SINGULAIR. 4 mg. 28 tablets
SINGULAIR. 4 mg. 28 tablets
Qualitative and quantitative composition :
Each chewable tablet contains 4 mg 4.2 mg montelukast sodium, which is the molar equivalent of 4.0 mg free acid.
Each chewable tablet contains 5 mg 5.2 mg montelukast sodium, which is the molar equivalent of 5.0 mg free acid.
Each film tablet contains 10 mg 10.4 mg montelukast sodium, which is the molar equivalent of 10.0
SINGULAIR is provided as chewable tablets of 4 mg or 5 and as a film -coated tablets of 10 mg.
4 . clinical data
• Bronchial asthma.
• Relief of the day and night symptoms of seasonal allergic rhinitis.
4.2 Posology and method of administration
SINGULAIR should be taken once daily . In asthma , the dose should be taken in the evening . Seasonal allergic rhinitis , the application time may be changed according to individual patient needs .
Patients in whom there is and asthma and allergic rhinitis should take only one tablet once daily in the evening .
The dosage for children over 15 years of age and older with asthma and / or seasonal allergic rhinitis is one film tablet of 10 -mg daily.
The dosage for pediatric patients 6 - 14 years of age with asthma and / or seasonal allergic rhinitis is a chewable tablet of 5 -mg daily.
The dosage for pediatric patients 2-5 years of age with asthma and / or seasonal allergic rhinitis is a chewable tablet of 4 -mg daily.
Safety and effectiveness in pediatric patients less than 2 years have not been established .
Therapeutic effect of SINGULAIR on parameters of asthma control occurs within one day. SINGULAIR tablets may be taken with or without food. Patients should be advised to continue taking SINGULAIR, while their asthma is under control , as well as during periods of worsening asthma .
There is no need dosage adjustment in pediatric patients from both age groups , in adult patients with renal impairment or mild to moderate hepatic impairment , and gender.
Therapy with SINGULAIR in conjunction with other treatments for asthma SINGULAIR can be added to an existing treatment regimen of the patient.
Reduction in concurrent therapy:
Bronchodilator therapy : SINGULAIR may be added to the treatment regimen of patients who are not adequately controlled by the self -administration of a bronchodilator . When there is a clinical response (typically after the first dose ), treatment with bronchodilators may be reduced depending on tolerance .
Inhaled corticosteroids : Treatment with SINGULAIR has additional clinical benefit for patients treated with inhaled corticosteroids. Reducing the dose of corticosteroids may be made depending on tolerability. The dose should be reduced gradually under medical supervision . Some patients may gradually emerge from treatment with inhaled corticosteroids . SINGULAIR should not be abruptly substituted inhaled corticosteroids .
• Hypersensitivity to any component of the product
4.4 Special warnings and special precautions for use
The efficacy of oral SINGULAIR in the treatment of acute episodes of asthma has not been established . It should therefore not be used for oral tablets SINGULAIR treatment of acute asthma attacks . Patients should be advised to have available adequate life-saving medicines .
The dose of concomitant inhaled corticosteroid may be reduced gradually under medical supervision , but SINGULAIR should not be abruptly substituted inhaled or oral corticosteroids.
Decrease the dose of systemic corticosteroids , especially during prolonged treatment with these patients receiving antiasthmatic agents, including antagonists levotrienovite receptors in rare cases is followed by the occurrence of one or more of the following conditions eozinfilniya , vasculitic rash, worsening pulmonary symptoms , complications from the heart , and / or neuropathy - sometimes diagnosed syndrome Churg-Strauss ( systemic eosinophilic vasculitis) , which may be associated with reduction of corticosteroids. In the case of asthma as a component of an unrecognized CSS ( syndrome Churg-Strauss) reducing it with systemic corticosteroids , the latter may manifest clinically. Although not a causal connection with the leukotriene receptor antagonism , caution is advised and appropriate clinical monitoring when they take to reduce systemic corticosteroids in patients receiving SINGULAIR.
