Leukotrienes cause narrowing and swelling of airways in the lungs. By blocking leukotrienes, montelukast improves asthma symptoms and helps control asthma. Your doctor will determine how montelukast should be used depending on the symptoms and severity of your child's asthma. Asthma is a long-term disease, which includes: Symptoms of asthma include: What you need to know before you take Montelukast 4mg Tell your doctor about any medical problems or allergies your child has now or has had.
If an attack occurs, follow the instructions your doctor has given you or your child. Use in children For children 2 to 5 years old, Montelukast 4mg chewable tablets are available.
For children 6 to 14 years old, Montelukast 5mg chewable tablets are available. Tell your doctor or pharmacist if your child is taking, has recently taken or might take any other medicines. Tell your doctor if your child is taking the following medicines before starting montelukast: Pregnancy, breast-feeding and fertility Women who are pregnant, think they may be pregnant or planning to have a baby, should ask their doctor or pharmacist for advice before taking this medicine.
It is not known if montelukast appears in breast milk. Women who are breast-feeding or intend to breast-feed, should ask their doctor or pharmacist for advice before taking this medicine. Montelukast is not expected to affect the ability to drive a car or operate machinery. However, individual responses to medication may vary. Low level of magnesium and potassium in the blood. Your doctor will monitor this and take any necessary measures. Tearing of the eye, eye sensitivity to light. Sudden coldness with fainting, limpness or collapse.
Difficulty in breathing with wheezing or coughing. Rare may affect up to 1 in 1, people Slow heart beat Confusion Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur rarely.
Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or groin as this may be an early indication of a possible fracture of the thigh bone Interstitial lung disease inflammation of the tissue around the air sacks of the lungs Very rare may affect up to 1 in 10, people Fainting due to low blood pressure.
Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. Hoe bewaart u dit middel? Keep this medicine out of the sight and reach of children.
Your doctor, nurse or pharmacist knows how to store [Product name] properly see section 6, Further information. Do not use this medicine after the expiry date which is stated on the carton and on the vial. The expiry date refers to the last days of that month. This medicinal product does not require any special storage conditions.
After first opening, [Product name] should be used immediately. The refrigerated solution should then be equilibrated to room temperature prior to administration.
Exposure of montelukast to light causes its isomerization while a montelukast derivative with geometry Z is generated in the location of the double bond Smith Glen A.
The impurity resulting from photo-instability is Z -montelukast, chemically the sodium salt of 1-[[[ 1R [3-[ 1Z 7-chloroquinolinyl ethenyl]phenyl][2- 1-hydroxymethylethyl phenyl]propyl]thio]methyl]cyclopropane acetic acid, which is described by chemical formula V , see equation 2.
Another degradation impurity described in literature WO A1 is montelukast dehydrated, chemically the sodium salt of 1-[[[ 1R [3-[ 1E 7-chloroquinolinyl ethenyl]-phenyl][2- 1-methylethenyl phenyl]propyl]thio]methyl]cyclopropane acetic acid, described by chemical formula VI , see equation 3.
The organic impurities of the target substance have their origin in chemical instability of montelukast as well as instability of the ingredients used for its synthesis or these may be residues of the used raw materials or solvents. An example of a source of contamination due to instability of intermediate products is the commonly used ingredient montelukast mesylate, chemically 2- 2- 3 S - 3- 2- 7-chloroquinolinyl ethenyl phenyl methanesulfonyl-oxypropyl phenyl propanol, characterized by formula VII.
Montelukast mesylate is prepared via a reaction of the relatively stable montelukast alcohol, chemically 2- 2- 3 S - 3- 2- 7-chloroquinolinyl ethenyl -phenyl methanesulfonyloxypropyl -phenyl propanol, characterized by formula VIII , and methane sulfonyl chloride. Subsequently montelukast mesylate is converted by the action of a salt of [1- mercapto-methyl cyclopropyl]acetic acid with an alkaline metal IX to the target montelukast, see Scheme 1. In parallel to this reaction the considerably instable montelukast mesylate VII is subject to undesired intramolecular conversions J.
The considerable chemical instability of montelukast and its intermediates also influences its industrial production. The preparation processes of montelukast sodium are usually based on prevention of the formation of impurities, mainly those that result from photo-instability and oxidation instability.
