Singulair. 5 mg. 28 table
Singulair. 5 mg. 28 table
Facilitation of daily and nocturnal symptoms of seasonal allergic rhinitis.
Posology and method of administration
SINGULAIR should be taken once daily. In asthma, the dose should be taken at night. In seasonal allergic rhinitis, the time of application can be changed according to individual patient needs.
Patients there and asthma and allergic rhinitis should take only one tablet once daily in the evening.
Dosing for children over 15 years of age and older with asthma and / or seasonal allergic rhinitis is a film-coated tablets of 10-mg daily.
The dosage for pediatric patients 6 to 14 years with asthma and / or seasonal allergic rhinitis is a chewable tablet 5-mg daily.
The dosage for pediatric patients 2 to 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 and tablet may be taken with or without food. Patients should be advised to continue taking SINGULAIR, while asthma is under control, as well as during periods of worsening asthma.
You do not need dosage adjustment in pediatric patients in both age groups, adults, patients with renal impairment or mild to moderate hepatic impairment, and gender of patients.
Therapy with SINGULAIR on other asthma SINGULAIR can be added to an existing treatment regimen for the patient.
Reduction in concurrent therapy:
Treatment with bronchodilators: SINGULAIR can be added to the treatment regimen of patients who are not adequately controlled with either a bronchodilator. When a clinical response (usually after the first dose), treatment with bronchodilators can be reduced as tolerated.
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 dosage 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
Special warnings and special precautions for use
The efficacy of SINGULAIR oral treatment of acute asthma has not been established. Therefore should not be used oral SINGULAIR tablets for the treatment of acute asthma. Patients should be advised to have appropriate life-saving drugs.
The dose of concomitant inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR but should not replace suddenly inhaled or oral corticosteroids.
Decrease the dose of systemic corticosteroids especially during prolonged treatment with these patients receiving protivoastmatichni means including levotrienovite receptor antagonists, in rare cases, followed by the occurrence of one or more of the following eozinfilniya, vasculitic rash, worsening pulmonary symptoms, cardiac complications from the heart, and / or neuropathy - sometimes diagnosed as syndrome Churg-Strauss (systemic eosinophilic vasculitis) which may be associated with reduced corticosteroids. In the case of asthma, as a component of unrecognized CSS (syndrome Churg-Strauss) then in reducing systemic corticosteroids, the latter may manifest clinically. Although no causal connection with a leukotriene receptor antagonism, it is recommended that attention and appropriate clinical monitoring when taking reducing 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 administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma and allergic rhinitis. In clinical interaction studies, the recommended clinical dose of montelukast no clinically relevant effects 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.
Pregnancy and lactation Use in 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 needed when SINGULAIR is given to nursing mothers.
Effects on ability to drive and use machines
There is no evidence that SINGULAIR affect your ability to drive or operate machinery.
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. 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 frequency of these cases is 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 patients with asthma 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 event reported as drug related in> 1% of patients treated with SINGULAIR and at a greater incidence than in patients receiving placebo was headache. The frequency 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 studied in 573 pediatric patients with asthma from 2 to 5 - years. In a 12-week, placebo-kontralirano trial, the only adverse reaction reported as drug related in> 1% of patients treated with SINGULAIR and at a greater frequency than placebo-treated patients was thirsty. The incidence of hunger was slightly different for the two treatment groups.
A total of 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 - for 6 months or longer, and 63 patients - for 12 months or longer . With a treatment duration 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 placebo - controlled clinical studies, adverse reactions that have been reported as associated with the administration of the drug in more than 1% of patients took SINGULAIR, and chastota greater than that 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 evaluated 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 placebo. In this study there were no adverse reactions that have been reported as associated with the administration of the drug in more than 1% of patients took SINGULAIR, and chastota greater than that 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 product from the market: hypersensitivity reactions (including anaphylaxis, engioedem, pruritus, rash, urticaria and rarely, eosinophilic infiltration of the liver), sleep disturbances and hallucinations drowsiness, irritability, agitation including aggressive behavior, restlessness, insomnia, paresthesia / hypoesthesia and rarely convulsions, nausea, vomiting, dyspepsia, diarrhea, arthralgia, myalgia including muscle cramps, abnormal bleeding, bruising, swelling and palpitations.
Very rare cases of the syndrome Churg-Strauss during treatment with montelukast.
No deaths after single oral administration of monteluklast sodium at doses up to 5000 mg / kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 for mice and rats, respectively) the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily human adult dose. *
No specific information on the treatment of overdosage with SINGULAIR. In chronic asthma studies, SINGULAIR was administered to adult patients at doses up to 200 mg / day for 22 weeks and in short-term studies - up to 900 mg / day for approximately a week without clinically important adverse reactions.