SINGULAIR contains aspartame, a source of phenylalanine. Patients with phenylketonuria should be aware that each chewable tablet contains 5 mg of phenylalanine in an amount equivalent to 0.842 mg phenylalanine per dose and that each chewable tablet contains 4 mg phenylalanine in an amount equivalent to 0.674 mg phenylalanine per dose .
SINGULAIR may be used with other types of treatment , routinely used for the prophylaxis and chronic treatment of asthma and in the treatment of allergic rhinitis . In clinical interaction studies , the recommended clinical dose of montelukast no clinically relevant effect on the pharmacokinetics of the following drugs : theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol / norethindrone 35/1 ),, digoxin and warfarin.
The area under the plasma concentration-time (AUC) for montelukast was decreased approximately 40% in subjects with concomitant administration of phenobarbital. Not recommended dosage adjustment of SINGULAIR.
4.6 Pregnancy and lactation
Use during pregnancy
SINGULAIR has not been studied in pregnant women. SINGULAIR may be used during pregnancy only if necessary.
Use during lactation
It is not known if SINGULAIR is excreted in human milk. Because many drugs are excreted in human milk, caution is when SINGULAIR is given to nursing mothers.
4.7 Effects on ability to drive and use machines
There is no evidence that SINGULAIR affect the ability to drive and use machines.
4.8 Undesirable effects
Generally SINGULAIR is well tolerated . Adverse reactions are usually mild in most cases do not require interruption of therapy. All cases of adverse reactions reported with SINGULAIR were comparable to placebo.
SINGULAIR has been evaluated in clinical trials, "approximately " 2,600 patients aged 15 and over 15 years of age with asthma. In two similar in design , 12-week placebo -controlled clinical trials , the only adverse events reported as drug related in> 1 % of patients treated with SINGULAIR, and more - greater frequency than in placebo-treated patients were abdominal pain and headache . The incidence of these events was not significantly different in the two groups. With prolonged treatment in clinical trials within two years , the profile of adverse events did not change.
SINGULAIR is also studied in approximately 320 pediatric asthma patients 6 to 14 years of age. The safety profile in pediatric patients is similar to that in adults and placebo. In an 8-week , placebo -controlled trial , the only adverse reaction reported as drug-related in> 1 % of patients treated with SINGULAIR and with greater frequency than in placebo-treated patients were headache. The incidence of headache was not significantly different in the two groups. With prolonged treatment in clinical studies up to 6 months , the profile of adverse events did not change.
SINGULAIR is also evaluated in 573 pediatric patients with asthma from 2 to 5 - years. In a 12-week , placebo- kontralirano clinical study , the only adverse reactions reported as drug related in> 1 % of patients treated with SINGULAIR and with greater frequency than in placebo patients was thirsty. Frequency of thirst was slightly different for the two treatment groups.
Generally, the 426 pediatric patients from 2 to 5 years of age were treated with SINGULAIR for at least 3 months 230 - for 6 months or longer, and patient 63 - C for 12 months or longer . Duration of treatment profile of adverse events did not change.
Adults over 15 years with seasonal allergic rhinitis
SINGULAIR has been evaluated in clinical trials in 2199 adults over 15 years for the treatment of seasonal allergic rhinitis. SINGULAIR, administered once daily in the morning or in the evening was generally well tolerated with a safety profile similar to placebo. In a placebo - controlled clinical studies no adverse reactions that are reported to be associated with the administration of the drug in more than 1 % of patients , taking SINGULAIR, and more frequently than in patients receiving placebo. The 4 - week placebo kortrolirano study , the safety profile was in line with that observed in 2- week studies . The incidence of somnolence was similar to paltsebo in all studies.
Pediatric patients 2 to 14 years with seasonal allergic rhinitis.
SINGULAIR has been studied in 280 pediatric patients aged 2 to 14 years for the treatment of seasonal allergic rhinitis in 2- week, placebo -controlled trial . SINGULAIR, administered once daily in the evening was generally well tolerated with a safety profile similar to that of placebo. In this study there were no adverse effects that have been reported as associated with the use of the drug in more than 1 % of patients , taking SINGULAIR, and more frequently than in patients receiving placebo.
