Approval date: November 30, 2006
Modification date: November 14, 2008
Modification date: December 21, 2009
Modification date: September 11, 2010
Modification date: December 27, 2011
Revision date: August 23, 2012
Revision date: 08/28/2012
Revision Date: 08/03/2013
Revision date: October 25, 2013
Revision date: September 05, 2014
Date of revision: 07/11/2016
Montelukast Sodium Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name]
Generic name: montelukast sodium tablets
Trade name: Soonerin® (Singulair®)
English name: Montelukast Sodium Tablets
Hanyu Pinyin：Menglusitena Pian
[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
[Characteristic]
This product is a light yellow shaped film coated tablet.
[Indications]
This product is indicated for the prevention and long-term treatment of asthma in adults 15 years of age and older, including prevention of daytime and nocturnal asthma symptoms, treatment of aspirin-sensitive asthma patients and 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 adults 15 years of age and older).
[Specification]
10mg (as montelukast).
[Dosage]
One tablet (10mg) once daily. Asthma patients should take it at bedtime. Patients with allergic rhinitis can take the medication as needed according to their condition.
Patients with both asthma and allergic rhinitis should take the medication once a night.
Adult patients 15 years of age and older with asthma and/or allergic rhinitis should take 10 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 whether in the asthma control or worsening phase.
No dose adjustment is required in elderly patients, patients with renal insufficiency, patients with mild to moderate hepatic impairment, and patients of different genders.
Relationship of Montelukast Sodium Tablets with other asthma treatment drugs
This product may be added to a patient’s existing treatment regimen.
Reduce the dose of the combined medication:
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 as tolerated once there is a clinically significant efficacy response (usually after the first dose).
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 replacement for inhaled glucocorticosteroids.
[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 was similar to that of placebo.
Patients 15 years of age and older with asthma
Clinical studies have been conducted to evaluate the safety of this product in approximately 2600 adult asthma patients 15 years of age and older. In two similarly designed, placebo-controlled 12-week clinical studies, the drug-related adverse events with an incidence ³1% higher in the drug-treated group than in the placebo group were abdominal pain and headache. However, there was no significant difference in the incidence of these adverse events between the two groups.
Cumulatively, 544 patients have been treated with this drug for at least 6 months, 253 for 1 year, and 21 for 2 years in the clinical study. The incidence of adverse events did not change with longer treatment with this product.
Patients aged 15 years and older with seasonal allergic rhinitis
A clinical study has been conducted to evaluate the safety of this product in 2199 adult patients aged 15 years and older with seasonal allergic rhinitis. A single daily morning or nighttime dose of this product was well tolerated, with an incidence of adverse reactions similar to that of placebo. In the placebo-controlled clinical study, no drug-related incidence of ³1% was found in the drug-treated group, and the incidence of adverse events was higher than 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 to the placebo group in all clinical studies.
Patients 15 years of age and older with perennial allergic rhinitis
Two six-week placebo-controlled clinical studies have been conducted to evaluate the safety profile of this product in 3,235 adult patients aged 15 years and older with perennial allergic rhinitis. The once-daily dose was well tolerated, with an incidence of adverse reactions similar to that of the placebo group and consistent with the results of clinical studies in seasonal allergic rhinitis. In both clinical studies, the incidence of adverse events in the treatment group was less than 1% and was not found to be drug-related, and the incidence was higher than that in the placebo group. The incidence of drowsiness was similar to that 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 validated methods for assessing suicidal behavior. Of the 9929 patients taking this product and 7780 patients taking placebo, one patient with suicidal ideation took this 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; 11 studies in pediatric patients aged 3 months to 14 years) was conducted to assess behaviorally relevant adverse events. Among 11,673 patients taking this product 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 the marketed use of this 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 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 components of 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.
This product should not be used as an abrupt replacement for inhaled or oral glucocorticosteroids, although the combined inhaled glucocorticosteroid dose may be tapered under the direction of a physician.
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.
This drug should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Montelukast may have no or minor effects 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 this product. Postmarketing reports of administration of this product include euphoria, aggressive behavior or hostility, anxiety, depression, disorientation, attention disorders, dream abnormalities, hallucinations, insomnia, irritability, memory deficits, restlessness, sleepwalking disorder, suicidal thoughts and behavior (including suicide), convulsions, and tremors. Some post-marketing reports of this product have clinical details that appear to be consistent with drug-induced effects.