There have been reports of acute svrahdozirovka in children during postmarketing and clinical studies at doses up to 150 mg / day with SINGULAIR. The clinical and laboratory findings were consistent with the safety profile in adults and older children.
No adverse reactions reported in most cases of overdose. The most commonly observed adverse reactions were thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain.
It is not known whether monteluklast dialysable by peritoneal or hemodialysis.
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 receptors, (CysLT) receptors. Type I CysLT receptors are located in human airways, including smooth muscle cells and macrophages, and other pro-inflammatory cells (including eosinophils and certain myeloid stem cells).
Cysteinyl - leukotrienes (CysLT) are associated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a number of reactions an aircraft nasal passages, such as bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, cysteinyl leukotrienes are released from the nasal mucosa after allergen exposure, during both the early phase and the late-phase reactions and are associated with symptoms of allergic rhinitis. It has been demonstrated increased resistance of the nasal passages and symptoms of nasal obstruction in intranasal challenge with cysteinyl-leukotrienes.
Montelukast is a potent, orally active substance with anti-inflammatory properties that significantly improve the characteristics of asthmatic inflammation. Based on biochemical and pharmacological bioizmervaniya, found that montelukast is associated with high affinity and selectivity to the CysLT1 receptor (with higher affinity than to other pharmacologically important receptors in the airways, such as prostanoid, cholinergic, or B-adrenergic receptor) .
Montelukast inhibits powerful physiological action of LTC4, LTD4, LTE4 in CysLT) receptor agonist with no activity.
In patients with asthma, montelukast led to potent inhibition of cysteinyl-leukotriene receptors in the airways, as demonstrated by inhibition of bronchoconstriction induced by inhaled LTD4. Small doses of about 5 mg, leading to a significant blockade of LTD4-induced bronchoconstriction. Montelukast causes bronchodilation within 2 hours after oral administration, these effects are additive to the bronchodilation induced by B-agonists.
Clinical Trials - Asthma
In clinical studies, SINGULAIR is effective in adults and pediatric patients for the prophylaxis and chronic treatment of asthma, including prevention simtomatika day and night, for the treatment of patients with asthma are sensitive to aspirin for preventing bronchoconstriction induced by exercise. SINGULAIR is effective alone or in combination with other drugs used for maintenance treatment of chronic asthma. SINGULAIR and inhaled corticosteroids may be used concomitantly with additive effects on asthma control or reduce the dose of inhaled corticosteroid, while maintaining clinical stability
Adults (over 15 years)
Two similar in design 12-week, double-blind, placebo-controlled studies in adult asthmatics over 15 years, SINGULAIR 10 mg once daily in the evening, showed significant improvement in parameters of asthma control in assessing the symptoms of asthma related consequences asthma, respiratory function and use of p-agonists "on demand".
SINGULAIR shared significantly improves the patient's daily symptoms and nocturnal awakenings compared with placebo. The specific effects of asthma, including asthma attacks, lifesaving 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 doctors and patients and assessment 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 morning forced expiratory volume in 1 second (<FEV1), AM and PM peak expiratory rate flow and significantly reduces the use of p-agonists "on demand" compared 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 long-term once-daily administration in advanced studies in one year. Discontinuation of treatment with SINGULAIR, after 12 weeks of use, leading to worsening asthma back.
Compared with inhaled beclomethasone (200 pg twice daily with a device for spraying), SINGULAIR demonstrated a more rapid initial response, although over the 12-week study, beclomethasone achieved higher 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
In pediatric patients 6 to 14 years of age, one chewable tablet daily 5-mg evening significantly reduces asthma exacerbations and improved global assessment of parents and pediatric-specific estimates of the asthma quality of life compared with placebo. SINGULAIR also significantly improves morning FEV] and reduces the daily use of p-agonists "on demand". The therapeutic effect is achieved after the first dose and remained constant during the once-daily dosing to 6 months.
Pediatric patients aged 2 to 5 years
In a 12-week, placebo-controlled study in pediatric patients 2 to 5 years of age, SINGULAIR 4 mg once daily significantly improved parameters of asthma control, nezavsimo of concomitant therapy compared with placebo. Sixty percent of patients were not on any therapy. SINGULAIR daily significantly improved symptoms (including coughing, wheezing, difficulty breathing and activity limitation) and nocturnal symptoms compared with placebo SINGULAIR also significantly reduce the need for use of beta-agonioti zhvotospasyavashti and corticosteroids compared to placebo. Patients receiving
SINGULAIR had significantly more days without asthma symptoms than those receiving placebo. The effect of treatment was achieved after the first dose. In addition, the total number of blood eosinophils h significantly decreased.