Experience after placing the medicinal product on the market
The following additional adverse reactions have been reported during use of the medicinal product after marketing : hypersensitivity reactions (including anaphylaxis, engioedem , pruritus , rash , urticaria, and very rarely , eosinophilic infiltration of the liver) , sleep disturbances and hallucinations, drowsiness , irritability , agitation including aggressive behavior , restlessness , insomnia, paresthesia / hypoesthesia and very rarely seizures, nausea , vomiting , dyspepsia, diarrhea , arthralgia, myalgia including muscle cramps , increased bleeding , bruising , swelling and palpitations .
Reported cases are very rare syndrome Churg-Strauss during treatment with montelukast.
No deaths after single oral administration of doses at monteluklast sodium to 5000 mg / kg in mice and rats ( 15, 000 mg/m2 and 30, 000 mg/m2 of mice and rats , respectively ) the maximum dose tested . This dose is equivalent to 25 000 times the recommended daily dose for a human adult . *
No specific information on the treatment of overdosage with SINGULAIR. In chronic asthma studies , SINGULAIR is administered to adult patients at doses up to 200 mg / day for 22 weeks, and in short-term studies - to 900 mg / day for approximately one week without clinically significant side effects .
There have been reports of acute svrahdozirovka in children during postmarketing and clinical studies at doses up to 150 mg / day with SINGULAIR. The observed clinical and laboratory findings were consistent with the safety profile in adults and older children .
No reported side effects in the majority of cases of overdose. The most commonly observed adverse reactions were thirst , somnolence , mydriasis , hyperkinesia, and abdominal pain.
It is not known whether monteluklast dialyzed by peritoneal or hemodialysis.
5 . Pharmacological
5.1 Pharmacodynamic properties
Cysteinyl leukotrienes "(LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils . These important pro- asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. Type I CysLT receptor is located in the the human airway , including smooth muscle cells and macrophages, and other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells).
Cysteinyl - leukotrienes (CysLT) are associated with the pathophysiology of asthma and allergic rhinitis. In asthma , leukotriene mediated effects include effects of a number of aircraft the nasal passages , such as bronchoconstriction , mucous secretion , vascular permeability, and eosinophil recruitment. In allergic rhinitis , cysteinyl leukotrienes are released from the nasal mucosa following allergen exposure , during both the early phase and the late - phase response and are associated with the symptoms of allergic rhinitis . It has been demonstrated increased resistance of the nasal passages and the symptoms of nasal obstruction in an intranasal challenge with cysteinyl- leukotrienes.
Montelukast is a potent , orally active anti-inflammatory properties , which significantly improve the parameters of asthmatic inflammation . On the basis of biochemical and pharmacological bioizmervaniya , it has been found that montelukast binds with high affinity and selectivity to the CysLT1 receptor ( with a greater affinity than to other pharmacologically important receptors in the airways , such as prostanoids , cholinergic or adrenergic receptor - B ) .
Montelukast potently inhibits the physiological action of LTC4, LTD4, LTE4 in CysLT) receptor , without any agonistic activity.
In patients with asthma , montelukast leads to potent inhibition of the cysteinyl- leukotriene receptors in the airways as demonstrated by inhibition of bronchoconstriction induced by inhaled LTD4. Small doses of about 5 mg, resulting in a significant blockage of the LTD4- induced bronchoconstriction . Montelukast induce bronchodilation within 2 hours after oral administration , this effect was additive to bronchodilation induced by B - agonists.
Clinical Trials - Asthma
In clinical studies, SINGULAIR is effective in adult and pediatric patients for the prophylaxis and chronic treatment of asthma , including the prevention of daytime and night symptomatology , for the treatment of patients with asthma , aspirin-sensitive , and to prevent the induced bronchoconstriction . SINGULAIR is effective alone or in combination with other drugs used for the maintenance treatment of chronic asthma . SINGULAIR and inhaled corticosteroids can be used simultaneously with the additive effects on asthma control , or to reduce the dose of inhaled corticosteroids , while maintaining clinical stability
Adults ( over 15 years)
In two similar in design 12-week, double-blind , placebo- controlled trial in adult asthmatics over 15 years , SINGULAIR 10 mg once daily in the evening , showed significant improvement in parameters of asthma control , the assessment of asthma symptoms , associated asthma effects , respiratory function and use of beta- agonists "on demand ."