Psychoneurological events have been reported in patients taking this product (see Adverse Reactions). Because other factors may also contribute to these events, it is not possible to confirm whether they are related to this product. Physicians should discuss these adverse events with the patient and/or caregiver. Patients and/or caregivers should be advised to notify their physician if these occur.
Patients with known sensitivity to aspirin should continue to avoid aspirin or nonsteroidal anti-inflammatory drugs while taking this product.
[Use in Pregnant and Lactating Women]
No studies are available 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 use of this product 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.The use of montelukast sodium chewable tablets in children 2 years to 14 years of age is described in [DOSAGE].The safety and efficacy of montelukast sodium chewable tablets in children less than 6 months of age have not been studied.
Studies have shown that this product does not affect the growth rate in children.
[Geriatric Use]
There were no age differences in the effectiveness or safety of this product in clinical studies.
[Drug Interactions]
This product may be used in combination with other drugs routinely used for the prophylaxis 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/norethindrone 35/1), terfenadine, digoxin, and warfarin.
Thyroid hormones, sedative hypnotics, NSAIDs, benzodiazepines and decongestants: Although no additional specific interaction studies have been conducted, there is no evidence of clinical adverse interactions when this product is combined with commonly prescribed drugs that have been 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, suggest 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 CYP 2C8, 2C9 and 3A4. A clinical study involving drug-drug interactions between montelukast and gemfibezil, an inhibitor of CYP 2C8 and 2C9, demonstrated that gemfibezil increased systemic exposure levels of montelukast by 4.4-fold. Itraconazole, a potent inhibitor of CYP 3A4 —-, did not further increase systemic exposure levels of montelukast when administered concomitantly with gemfibezil and montelukast. In 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), no clinically meaningful adverse events were observed, and based on such data, 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 CYP 2C8 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]
No information is available specifically regarding overdose of this product in clinical therapy. No clinically significant adverse events were observed in studies for the treatment of chronic asthma 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.
Acute post-marketing overdoses and clinical studies with this product have been reported. These include reports of doses up to 1000 mg in adults and children. Clinical and laboratory findings have consistently demonstrated its 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 is 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 b-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 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 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 toxicity studies on development, when doses up to 400 mg/kg/day were administered to rats and doses up to
100 mg/kg/day of montelukast sodium, no treatment-related adverse effects were observed. Exposure of the fetus 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. Plasma drug concentrations reached peak concentrations (Cmax) at 3 hours (Tmax) following fasting doses of 10 mg film-coated tablets in adults. The average oral bioavailability was 64%. Normal diet had no effect on oral bioavailability or Cmax. Clinical studies have shown that montelukast sodium in a 10 mg film-coated tablet is safe and effective when taken at any time after eating.
Distribution
More than 99% of montelukast sodium is bound to plasma proteins. The steady-state volume of distribution of montelukast averaged 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, 2A6, 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 50 kg.
[Clinical Studies]
Clinical Studies – Asthma
Adult patients aged 15 years and older
Two (US and multinational) equally designed 12-week, double-blind, placebo-controlled studies of 1325 patients (795 patients treated with this product and 530 patients treated with placebo) confirmed the efficacy of this product in the treatment of adults 15 years of age and older with chronic asthma. Patients had symptoms of asthma and used a b agonist approximately 5 times daily as needed. The mean baseline expected percentage of exertional expiratory volume in 1 second (FEV1) was 66% (range 40%-90%). In these studies, asthma symptoms, asthma-related outcomes, respiratory function, and on-demand use of b agonists were measured. Endpoints were analyzed in each study and in a combined analysis according to a predefined data analysis plan. The following clinical outcomes were obtained.
Asthma symptoms and asthma-related outcomes.
In each study and in the combined analysis, one daily dose of 10 mg of this product at night significantly improved patient-reported daytime symptoms and nocturnal awakenings compared with the placebo group. In patients with nocturnal awakenings on at least 2 nights per week, it reduced nocturnal awakenings by 34% relative to baseline, significantly better than 14% in the placebo group (pooled analysis).
This product significantly improved asthma-related outcomes compared with placebo. In the combined analysis, compared with placebo, this product reduced asthma attacks by 37%, glucocorticoid rescue by 39%, discontinuation due to worsening asthma by 65%, acute asthma attacks by 38%, and increased asthma-free days by 42%.
Overall physician and patient asthma assessments and asthma-specific quality of life assessments (in all domains, including normal daily activities and asthma symptoms) were significantly better with this product than with placebo in various studies and in a combined analysis.