Effects in patients concomitantly receiving inhaled corticosteroids
Separate studies in adults demonstrated the ability of SINGULAIR to add to the clinical effect of inhaled corticosteroid and allows for simultaneous use, a gradual reduction of steroid. In a placebo-controlled study, patients received an initial dose inhaled corticosteroid approximately 1,600 mcg per day reduced their use by approximately 37% during the placebo run-in period. SINGULAIR allows further 47% reduction in the dose of inhaled corticosteroid, compared with 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 discontinuation 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. Patients sensitive to aspirin, almost all of whom received 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 reduces the extent and duration of the decline in FEV1 over 60 minutes of effort, maximum percentage decrease in FEV 1 after the effort and time to recovery to within 5% of FEV1 prior effort. Protection has persisted during the treatment, suggesting that tolerance does not arise. In a separate crossover study, protection was observed after two once-daily doses. In pediatric patients aged 6 to 14 years who use chewable tablets of 5 mg, a similar survey showed identical protection, which is maintained during the dosing interval (24 hours).
Effects on asthmatic inflammation
In clinical studies, SINGULAIR inhibited bronchoconstriction induced by antigen stimulation, both in the early and the late phase. Since infiltration of inflammatory cells (eosinophils) is an important feature of asthma were examined effect of SINGULAIR on eosinophils in the peripheral blood and airways. In Phase Ilb / III clinical studies, SINGULAIR significantly lowered eosinophil counts in peripheral blood, approximately 15% from baseline compared with placebo. In pediatric patients 6 to 14 years of SINGULAIR 13% decrease in peripheral blood eozinfilite for a treatment period of more than eight weeks, compared with placebo SINGULAIR also decreased significantly from airway eosinophils in sputum, compared with placebo. In this study, treatment with SINGULAIR, peripheral blood eosinophils decreased and improve the 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, controlled studies pratsebo with 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.
In the combined analysis of three fundamental studies, SINGULAIR, in the form of 10 mg tablets, administered to 1,189 patients daily in the evening resulted in 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 at night ) composite endpoint evaluation (including estimates for general day and night symptoms) total score (global evaluation) of allergic rhinitis by patients and physicians.
In a separate 4-week study in which SINGULAIR was administered once daily in the morning for the first performance period of 2 weeks was significantly different from placebo and consistent with the results observed in studies with evening dosing. Moreover, the effect for 4 weeks was consistent with the results of the first two weeks.
In patients with seasonal allergic rhinitis aged 15 years and older who received SINGULAIR, noted an average reduction of 13% in the number of peripheral eosinophils versus placebo double-blind period.
After oral montelukast is absorbed rapidly and almost completely. The mean peak plasma concentration (Cmax) for film tablets 10mg, reached 3 hours (Tmax) after fasting for adults. Average. Oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal.
With chewable tablet 5 mg, Cmax is achieved 2 hours after administration in adults in the fasted state. The average oral bioavailability is 73%. Food has no important influence clinic after prolonged use.
With chewable tablet 4 mg, Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.
Safety and efficacy were demonstrated in clinical studies where chewable tablets 4 and 5 mg film-coated tablets and 10 mg were taken regardless of mealtime.
Montelukast has more than 99% bound to plasma proteins. Steady-state volume of distribution of montelukast averages by 8 to 11 liters. Studies in rats with radiolabeled monteluklast, indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose 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 they used human liver microsomes indicate that the metabolism of montelukast include cytochromes 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 faeces 5 days and <0.2% - in the urine. What 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 adults. The pharmacokinetics of montelukast is nearly linear for oral doses up to 50 mg. There was no difference in pharmacokinetic properties between morning and evening doses. There is little accumulation of undegraded products in plasma (~ 14%) at doses of 10 mg monteluklast vadnazh day.
Characteristics of patients
There is no need for dosage adjustment in elderly patients where renal impairment or mild to moderate hepatic insufficiency. No clinical data in patients with severe hepatic impairment (Child - Pugh score> 9).
Preclinical safety data
In animal studies, the safety of the 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. These occurred at doses 17 times higher than clinical. In monkeys, the side effects occurred at doses of 150 mg / kg / day (> 232 times the clinical dose). In animal studies montelukst had no effect on fertility or reproductive performance at doses exceeding clinical 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 rats. Montelukast crosses the placental barrier and is excreted in zhivotni.Smart not nastapve single-dose administration 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 ) maximum dose tested.
It was found that montelukast is not phototoxic in mice for narrow band or UVB rays and 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.
Spisak of excipients and their amounts
Each film-coated tablets 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. 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.
The shelf life of SINGULAIR 10 mg film 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;
Special precautions for storage
Store up to 30 ° C in a dry, protected from light.