MONTAIR Tablets / Chewable Tablets / Oral Granules (Montelukast sodium)

Table of Content

Asthma affects the lives of many children and adults. It is a chronic disease with a high and increasing prevalence. A cure for asthma is not yet available but the therapeutic options for controlling the disease are gradually improving.

Current guidelines for the management of moderate-to-severe persistent asthma recommend inhaled corticosteroids as first-line therapy. Although inhaled corticosteroids improve lung function and reduce exacerbations of asthma, some patients receiving corticosteroid therapy continue to experience poorly controlled asthma.

Leukotrienes are important pro-inflammatory mediators in asthma and appear to be poorly suppressed by corticosteroids. Cysteinyl leukotrienes not only have pro-inflammatory effects in patients with asthma, they are also more potent mediators of bronchoconstriction than either histamine or methacholine.

Montelukast is a cysteinyl leukotriene receptor antagonist indicated for the management of persistent asthma. Its rapid onset of action, once-daily administration and oral dosage formulation may confer compliance benefits.

Montelukast, a leukotriene receptor antagonist, represents a new class of anti-asthma drug, with a novel mechanism of action. Clinical studies have demonstrated the usefulness of this drug as first-line therapy in mild-to-moderate asthma, while other studies have shown its potential as an add-on therapy for the improvement of moderate-to-severe persistent disease.

In summary, montelukast appears to be a useful alternative or adjunct to inhaled corticosteroid therapy in adults as well as in children.

MONTAIR (montelukast) is available in various dosage forms such as tablets, chewable tablets and oral granules making drug administration easy and patient-friendly. MONTAIR is indicated in the long-term treatment of asthma, prevention of exercise-induced bronchoconstriction and for the relief of symptoms of seasonal and perennial allergic rhinitis.

Qualitative and Quantitative Composition

MONTAIR-10 Tablets

Each film coated tablet contains

Montelukast sodium IP equivalent to montelukast.........10 mg

MONTAIR-5 CHEWABLE Tablets

Each film coated tablet contains

Montelukast sodium IP equivalent to montelukast..........5 mg

MONTAIR-4 CHEWABLE Tablets

Each film coated tablet contains

Montelukast sodium IP equivalent to montelukast...........4mg

Dosage Form

Tablets, chewable tablets

Clinical Particulars

Therapeutic Indications

Asthma

MONTAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.

In the treatment of asthma as add-on therapy in those 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.

As an alternative treatment option to low-dose inhaled corticosteroids for 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.

Exercise- Induced Bronchospasm

MONTAIR is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older.

Allergic Rhinitis

MONTAIR is indicated in the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older. 

Posology and Method of Administration

Dosage

Asthma

MONTAIR should be taken once daily in the evening. The following doses are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.

For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.

Exercise- Induced Bronchoconstriction

For prevention of EIB, a single dose of MONTAIR should be taken at least 2 hours before exercise.

The following doses are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.

For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.

An additional dose of MONTAIR should not be taken within 24 hours of a previous dose. Patients already taking MONTAIR daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting beta-agonist. Safety and efficacy in patients younger than 6 years of age have not been established. Daily administration of MONTAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

Allergic Rhinitis

For allergic rhinitis, MONTAIR should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.

For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.

For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

Asthma and Allergic Rhinitis

Patients with both asthma and allergic rhinitis should take only one MONTAIR dose daily in the evening.

Method of Administration

MONTAIR Tablets and Chewable Tablets

These dosage forms can be administered without regard to the time of meals.

Contraindications

Hypersensitivity to any component of this product.

Special Warnings & Precautions for Use

Acute Asthma

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. There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled beta2-agonist.

Concomitant Corticosteroid Use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

Aspirin Sensitivity

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.

Eosinophilic Conditions

Patients with asthma on therapy with 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 events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast and these underlying conditions has not been established. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast. Post-marketing reports with montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor. The clinical details of some post-marketing reports involving montelukast appear consistent with a drug-induced effect.

Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.

Phenylketonuria

Phenylketonuric patients should be informed about presence of phenylalanine (a component of aspartame).