SINGULAIR significantly improved shared symptoms from the patient daily and nocturnal awakenings , as compared to placebo . The specific effects of asthma , including asthma attacks, life-saving corticosteroid interruptions of studies due to worsening asthma exacerbations of asthma and asthma -free days are also better than placebo . Global assessment of asthma by physicians and patients and the evaluation of specific asthma quality of life ( in all areas, including normal daily activity and asthma symptoms ) were significantly better than placebo. SINGULAIR leads to significant improvements in the morning forced expiratory volume in 1 second (< FEV1 ) , AM and PM peak expiratory velocity flow and substantially reduces the use of beta -agonists, " on demand" , in comparison with placebo.
The therapeutic effect was achieved after the first dose and was maintained throughout the 24 -hour dosing interval. The therapeutic effect remains constant , and during continuous once-daily administration in advanced studies of up to one year. Discontinuation of treatment with SINGULAIR, after 12 weeks of use, does not lead to reverse worsening asthma .
Compared with inhaled beclomethasone ( 200 pg twice daily with sprayer ), SINGULAIR demonstrated a more rapid initial response, although over the 12 -week study , beclomethasone provided a greater average treatment effect . In a high percentage of patients treated with SINGULAIR, however, achieved a clinical response similar to that of inhaled beclomethasone.
Pediatric patients 6 to 14 years old
In pediatric patients, aged 6 to 14 years of age , a chewable tablet 5-mg daily in the evening , significantly reduced exacerbations of asthma and improving the global evaluation of the parents and pediatric specific asthma ratings of quality of life , as compared to placebo . SINGULAIR also significantly improves morning FEV ] and reduces the daily use of beta- agonists "on demand ." The therapeutic effect is achieved after the first dose and remained constant during the once-daily administration to 6 months.
Pediatric patients aged 2 to 5 years
In a 12 -week, placebo - controlled study in pediatric patients from 2 to 5 years old , SINGULAIR 4 mg once daily significantly improved parameters for the control of asthma , nezavsimo of concomitant therapy compared with placebo. Sixty percent of patients were not on any therapy. SINGULAIR significantly improve daytime symptoms ( including coughing, wheezing , shortness of breath , and reduced physical activity ) and nighttime symptoms as compared to placebo SINGULAIR is also substantially reduce the need for the use of beta- and agonioti zhvotospasyavashti corticosteroids as compared to placebo . Patients receiving
SINGULAIR had significantly more days without asthma symptoms than those receiving placebo. A treatment effect was achieved after the first dose. In addition , the total number of eosinophils in the blood dropped significantly .
Effects in patients receiving concomitant inhaled corticosteroids
Separate studies in adults have shown the ability of SINGULAIR to add to the clinical effect of inhaled corticosteroid and allows for concomitant use gradual reduction of steroid . In a placebo -controlled study , patients received an initial dose inhaled corticosteroid approximately 1600 mcg per day reduced their use by approximately 37% during the placebo run-in period . SINGULAIR allows a further 47% reduction of the dose of inhaled corticosteroid as compared to 30% for placebo. In another study , SINGULAIR offer additional clinical benefit of such a population of patients maintained but not adequately controlled by inhaled corticosteroids (beclomethasone 400 mcg daily). Full abrupt cessation of beclomethasone in patients receiving and SINGULAIR and beclomethasone, leading to clinical deterioration in some patients , suggesting that the gradual tolerated reduction is preferable to a sudden stop. In patients sensitive to aspirin, nearly all of whom were receiving concomitant inhaled and / or oral corticosteroids , SINGULAIR significantly improved parameters of asthma control .
Effects on exercise-induced bronchoconstriction
SINGULAIR, 10 mg once daily prevents exercise-induced bronchoconstriction (EIB) in patients over 15 years of age. In a 12 -week study , SINGULAIR significantly reduced the rate and duration of the decline in FEV1 over 60 minutes of effort , the maximum percentage fall in FEV1 after the effort and time to recovery to within 5% of FEV1 before the effort. The protection persisted during the period of treatment , indicating that no tolerance arises . In a separate crossover study , protection was observed after two once-daily doses. In pediatric patients aged 6 to 14 years , using chewable tablets of 5 mg, a similar study showed an identical protection , which was maintained throughout the dosing interval (24 hours).
