Asthmatin/Asthmatin 4

Montelukast sodium.

Asthmatin: Each film-coated tablet contains montelukast 10 mg (as montelukast sodium 10.4 mg).
Asthmatin 4: Active ingredient: Montelukast (as montelukast sodium) 4 mg.
Excipients/Inactive Ingredients: Asthmatin 4: Mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, aspartame, red iron oxide, cherry flavor.

Pharmacology: Pharmacodynamics: The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. 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 early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT₁ receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD₄ at the CysLT₁ receptor without any agonist activity.
Pharmacokinetics: Peak plasma concentrations of montelukast are achieved in 3 to 4 hours after oral administration. The mean oral bioavailability is 64%. Montelukast is more than 99% bound to plasma proteins. It is extensively metabolised in the liver by cytochrome P450 isoenzymes CYP3A4, CYP2A6, and CYP2C9, and is excreted principally in the faeces via the bile. Metabolism was reduced and the elimination half-life prolonged in patients with mild to moderate hepatic impairment.

Asthmatin: The prophylaxis and chronic treatment of asthma; the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis) in adults and adolescents 15 years of age and older.
Asthmatin 4: Montelukast is indicated in the treatment of asthma as add-on therapy in those 2 to 5 year old patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom ''as-needed" short-acting β-agonists provide inadequate clinical control of asthma.
Montelukast may also be an alternative treatment option to low-dose inhaled corticosteroids for 2 to 5 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids.
Montelukast is also indicated in the prophylaxis of asthma from 2 years of age and older in which the predominant component is exercise-induced bronchoconstriction.

Administration: Asthmatin: Asthmatin 10 should be taken once daily. For asthma, the dose should be taken in the evening. For allergic rhinitis, the time of administration may be individualized to suit patient needs. Patients with both asthma and allergic rhinitis should take only one tablet daily in the evening.
Asthmatin 4: ASTHMATIN 4 CHEWABLE TABLETS 4MG is administered orally. The tablets are to be chewed before swallowing.
Dosage: Asthmatin: Adult and adolescents 15 years of age and older with asthma or allergic rhinitis: 10 mg once daily.
Asthmatin 4: This medicinal product is to be given to a child under adult supervision. The recommended dose for paediatric patients 2-5 years of age is one 4 mg chewable tablet daily to be taken in the evening. If taken in connection with food, montelukast should be taken 1 hour before or 2 hours after food. No dosage adjustment within this age group is necessary.
The tablets are to be chewed before swallowing.
General recommendations: The therapeutic effect of montelukast on parameters of asthma control occurs within one day. Patients should be advised to continue taking montelukast even if their asthma is under control, as well as during periods of worsening asthma.
No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.
Do not give montelukast 4 mg chewable tablets to children less than 2 years of age. The safety and efficacy of 4 mg chewable tablets in children below 2 years of age has not been established.
Montelukast as an alternative treatment option to low-dose inhaled corticosteroids for mild persistent asthma: Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids. Mild persistent asthma is defined as asthma symptoms more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.
Montelukast as prophylaxis of asthma for 2 to 5 year old patients in whom the predominant component is exercise-induced bronchoconstriction: In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant manifestation of persistent asthma that requires treatment with inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with montelukast. If satisfactory response is not achieved, an additional or different therapy should be considered.
Therapy with montelukast in relation to other treatments for asthma: When treatment with montelukast is used as add-on therapy to inhaled corticosteroids, montelukast should not be abruptly substituted for inhaled corticosteroids.

In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdosage reports.
Symptoms: The most frequently occurring adverse experiences were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.
Management: No specific information is available on the treatment of overdosage with montelukast. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Hypersensitivity to the active substance or to any of the excipients of the product.

Restriction of use in allergic rhinitis: Because the benefits of montelukast may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis, reserve use for patients who have an inadequate response or intolerance to alternative therapies.
Neuropsychiatric events: Serious neuropsychiatric (NP) events have been reported with use of montelukast. These post-marketing reports have been highly variable and included, but were not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including suicide), tic, and tremor. NP events have been reported in adult, adolescent, and pediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during montelukast treatment, but some were reported after montelukast discontinuation. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with montelukast use.
Discuss the benefits and risks of montelukast use with patients and caregivers when prescribing montelukast. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking montelukast. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue montelukast and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping montelukast therapy; however, in some cases symptoms persisted after discontinuation of montelukast. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with montelukast if such events occur.
Asthmatin: Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.
Patients should be advised to have appropriate rescue medication available. Therapy with montelukast can be continued during acute exacerbations of asthma.
While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids.
Montelukast should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled β-agonists as prophylaxis and have available for rescue a short-acting inhaled β-agonist.
Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast. Although montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Asthmatin 4: Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled β-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.
Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.
In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.
Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.
The product contains aspartame, a source of phenylalanine. Patients with phenylketonuria should take into account that each chewable tablet contains phenylalanine.
Effects on ability to drive and use machines: Montelukast has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.