Drug Interactions

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers. In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

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 CYP 3A4, it is reasonable to employ appropriate clinical monitoring in children, when montelukast is co-administered with inducers of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.

Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 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). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

In vitro studies have shown that montelukast is a substrate of CYP 2C8, 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 CYP 2C8 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 CYP 2C8, 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 CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

Use in Special Population

Hepatic Impairment

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated. No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Renal Impairment

Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Pregnancy

Pregnancy Category B

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 needed. During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast has not been established.

Lactation

Because many drugs are excreted in human milk, caution should be exercised when montelukast is given to a nursing mother. A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly or through breast milk, do not suggest a significant risk of adverse events from exposure to montelukast. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for montelukast and any potential adverse effects on the breastfed infant from montelukast or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of montelukast have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults. The efficacy of montelukast for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.

The safety of montelukast 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data. Efficacy of montelukast in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.

The safety of montelukast 4-mg and 5-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile.

The safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established.

Geriatric Use

No overall differences in safety or effectiveness were observed between subjects aged 65 years and above and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.

Effects on Ability to Drive and Use Machines

Montelukast is not expected to affect a patient's ability to drive a car or operate machinery. However, in very rare cases, individuals have reported drowsiness or dizziness.

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Asthma

Adults and Adolescents 15 Years of Age and Older

Montelukast has been evaluated for safety in approximately 2950 adult and adolescent patients with asthma 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with montelukast occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

Body as a whole: Abdominal pain, asthenia/fatigue, fever, trauma

Digestive system disorders: Dyspepsia, dental pain, infectious gastroenteritis, dry mouth.

Nervous/Psychiatric disorders: Headache, dizziness

Respiratory system disorders: Influenza, cough, nasal congestion

Skin/Skin appendages disorder: Rash

Laboratory adverse experiences: Increased alanine amino transaminase (ALT) and aspartate amino transaminase (AST) and pyuria

The frequency of less common adverse events was comparable between montelukast and placebo. The safety profile of montelukast, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for montelukast.

Cumulatively, 569 patients were treated with montelukast for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.

Pediatric patients 6 to 14 years of age 

Montelukast has been evaluated for safety in 476 pediatric patients with asthma 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with montelukast for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of montelukast in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving montelukast, the following events occurred with a frequency ≥ 2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The other adverse effect reported frequently in clinical trials with montelukast in this age group was headache.  The frequency of less common adverse events was comparable between montelukast and placebo. With prolonged treatment, the adverse experience profile did not significantly change.

The safety profile of montelukast, when administered as a single dose for prevention of EIB in pediatric patients 6 years of age and older, was consistent with the safety profile previously described for montelukast.

In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for montelukast. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving montelukast, the following events not previously observed with the use of montelukast in this age group occurred with a frequency ≥ 2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.

Pediatric Patients 2 to 5 Years of Age

Montelukast has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with montelukast for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving montelukast, the following events occurred with a frequency ≥ 2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis. Another adverse effect commonly reported in the clinical trials with montelukast in this age-group was thirst.

Pediatric Patients 6 to 23 Months of Age with Asthma

Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.

Montelukast has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of montelukast in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23 months of age receiving montelukast, the following events occurred with a frequency ≥ 2% and more frequently than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between montelukast and placebo.

Allergic Rhinitis

Adults and adolescents 15 years of age and above

Seasonal Allergic Rhinitis

Montelukast has been evaluated for safety in 2199 adult and adolescent patients with seasonal allergic rhinitis 15 years of age and older in clinical trials. Montelukast administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with montelukast with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving montelukast vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.

Perennial Allergic Rhinitis

Montelukast has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received montelukast in two, 6-week, clinical studies. Montelukast administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with montelukast with a frequency ≥ 1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.

Pediatric Patients 2 to 14 Years of Age

Seasonal Allergic Rhinitis

Montelukast has been evaluated in 280 pediatric patients with seasonal allergic rhinitis 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. Montelukast administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥ 2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.

