidence of montelukast sodium was similar to placebo.

4) A two-phase clinical study of children with mild persistent asthma aged 6-9 years (N = 360) showed:

Montelukast sodium does not affect children's growth rate.