Composition
MONTAIR PLUS Tablets
Each film-coated tablet contains:
Montelukast sodium....................10 mg
Bambuterol hydrochloride BP....10 mg
MONTAIR PLUS KID Dispersible tablets
Each dispersible tablet contains:
Montelukast sodium.....................4 mg
Bambuterol hydrochloride BP......5 mg
Dosage Form
Oral Tablets
Description
MONTAIR PLUS Tablets and MONTAIR PLUS KID Dispersible tablets are a combination of montelukast sodium and bambuterol.
Montelukast sodium is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. It therefore acts as a leukotriene receptor antagonist.
Bambuterol hydrochloride, a prodrug of terbutaline, is the first once daily oral beta2 agonist with 24-hour duration for the treatment of asthma. Following slow absorption from the GI-tract, the drug is metabolized via hydrolysis (plasma cholinesterase) and gets converted into its active metabolite terbutaline.
The combination of an oral bronchodilator (bambuterol) and an anti-inflammatory agent (montelukast) would take care of both the components of asthma, bronchoconstriction and inflammation which give greater clinical efficacy.
Pharmacology
Pharmacodynamics
Montelukast:
The cysteinyl leukotrienes (LTC4, LTD4, and 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 proinflammatory 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. 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.
Bambuterol:
Bambuterol is an active precursor of the selective beta2-adrenergic agonist, terbutaline. Bambuterol is the bis-dimethylcarbamate of terbutaline, and is present in the formulation as a 1:1 racemate.
Following slow absorption from the gastrointestinal tract, the drug is metabolized via hydrolysis (plasma cholinesterase) and is converted into its active metabolite, terbutaline. Maximum plasma concentration of terbutaline is achieved within 2-6 hours. The plasma half-life of bambuterol after oral administration is about 9-17 hours. Pharmacodynamic studies have shown that after oral administration of bambuterol to guinea pigs, a sustained protective effect was achieved against histamine-induced bronchoconstriction. At equipotent doses, the duration of the relaxing activity was more prolonged than after plain terbutaline. Bambuterol, or the monocarbamate ester, did not exert any smooth muscle relaxing properties. The bronchoprotective effects seen after oral administration of bambuterol were related to the generation of terbutaline, as were the secondary effects (effects on other organs). Pharmacodynamic studies have been conducted in asthmatics and healthy volunteers. The effects observed were bronchodilation, tremor and increases in heart rate. The metabolic effects included a small increase in blood glucose, while the effect on serum potassium was negligible. In short-term studies on lipoprotein metabolism, an increase in HDL cholesterol has been observed. In conclusion, all pharmacodynamic effects observed can be ascribed to the active metabolite, terbutaline.
Pharmacokinetics
Montelukast:
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 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.
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 and 2C9 are involved 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 CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 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%).
Bambuterol:
On average, 17.5% of an oral dose is absorbed. Approximately 70–90% of the absorption occurs in the first 24 hours.
Bambuterol is metabolized in the liver and terbutaline is formed by both hydrolysis and oxidation. After absorption from the gut, about two-thirds of terbutaline is first-pass metabolized; bambuterol escapes this first-pass metabolism. Of the absorbed amount, about 65% reaches the circulation. Bambuterol, therefore, has a bioavailability of about 10%. Protein binding of bambuterol is low (40–50%) at therapeutic concentrations. The terminal half-life of bambuterol after an oral dose is 9–17 hours. Studies on the effects on plasma cholinesterase showed that bambuterol inhibited activity, but that this was reversible. All categories of subjects studied were able to form terbutaline in a predictive way, except for liver cirrhotics.
Indications
MONTAIR PLUS Tablets are indicated for chronic treatment of asthma, bronchospasm and/or reversible airways obstruction in patients 15 years of age and older.
MONTAIR PLUS KID Dispersible tablets are indicated for chronic treatment of asthma, bronchospasm and/or reversible airways obstruction in patients 2-5 years of age.
Dosage and Administration
Adults (≥15 years):
One tablet once daily given in the evening.
Children (2-5 years):
One tablet once daily given in the evening.
Contraindications
Hypersensitivity to any component of the product.
Warnings and Precautions
Montelukast:
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. 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 (beta)-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.
Eosinophilic Conditions:
In rare cases, 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.
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, restlessness, somnambulism, suicidal thinking and behavior (including suicide), 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.