Pregnancy: Asthmatin: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast should be used during pregnancy only if clearly essential.
Asthmatin 4: Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.
Available data from published prospective and retrospective cohort studies with montelukast use in pregnant women evaluating major birth defects have not established a drug-associated risk. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.
Montelukast may be used during pregnancy only if it is considered to be clearly essential.
Lactation: Asthmatin: It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast is given to a nursing mother.
Asthmatin 4: Studies in rats have shown that montelukast is excreted in milk. It is unknown whether montelukast/metabolites are excreted in human milk. Montelukast may be used in breast-feeding mothers only if it is considered to be clearly essential.

Asthmatin: Blood and lymphatic system disorders: Increased bleeding tendency.
Immune system disorders: Hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.
Psychiatric disorders: Including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor.
Nervous system disorders: Dizziness, drowsiness, paraesthesia/hypoesthesia, seizure.
Cardiac disorders: Palpitations.
Gastrointestinal disorders: Diarrhoea, dry mouth, dyspepsia, nausea, vomiting.
Hepatobiliary disorders: Elevated levels of serum transaminases (ALT, AST), cholestatic hepatitis.
Skin and subcutaneous tissue disorders: Angioedema, bruising, urticaria, pruritus, rash.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia including muscle cramps.
General disorders: Asthenia/fatigue, malaise, oedema.
Asthmatin 4: The following drug-related adverse reactions in clinical studies were reported commonly (≥1/100 to <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo: See table.

Click on icon to see table/diagram/image

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change.
Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least 3 months, 338 for 6 months or longer, and 534 patients for 12 months or longer. With prolonged treatment, the safety profile did not change in these patients either.
Frequency Category: Defined for each Adverse Reaction by the incidence reported in the clinical trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very Rare (<1/10,000).
Infections and infestations: Very common: Upper respiratory infection.
Blood and lymphatic system disorders: Rare: Increased bleeding tendency.
Very rare: Thrombocytopenia.
Immune system disorders: Uncommon: Hypersensitivity reactions including anaphylaxis.
Very rare: Hepatic eosinophilic infiltration.
Psychiatric disorders: Uncommon: Dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor).
Rare: Disturbance in attention, memory impairment, tic.
Very rare: Hallucinations, disorientation, suicidal thinking and behaviour (suicidality), obsessive-compulsive symptoms, dysphemia.
Nervous system disorders: Uncommon: Dizziness, drowsiness paraesthesia/hypoesthesia, seizure.
Cardiac disorders: Rare: Palpitations.
Respiratory, thoracic and mediastinal disorders: Uncommon: Epistaxis.
Very rare: Churg-Strauss Syndrome (CSS), pulmonary eosinophilia.
Gastrointestinal disorders: Common: Diarrhoea, nausea, vomiting.
Uncommon: Dry mouth, dyspepsia.
Hepatobiliary disorders: Common: Elevated levels of serum transaminases (ALT, AST).
Very rare: Hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).
Skin and subcutaneous tissue disorders: Common: Rash.
Uncommon: Bruising, urticaria, pruritus.
Rare: Angioedema.
Very rare: Erythema nodosum, erythema multiforme.
Musculoskeletal, connective tissue and bone disorders: Uncommon: Arthralgia, myalgia including muscle cramps.
Renal and urinary disorders: Uncommon: Enuresis in children.
General disorders and administration site conditions: Common: Pyrexia.
Uncommon: Asthenia/fatigue, malaise, oedema.
Post-marketing experience: The following adverse reactions related to psychiatric disorders which include but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor have been identified during post-approval use of montelukast.

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: Theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.
In vitro studies have shown that montelukast is a potent inhibitor of CYP2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).
In vitro studies have shown that montelukast is a substrate of CYP2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP2C8 and 2C9), gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon co-administration with gemfibrozil or other potent inhibitors of CYP2C8, but the physician should be aware of the potential for an increase in adverse reactions.
Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP3A4, resulted in no significant increase in the systemic exposure of montelukast.

Store in a well-closed container, in a dry place. Do not store above 30°C.

Antiasthmatic & COPD Preparations

R03DC03 - montelukast ; Belongs to the class of leukotriene receptor antagonists. Used in the systemic treatment of obstructive airway diseases.

P₁S₁S₃