Effects on asthmatic inflammation
In clinical studies, SINGULAIR inhibits bronchoconstriction induced by antigen stimulation, as in the early and the late phase . Since the infiltration of inflammatory cells ( eosinophils ) is an important feature of asthma were studied effects of SINGULAIR on peripheral blood eosinophils and airway . In phase Ilb / III clinical trials , SINGULAIR significantly reduces peripheral blood eosinophils , approximately 15 % from baseline , compared with placebo. For pediatric patients 6 to 14 years of 13% lowers SINGULAIR eozinfilite in peripheral blood, for a treatment period of more than 8 weeks, compared to placebo SINGULAIR also decreases significantly , and eosinophils in the airways of sputum when compared to placebo. In this study , when treated with SINGULAIR, peripheral blood eosinophils decreased and improve the final clinical indicators of asthma.
Clinical trials - seasonal allergic rhinitis
The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis was investigated in randomized , 2- week, double -blind, pratsebo controlled studies of similar design, including 4924 patients ( 1751 patients received SINGULAIR). Patients were aged 15 years and older with a history of seasonal allergic rhinitis, positive skin test to at least one corresponding seasonal allergen , and active symptoms of seasonal allergic rhinitis at baseline .
According to the combined analysis of three fundamental studies , SINGULAIR, in the form of 10 mg tablets, administered to 1189 patients daily in the evening , led to a statistically significant improvement over placebo in the primary endpoint , overall assessment of daytime nasal symptoms (daytime nasal symptoms score ) to include the individual components ( nasal congestion, rhinorrhea , itchy nose and sneezing ), the overall assessment of nocturnal nasal symptoms (nighttime symptoms score), to include the components ( nasal congestion upon awakening , difficulty sleeping and waking in the night ) composite endpoint evaluation ( including common assessments daily and nocturnal symptoms ) total score (global evaluation) of allergic rhinitis by patients and doctors.
In a separate 4 -week study in which SINGULAIR was administered once daily in the morning for the first performance period of two weeks was significantly different from placebo and consistent with results observed in studies with evening dosing . Furthermore, the effect for four weeks was in accordance with the results of the first 2 weeks.
In patients with seasonal allergic rhinitis aged 15 years and older who received SINGULAIR, a decrease on average by 13 % in the number of peripheral eosinophils compared with placebo for the double-blind period.
5.2 Pharmacokinetic properties
After oral montelukast is absorbed rapidly and almost completely . The mean peak plasma concentration ( Cmax ) film coated tablets of 10mg, is achieved 3 hours ( Tmax ) after fasting in adults. Average . Oral bioavailability is 64 %. Oral bioavailability and are not influenced by a standard meal.
With chewable tablets of 5 mg, Cmax is reached 2 hours after administration in adults under fasting conditions. The mean oral bioavailability is 73% . Food has no important influence to the clinic after prolonged use.
With chewable tablets of 4 mg, Cmax is reached 2 hours after administration in pediatric patients from 2 to 5 years of age in the fasted state .
Safety and efficacy were demonstrated in clinical trials where chewable tablets of 4 and 5 mg film-coated tablets and 10 mg was taken regardless of mealtime .
Montelukast has more than 99 % bound to plasma proteins. Steady-state volume of distribution of montelukast averages less than 8-11 liters. Studies in rats with radiolabelled monteluklast, indicate minimal across the blood -brain barrier . Furthermore, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.
Montelukast is extensively metabolized . In studies , plasma concentrations of metabolites of montelukast in therapeutic doses are undetectable at steady - state in adults and children.
In vitro studies in which were used human liver microsomes , suggest that the metabolism of montelukast included cytochrome P450 2C9 and ZA4 . Based on further in vitro results in human liver microsomes , therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 ZA4 , 2C9, 1A2, 2A6, 2C19 and 2D6.