Bambuterol:
As terbutaline is excreted mainly via the kidneys, the dose of Bambuterol should be halved in patients with an impaired renal function (GFR 
50 mL/min).Care should be taken with patients suffering from myocardial insufficiency or thyrotoxicosis.
Cardiovascular effects may be seen with sympathomimetic drugs, including bambuterol. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta agonists. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving bambuterol should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.
Due to the hyperglycaemic effects of beta2-stimulants, additional blood glucose measurements are recommended initially when bambuterol therapy is commenced in diabetic patients.
In patients with liver cirrhosis, and probably in patients with other causes of severely impaired liver function, the daily dose must be individualised, taking into account the possibility that the individual patient could have an impaired ability to metabolise bambuterol to terbutaline. Therefore, from a practical point of view, the direct use of the active metabolite, terbutaline, is preferable in these patients.
Unpredictable inter-individual variation in the metabolism of bambuterol to terbutaline has been shown in subjects with liver cirrhosis. The use of an alternative β2-agonist is recommended in patients with cirrhosis and other forms of severely impaired liver function.
Due to the positive inotropic effects of beta2-agonists, these drugs should not be used in patients with hypertrophic cardiomyopathy.
Beta2-agonists may be arrhythmogenic and this must be considered in the treatment of the individual patient.
Potentially serious hypokalaemia may result from beta2-agonist therapy, mainly from parenteral or nebulized administration. Particular caution is advised in acute severe asthma as this effect may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids, and/or diuretics. It is recommended that serum potassium levels be monitored in such situations.
Asthma patients who require treatment with bambuterol must have optimum anti-inflammatory treatment with corticosteroids. The patients must be instructed to continue taking their anti-inflammatory medication after the start of treatment with bambuterol, even if the asthma symptoms diminish. If a previously effective dosage regimen no longer gives the same symptomatic relief, the patient should urgently seek further medical advice. Consideration should be given to the requirements for additional therapy (including increased dosages of anti-inflammatory medication). Severe exacerbations of asthma should be treated as an emergency in the usual manner.
Although bambuterol is not indicated for the treatment of premature labour it should be noted that bambuterol is metabolised to terbutaline and that terbutaline should not be used as a tocolytic agent in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease.
Drug Interactions
Montelukast:
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 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 CYP 3A4, caution should be exercised, particularly 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.)
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.
Bambuterol:
Bambuterol may interact with suxamethonium (succinylcholine). A prolongation (up to two-fold) of the muscle-relaxing effect of suxamethonium has been observed in some patients after taking bambuterol 20 mg on the evening prior to surgery. The inhibition is dose-dependent and fully reversible after cessation of treatment with bambuterol. This is because plasma cholinesterase, which inactivates suxamethonium, is partly but fully reversibly inhibited by bambuterol. In extreme situations, the interaction may result in a prolonged apnoea time which may be of clinical importance.
Bambuterol may also interact with other muscle relaxants metabolized by plasma cholinesterase.
Beta-receptor blocking agents, including eyedrops, especially non-selective ones, may partly or totally inhibit the effect of beta-stimulants. Therefore, bambuterol and non-selective beta-blockers should not normally be administered concurrently. Bambuterol should be used with caution in patients receiving other sympathomimetics.
Hypokalemia may result from beta2-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids and diuretics.
Six cases have been reported where concomitant treatment with salbutamol and ipratropium, used in asthma (nebuliser), has caused narrow angle glaucoma. Terbutaline is likely to interact, similar to salbutamol, with ipratropium when administered in a nebuliser. The combination is discouraged in predisposed patients.
Hepatic Impairment
Montelukast is mainly excreted through bile; caution is to be exercised while prescribing this combination in patients with impaired hepatic function.
Renal Impairment
As terbutaline is excreted mainly via the kidneys, the dose of bambuterol should be halved in patients with moderately to severely impaired renal function (GFR 50 mL/min). The combination thus should be used with caution in patients with impaired renal function.
Pregnancy
There are no adequate and well-controlled studies of montelukast and bambuterol in pregnant women. Because animal reproduction studies are not always predictive of human response, MONTAIR PLUS Tablets should be used during pregnancy only if clearly needed. Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/ foetal development. Limited data from available pregnancy databases do not suggest a causal relationship between Montelukast and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.
Terbutaline, the active metabolite of bambuterol, has been in widespread clinical use for many years and may be considered in such patients. Terbutaline should be used with caution in the first trimester of pregnancy. Beta2- agonists should be used with caution at the end of pregnancy because of the tocolytic effect. Maternal beta2-agonist treatment may result in transient hypoglycaemia in pre-term newborn infants.