The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.

Pediatric Patients 6 Months to 14 Years of Age

Perennial Allergic Rhinitis

The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.

Post-marketing Experience

The following adverse reactions have been reported in post-marketing use:

Blood and lymphatic system disorders: Increased bleeding tendency, thrombocytopenia.

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 including nightmares, dysphemia (stuttering) hallucinations, insomnia, , irritability, memory impairment, restlessness, obsessive compulsive symptoms, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor. These events were reported in all age groups. However, nightmare/night terrors, aggression and behavioural changes are more frequently reported in the pediatric population.

Nervous system disorders: Drowsiness, dizziness, paraesthesia/hypoesthesia, seizures.

Respiratory, thoracic and mediastinal disorders: Epistaxis, pulmonary eosinophilia

Cardiac disorders: Palpitations.

Gastro-intestinal disorders: Diarrhoea, dyspepsia, nausea, vomiting, pancreatitis 

Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with montelukast. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast was administered to patients who had underlying potential for liver disease, such as alcohol use or other forms of hepatitis.

Skin and subcutaneous tissue disorders: Angioedema, bruising, urticaria, pruritus, erythema nodosum, erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia including muscle cramps

Renal and urinary disorders: enuresis in children

General disorders and administration site conditions: Pyrexia, asthenia/fatigue, malaise, oedema.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product

Overdosage

No specific information is available on the treatment of overdosage with montelukast. 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 a week without clinically important adverse experiences. 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.

There have been reports of acute overdosage in post-marketing experience and clinical studies of up to at least 150 mg/day with montelukast. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and older pediatric patients. There were no adverse experiences reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, vomiting, psychomotor hyperactivity, and abdominal pain.

It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

Pharmacological Properties

Mechanism of Action

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. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or -adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1

receptor without any agonist activity.

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.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or beta-adrenergic receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. 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. In a placebo-controlled, crossover study (n=12), montelukast inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of montelukast on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of montelukast. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known.

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. 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 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.

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 safety and efficacy of montelukast in patients with asthma were demonstrated in clinical trials in which the 10 mg film-coated tablet and 5 mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of montelukast in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablet and 4 mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of montelukast in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10 mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of montelukast when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet has not been evaluated.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 litres. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.

In vitro studies using human liver microsomes indicate that cytochromes P450 3A4, 2C8 and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6. However, in vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme.

Elimination

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of 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. During once-daily dosing with 10 mg montelukast, there is little accumulation of the parent drug in plasma (14%).

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the area under the plasma concentration versus time curve (AUC) for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay. In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.

No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg). Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure). Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.

Description

Montelukast sodium, the active ingredient in MONTAIR, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. Montelukast sodium is described chemically as -1-phenyl]-3- • dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits) • palpitations • nose bleed, stuffy nose, swelling (inflammation) of the lungs • heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting • hepatitis • bruising, rash, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis) that may occur without warning • joint pain, muscle aches and muscle cramps • bedwetting in children • tiredness, swelling Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of MONTAIR. For more information ask your healthcare provider or pharmacist.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product

How should I store MONTAIR?

 · Store MONTAIR below 30°C. · Keep MONTAIR in the container it comes in. · Keep MONTAIR in a dry place and away from light. Do not use MONTAIR for a condition for which it was not prescribed. Do not give MONTAIR to other people even if they have the same symptoms you have. It may harm them. Keep MONTAIR and all medicines out of the reach of children.

This leaflet summarizes information about MONTAIR. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider for information about MONTAIR that is written for health professionals.

Details of Manufacturer

MONTAIR-5 CHEWABLE Tablets and MONTAIR-5 CHEWABLE Tablets

Cipla Ltd. Unit II, TAZA Block, Rorathang, East Sikkim 737133.

MONTAIR 10 Tablets

Cipla Ltd, Kumrek, Rangpo, Sikkim 737 132 INDIA

Details of Permission or Licence Number with Date

M/719/2016 (Valid upto 30.12.2020)

Last Updated: November 2019

Last Reviewed: November 2019