Respiratory Function
In various studies and in a combined analysis, this product significantly improved respiratory function parameters (FEV1 and peak expiratory flow rate, PEFR) compared to placebo.
Effect of 10 mg of this product once daily on respiratory function parameters in adult patients aged 15 years and older (combined analysis)
this product
n=795 placebo
n=530 morning FEV1 (% relative to baseline) 10.4*2.7AM PEFR (change L/min relative to baseline) 24.5*3.3PM PEFR (change L/min relative to baseline) 17.9*2.0 * Significantly better than placebo (p £ 0.001)
Use of b-receptor agonists
In the combined analysis, this product significantly reduced b agonist use on-demand by 26.1% relative to baseline, compared with a 4.6% reduction in the placebo group. There was also a significant difference in the reduction in b agonist on-demand use across studies (p £ 0.001).
Onset and maintenance benefit
In all studies and in the combined analysis, the therapeutic effect of the product was obtained after the first dose (as measured by daily diary card parameters, including ongoing score, b agonist use on demand and PEFR measurements) and was maintained throughout the inter-dose period (24 hours). This treatment effect was also obtained during continuous once-daily dosing in the extension study for up to 1 year. Discontinuation of the drug after 12 weeks of continuous use did not result in a rebound worsening of asthma. (See “Effect on exercise-induced bronchoconstriction”)
Effects related to inhaled glucocorticoids
In a 12-week double-blind study (multinational) in adult patients, this product was compared with inhaled beclomethasone (200 mg twice daily in a barrier device). The results showed that although beclomethasone had a better average treatment effect throughout the study period, it had a faster onset of efficacy. However, a higher proportion of patients treated with beclomethasone achieved clinical outcomes similar to those achieved with inhaled beclomethasone.
Effect of concomitant use of inhaled glucocorticoids in patients
Independent studies in adult patients have demonstrated the clinical effectiveness of this product in increasing the use of inhaled glucocorticosteroids when used concomitantly with glucocorticosteroids, as well as the ability to allow gradual tapering of the steroid.
Three large studies confirmed an additional benefit of this product in patients taking glucocorticoids. In a randomized, placebo-controlled, parallel-group study (n = 226), patients with stable asthma treated with a starting dose of glucocorticoids of approximately 1600 mg daily reduced their steroid dosage by approximately 37% during the placebo introduction period. It further reduced inhaled glucocorticoid use by 47% during 12 weeks of active drug therapy, compared with a 30% reduction in inhaled glucocorticoid use with placebo (p £ 0.050).
In another randomized, placebo-controlled, parallel-group study (n = 642), this product produced an additional clinical benefit compared with placebo in a similar population of patients treated with inhaled glucocorticoids (beclomethasone 400 mg/day) whose efficacy was maintained but whose symptoms were poorly controlled. Abrupt and complete discontinuation of beclomethasone in patients receiving both treatments may result in worsening of clinical symptoms in some patients. This suggests that the inhaled beclomethasone dose should be gradually reduced until it is tolerated by patients rather than abruptly discontinuing the steroid.
A 4-week, parallel-group study (n = 80) demonstrated significant improvement in asthma control parameters compared to placebo in aspirin-sensitive asthma patients who were almost all receiving inhaled and/or oral glucocorticoid therapy.
Effect on exercise-induced bronchoconstriction
In a 12-week, parallel-group study in 110 adult patients aged 15 years and older, 10 mg of this product prevented exercise-induced bronchoconstriction (EIB) compared to placebo, as evidenced by significant inhibition of the following parameters.
The degree and duration of FEV1 reduction (as measured by the area under the curve (AUC) of the percentage reduction relative to time) within 60 minutes after exercise.
The maximum percentage reduction in FEV1 after exercise.
Time to recovery of FEV1 to within 5% of pre-exercise
No change in protection during the 12-week treatment period, indicating that patients did not develop tolerance. In an independent crossover study, the protective effect occurred after 1 dose administered twice daily.
A similarly designed crossover study confirmed a similar protective effect with 5 mg chewable tablets in pediatric patients aged 6-14 years, and the protective effect was maintained throughout the interdose period (24 hours).
Effects on asthma inflammation
Several studies have shown that this product may inhibit the parameters of asthma inflammation. In a placebo-controlled crossover study (n = 12), it inhibited 75% and 57% of antigen-induced early and late bronchoconstriction, respectively.