This goal can be achieved by carrying out the production in equipments that are impermeable for light and working under an inert atmosphere with the exclusion of air oxygen. Chemical impurities of montelukast are usually removed by means of crystallization in the phase of its salts with amines or in the phase of montelukast acid.
The target form of the API is the sodium salt of montelukast, which cannot be efficiently further purified by common procedures since the resulting substance is soluble very well in numerous solvents from polar ones e. An exception is represented by non-polar solvents of the heptane, hexane, pentane and cyclohexane type. Our solution represents a new and beneficial way of obtaining pure montelukast sodium I with simultaneous removal of specific impurities below accepted limits.
Specific impurities are generated due to chemical instability of the target substance, which results from the structure of the target substance, or the substance gets contaminated during the preparation process, which can be attributed to non-selectivity of the chemical processes in the preparation of montelukast. Other objects of the invention include methods of isolation of specific impurities of montelukast and analytic methods used for controlling the production process and the final quality of montelukast.
The reactions leading to the target compound I were performed, according to the process now discovered, in such a way that first [1- mercaptomethyl cyclopropyl]acetic acid was mixed with sodium tert-butylate and polyethylene glycol PEG in the environment of an inert organic solvent and under the atmosphere of an inert gas.
Further, the reaction mixture was maintained under the inert atmosphere and stirred for several hours. Samples were continuously taken to determine the conversion and selectivity of the reaction. Crude montelukast sodium was then converted to a solution of montelukast acid III and further isolated and purified in the form of crystalline salts of montelukast with primary amines II.
The target amorphous form of montelukast sodium was obtained by direct conversion of the salt of montelukast with the primary amine by action of sodium tert-butylate as a suitable source of sodium ions.
The process used is described in a detailed way in Examples 1 to 5. Stress tests were used to assess factors influencing the stability of the obtained montelukast, mainly its sensitivity to light and oxygen.
For the purpose of analyzing the chemical stability a methanolic solution of montelukast was exposed to the influence of sunshine and air oxygen while this solution was continuously analyzed by means of the HPLC method Example 6. The found high sensitivity of the substance to light and air oxygen is documented by FIG. It has been found out that the transformation of montelukast I to Z -montelukast V was unexpectedly fast. Already within minutes the concentration of Z -montelukast may grow to a level of units of percent.
Simultaneously, but more slowly, the mercapto group was oxidized, producing E -montelukast sulfoxide IV. Besides the well-known impurities formation of another, not yet described substance, which was a product of both the chemical processes, isomerism on the double bond as well as oxidation of the mercapto group, was observed.
The substance was Z -montelukast sulfoxide, chemically the sodium salt of [R- Z ]][[[1-[3-[2- 7-chloroquinolinyl ethenyl]phenyl][2- 1-hydroxymethylethyl -phenyl]propyl]sulfinyl]methyl]cyclopropane acetic acid, described by chemical formula XII ; see Scheme 2.
Z -Montelukast sulfoxide XII is exactly the final product in the whole sequence of undesired reactions induced by light or oxygen, which take place according to Scheme 2. This compound is a product of the second generation of degradation transformations of montelukast.
With regard to the relatively slow transformation of montelukast to Z -montelukast-sulfoxide XII this degradation impurity does not belong to critical impurities, unlike the degradation impurities of the first generation e. With regard to the rate of undesired degradation changes the most critical impurity is the Z isomer of montelukast V.
The impurities generated by degradation of the target substance are, on one hand, structurally very similar to the target substance and therefore it is very difficult to reduce their content in the API by common methods e. On the other hand, they are generated relatively easily and so they can contaminate the substance that had been subjected to the purification process and was already found acceptable in terms of content of impurities. For this reason it is advantageous to dispose with methods of removing impurities at the very end of the production process as well, i.
An interesting, unexpected and preferably process-feasible effect has been found for montelukast and its Z -isomer. While exposure to light induces an increase of the content of Z -montelukast V , in the case of heat exposure exactly the opposite is true; see equation 4. A montelukast solution maintained under the atmosphere of inert argon was first exposed to sunshine for a defined time period, while the concentration of the Z -isomer according to HPLC grew from the value of the original content below 0.