In healthy adult plasma clearance of montelukast averages 45 mL / min. After an oral dose of radiolabeled monteluklast, 86% of the radioactivity was recovered in the faeces of 5 days and <0.2% - in the urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast is excreted almost exclusively via the bile.
In several studies, the mean half-life of plasma montelukast ranged from 2.7 to 5.5 hours in healthy young subjects. The pharmacokinetics of montelukast is almost linear for the oral doses of up to 50 mg. There was no difference in pharmacokinetic properties between morning and evening doses. There is a small accumulation of intact plasma product ( ~ 14% ) at a dosage of monteluklast of 10 mg once daily .
Characteristics in Patients
There is no need for dosage adjustment in elderly patients , renal insufficiency, or mild to moderate hepatic insufficiency. There are no clinical data in patients with severe hepatic impairment (Child - Pugh score> 9).
5.3 Preclinical safety data
In animal studies, the safety of the medicinal product , minor biochemical changes in serum levels of ALT, glucose
phosphorus and triglycerides , but they were transient . Signs of toxicity in animals were increased saliva, gastrointestinal symptoms, loose stools and ion imbalance. Such symptoms were seen at doses 17 times higher than clinical . In monkeys, the adverse effects appeared at doses of 150 mg / kg / day (> 232 -fold higher dose of clinically ) . In animal studies montelukst had no effect on fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by more than 24 times . In a study with rats, fertility was observed a slight increase in pup body weight at 200 mg / kg / day (> 69 times the clinical dose). In studies in rabbits , there was a higher incidence of incomplete ossification , compared with concurrent control animals when exposed to a dose 24 times the clinical dose. No abnormalities were seen in the rat . Montelukast crosses the placental barrier and is excreted in the milk of animals. No deaths occurred following a single dose of montelukast sodium at doses up to 5000 mg / kg in mice and rats , (15,000 mg/m2 in mice and 30,000 mg/m2 in rats ) the maximum dose tested .
It has been found that montelukast is not phototoxic in mice for narrow band or UVB rays or visible radiation at doses up to 500 mg / kg / day (approximately 200 times the clinical dose ) .
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodents.
6 . PHARMACEUTICAL PARTICULARS
6.1Spisak of excipients and their amounts
Each film coated tablet 10 mg contain the following inactive ingredients : cellulose, microcrystalline - 89.3 mg; lactose monohydrate - 89.3 mg; crocarmellose sodium - 6.0 mg; hydroxypropylcellulose -1.73 mg; magnezium stearate - 1.0 mg. The film coating consists of : methylhydroxypropylcellulose - 1.73 mg; hydroxypropylcellulose - 1.73 mg; titanium dioxide - 1.50 mg; red ferric oxide - 0.004 mg; yellow ferric oxide - 0.036 mg and wax - carnauba.
Each chewable tablet 4 and 5 mg contain the following inactive ingredients : mannitol - 161.08/201.35 mg; cellulose, microcrystalline - 52.8/66.0 mg; Hydroxypropyl cellulose - 7.2/9.0 mg; red ferric oxide - 0.36/0.45 mg; crocarmellose sodium - 7.2/9.0 mg; cherry flavour - 3.6/4.5 mg; aspartame-1.2/1.5 mg; magnesium stearate - 2.4/3.0 mg.
6.2 Physical incompatibilities hnmichni
6.3 Shelf life
The expiry date of SINGULAIR 10 mg film -coated tablet is 36 months shelf life of SINGULAIR 5 mg chewable tablet is 24 months shelf life of SINGULAIR 4 mg chewable tablet is 24 months ;
6.4 Special precautions for storage
Store up to 30 ° C in a dry, protected from light .
6.5 Nature and contents of container
SINGULAIR 10 mg is available in packs of 14 and 28 film -coated tablets / blister 1 X 14 and 14 X 2 blisters / .
SINGULAIR 5 mg is available in packs of 14 and 28 chewable tablets / blister 1 X 14 and 14 X 2 blisters / .
SINGULAIR 4 mg is available in packs of 14 and 28 chewable tablets / blister 1 X 14 and 14 X 2 blisters / .
6.6 Recommendations for use