Since inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effect of this product on eosinophils in the peripheral blood and airways was determined. In a phase IIb/III clinical study in adults, it significantly reduced peripheral blood eosinophils compared to placebo (approximately 15% reduction relative to baseline). In pediatric patients aged 6-14 years, it also significantly reduced peripheral blood eosinophils compared to placebo over an 8-week treatment period (~13% reduction relative to baseline).
In a 4-week, randomized, parallel group human study (n = 40), this product significantly reduced airway eosinophils (as measured by sputum) (48% reduction relative to baseline versus 23% reduction with placebo). In this study, treatment with this product significantly reduced peripheral blood eosinophils and improved clinical asthma endpoints.
Clinical Studies – Allergic Rhinitis
The efficacy of this product in the treatment of seasonal allergic rhinitis was measured in a similarly designed randomized, 2-week, double-blind, placebo-controlled study enrolling 4924 patients (including 1751 treated with this product). Patients were 15 years of age and older with a history of seasonal allergic rhinitis, positive skin test results for at least one relevant seasonal allergen, and symptoms of active seasonal allergic rhinitis at the start of the study.
In a pooled analysis of 3 pivotal studies, the primary endpoints of daytime nasal symptoms and their individual (nasal congestion, runny nose, nasal itching and sneezing) scores, nighttime symptoms and their individual (nasal congestion on awakening, difficulty sleeping and nocturnal awakening) scores, daytime ocular symptoms and their individual (tearing, pruritus, redness and puffiness) scores, and daytime ocular symptoms and their individual (nasal congestion on awakening, difficulty sleeping and nocturnal awakening) scores, compared with placebo, in 1189 patients administered 10 mg of this product tablet once daily at night. Redness and puffiness), overall patient and physician assessment of allergic rhinitis, and overall symptom scores (including daytime nasal and nighttime symptom scores) all improved significantly.
In an independent 4-week study, the efficacy of once-daily dosing in the morning was significantly different from that of placebo for the first 2 weeks and was consistent with the efficacy obtained in the nighttime dosing study. In addition, efficacy over the entire 4-week period was consistent with efficacy over the first 2 weeks.
During the double-blind treatment period, the median eosinophil count reduction among patients 15 years of age and older with seasonal allergic rhinitis treated with this product was 13% compared to placebo.
The efficacy of this product in the treatment of perennial allergic rhinitis was measured in 2 randomized, 6-week, double-blind, placebo-controlled studies of similar design that included 3235 patients (including 1632 patients treated with this product). Patients were 15-82 years of age with a history of perennial allergic rhinitis, positive skin test results for relevant perennial allergens including dust mites, animal dander, and mold spores, and symptoms of active seasonal allergic rhinitis at the start of the study.
In one study, there was a significant improvement in the primary endpoint of daytime nasal symptoms and its various (nasal congestion, runny nose, nasal itching and sneezing) scores in 1,000 patients following once-daily administration of 10 mg of this product in tablet form compared to placebo. Compared to placebo, this product also significantly improved secondary endpoints in patients with allergic rhinitis, including patients’ overall assessment of allergic rhinitis and overall rhinoconjunctivitis quality of life scores (mean scores for seven activity domains, including sleep, non-nasal/non-eye symptoms, practical problems, nasal symptoms, eye symptoms, and mood).
The efficacy of this product in treating patients with seasonal rhinitis in children aged 2-14 years and in children aged 6 months to 14 years with perennial allergic rhinitis is supported by extrapolation from proven efficacy in patients aged 15 years and older with allergic rhinitis and based on the hypothesis that the course of disease, pathophysiology, and drug action are essentially similar in these populations.
[Storage].
Store at room temperature between 15-30°C, protected from moisture and light.
[Package]
Packed in aluminum-plastic sheet, 5 tablets/box or 7 tablets/box.
[Expiry date].
36 months.
[Executive Standard]
Imported drug registration standard JX20010356
[Imported drug registration certificate number]
[Manufacturer]
Company name: Merck Sharp & Dohme B.V.
Address: Waarderweg 39, 2031 BN Haarlem, P.O. Box 581, 2003 PC Haarlem, The Netherlands
Plant name: Merck Sharp & Dohme Ltd.
Address: Shotton Lane, Cramlington, Northumberland, NE23 3JU, U.K.
Name of packaging plant: Merck Sharp & Dohme B.V.
Address: Waarderweg 39, 2031 BN Haarlem, The Netherlands
Tel: 021-22118888
Fax Number: 021-22118500