This mixture of the two isomers was boiled in a light-insulated apparatus under decrease of the content of the Z -isomer in the mixture. When this back transformation of the undesired Z -isomer to the desired E isomer was implemented in a toluene solution, then the half-time of this reaction was 30 minutes; see FIG.
The chemical transformation of Z -montelukast to montelukast, induced by heat exposure of a solution of a mixture of the two substances represents a simple and advantageous way of reprocessing specifically contaminated montelukast sodium I. An important aspect of the inventive process for the removal of the Z -isomer of montelukast from the target substance involves carrying out the purification operation directly in the final form of the API the sodium salt , without the necessity of converting the API to another, well-crystallizing form.
Literature has not yet described a method for reprocessing of montelukast in case of later contamination of the API by degradation products or other impurities. However, its quality may be deteriorated very easily, e. According to the inventive process see Scheme 3 contaminated montelukast can be efficiently reprocessed by transformation to a well-crystallizing form, e.
Montelukast sodium contaminated with a specific impurity is dissolved in a suitable solvent, it is first transformed to a solution of montelukast acid III by the action of a solution of an acid and then to the well-crystallizing salt II by the action of an amine RR1R2N.
Further, it is necessary to remove impurities by crystallizations of the isolated salt of montelukast with the amine II from a suitable solvent or more solvents. The selection of a suitable solvent depends on the type of the impurity removed.
If montelukast is contaminated with polar specific impurities, polar solvents can be preferably used, e. If montelukast is contaminated with non-polar specific impurities, non-polar solvents can be preferably used, e. These eicosanoids bind to cysteinyl leukotriene CysLT receptors. The CysLT type-1 CysLT1 receptor is found in the human airway including airway smooth muscle cells and airway macrophages and on other pro -inflammatory cells including eosinophils and certain myeloid stem cells.
CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis , CysLTs are released from the nasal mucosa after allergen exposure during both earlyand late-phase reactions and are associated with symptoms of allergic rhinitis. Pharmacodynamics Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics.
Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies].
Pharmacokinetics Absorption Montelukast is rapidly absorbed following oral administration. After administration of the mg filmcoated tablet to fasted adults, the mean peak montelukast plasma concentration Cmax is achieved in 3 to 4 hours Tmax. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.
For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to 2. For the 4-mg chewable tablet, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The co-administration of the oral granule formulation with applesauce did not have a clinically significant effect on the pharmacokinetics of montelukast.
A portion of the obtained crude E -montelukast sulfoxide was subjected to auto-purification separation 4mg the Waters system description—see analytic methodsmontelukast ca. Example 11 Preparation of 1-[[[ 1R [3-[ 1E 7-chloroquinolinyl ethenyl]-phenyl][2- 1-methylethenyl phenyl]propyl]thio]methyl]cyclopropane acetic acid 4, montelukast zentiva 4mg. Symptoms of asthma include: For this purpose two methods of high 4mg liquid chromatography HPLC have been developed, montelukast zentiva 4mg. The benefits of the inventive zentiva consist in isolation 4mg specific impurities, by means of which the analytic methods that can be conveniently used for the montelukast control of montelukast zentiva been optimized. Samples were continuously taken to determine the conversion and selectivity of 4mg reaction. Breast-feeding It is not known whether montelukast appears in breast-milk, montelukast zentiva 4mg. The most common method used in practice consists in purifying crude montelukast I via its salts with secondary amines, montelukast with dicyclohexylamine EP B1. Both chromatographic methods are described in a more detailed way in the experimental part, montelukast zentiva 4mg. Tablet should be taken in the evening at least 1 hour before or 2 hours after a meal, montelukast zentiva 4mg. There is a general rule that chemical purity of the active pharmaceutical ingredient API produced in the industrial scale is one of the zentiva parameters for its commercialization. At the end of monitoring the reaction mixture contained One 4 mg chewable tablet daily to be taken in the 4mg. For unambiguous determination of the retention times of the analyzed substances it is necessary to montelukast standards of both the API alone and the individual impurities. The results of the Multinational trial on FEV1 were similar. Zentiva and using montelukast There have been very zentiva cases of drowsiness and sleepiness with the use of [Product name].
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