Lactation
It is not known whether bambuterol and montelukast are excreted in human milk. Terbutaline, the active metabolite of bambuterol, is excreted in breast milk, but at therapeutic doses of terbutaline no effect on breastfed newborns/infants are anticipated. Because many drugs are excreted in human milk, caution should be exercised when MONTAIR PLUS Tablets is given to a nursing mother.
Undesirable Effects
Montelukast:
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.
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: abdominal pain, asthenia/fatigue, fever, trauma, dyspepsia, dental pain, infectious gastroenteritis, headache, dizziness, influenza, cough, nasal congestion, rash, increased ALT and AST and pyuria.
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.
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.
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.
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.
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.
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.
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.
Montelukast has been evaluated for safety in 175 pediatric patients 6 to 23 months of age with asthma. 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. The other commonly reported adverse effects in clinical trials of montelukast in this age group included hyperkinesia, asthma, diarrhoea, eczematous dermatitis, rash.
Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.
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: Agitation including aggressive behaviour or hostility, anxiousness, depression, disorientation, psychomotor hyperactivity dream abnormalities including nightmares, hallucinations, insomnia, irritability, memory impairment restlessness, somnambulism, suicidal thinking and behaviour (including suicide), tremor, disturbance in attention.
Nervous system disorders: Drowsiness, dizziness, paraesthesia/hypoesthesia, seizure.
Respiratory, thoracic and mediastinal disorders: Epistaxis, Churg-Strauss Syndrome, pulmonary eosinophilia.
Cardiac disorders: Palpitations.
Gastro-intestinal disorders: Diarrhoea, dry mouth, dyspepsia, nausea, vomiting, pancreatitis.
Hepatobiliary disorders: Elevated levels of serum transaminases (ALT, AST), rare 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: Angiooedema, bruising, urticaria, pruritus, rash, erythema nodosum erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Pyrexia, Arthralgia, myalgia including muscle cramps
General disorders and administration site conditions: Asthenia/fatigue, malaise, oedema.
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.
Bambuterol
Side effects which have been reported e.g. tremor, headache, nausea, muscle cramps, tachycardia and palpitations are all characteristic of sympathomimetic amines. The intensity of the side effects is dose-dependent and the majority of these effects have reversed spontaneously within the first 1–2 weeks of treatment.
Hypersensitivity reactions including angioedema, urticaria, exanthema, bronchospasm, hypotension and collapse have been very rarely reported with beta2-agonist therapy.
Potentially serious hypokalaemia and hyperglycaemia may result from beta2-agonist therapy.
Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles, myocardial ischemia have been reported in association with beta2-agonists, usually in susceptible patients. One of the uncommon side effects includes paradoxical bronchospasm.
Sleep disturbances and behavioural disturbances such as dizziness, agitation, hyperactivity and restlessness have been observed.
Overdosage
Montelukast:
No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).
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 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 pediatric patients. There were no adverse experiences in the majority of overdosage reports. 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.
It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
Bambuterol
Overdosing may result in high levels of terbutaline. Possible signs and symptoms recorded after terbutaline overdose are headache, anxiety, tremor, nausea, tonic muscle cramps, palpitations, tachycardia, and cardiac arrhythmias. A fall in blood pressure sometimes occurs. Hypokalaemia, hyperglycaemia, and lactic acidosis sometimes occur.
Overdose of Bambuterol is also likely to cause a prolonged inhibition of plasma cholinesterase that may last for days.
In mild and moderate cases, the doses should be reduced. However, in severe cases, activated charcoal should be administered if ingestion is recent. Determination of acid-base balance, blood sugar and electrolytes, and monitoring of heart rate/rhythm and blood pressure should be initiated. Metabolic changes should be corrected. A cardio selective beta-blocker (e.g., metoprolol) is recommended for the treatment of haemodynamically significant cardiac arrhythmias. The beta-blocker should be used with care because of the possibility of inducing bronchoconstriction. Serum potassium levels should be monitored. If the beta2-mediated vasodilation contributes significantly to the fall in blood pressure, a volume expander should be given.
Packaging Information
MONTAIR PLUS Tablets…………………………………..Blister of 10 tablets
MONTAIR PLUS KID Dispersible tablets…………..Blister of 10 tablets
Last Updated: August 2015
Last Reviewed: August 2015