- Name of the medicinal product
Montelurama® 10 mg film-coated tablets
- Qualitative and quantitative composition
One film-coated tablet contains montelukast sodium, which is equivalent to 10 mg montelukast.
Excipient with known effect: This medicine contains 90 mg lactose monohydrate per tablet.
For the full list of excipients, see section 6.1.
- Pharmaceutical form
Film-coated tablet.
Light pink round biconvex film-coated .
- Clinical particulars
4.1 Therapeutic indications
Montelurama is indicated 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. In those asthmatic patients in whom Montelurama is indicated in asthma, Montelurama can also provide symptomatic relief of seasonal allergic rhinitis.
Montelurama is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.
4.2 Posology and method of administration
Posology
The recommended dose for adults and adolescents 15 years of age and older with asthma, or with asthma and concomitant seasonal allergic rhinitis, is one 10 mg tablet daily to be taken in the evening.
General recommendations
The therapeutic effect of Montelurama on parameters of asthma control occurs within one day. Montelurama may be taken with or without food. Patients should be advised to continue taking Montelurama even if their asthma is under control, as well as during periods of worsening asthma. Montelurama should not be used concomitantly with other products containing the same active ingredient, montelukast.
No dosage adjustment is necessary for the elderly, or 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.
Therapy with Montelurama in relation to other treatments for asthma
Montelurama can be added to a patient’s existing treatment regimen.
Inhaled corticosteroids: Treatment with Montelurama can be used as add-on therapy in patients when inhaled corticosteroids plus “as needed” short acting β-agonists provide inadequate clinical control. Montelurama should not be abruptly substituted for inhaled corticosteroids (see section 4.4).
Method of administration
Oral use.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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 doctors’ advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.
Montelukast should not be substituted abruptly 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
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 CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.
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 metabolized 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.
4.6 Fertility, pregnancy and lactation
Pregnancy
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 Montelurama and malformations (i.e. limb defects) that have been rarely reported in worldwide post-marketing experience.
Montelurama may be used during pregnancy only if it is considered to be clearly essential.
Breast-feeding
Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is unknown whether montelukast/metabolites are excreted in human milk.
Montelurama may be used in breast-feeding only if it is considered to be clearly essential.
4.7 Effects on ability to drive and use machines
Montelurama has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.
4.8 Undesirable effects
Montelukast has been evaluated in clinical studies as follows:
- 10 mg film-coated tablets in approximately 4,000 adult and adolescent asthmatic patients 15 years of age and older.
- 10 mg film-coated tablets in approximately 400 adult and adolescent asthmatic patients with seasonal allergic rhinitis 15 years of age and older.
- 5 mg chewable tablets in approximately 1,750 paediatric asthmatic patients 6 to 14 years of age.
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:
| Body System Class | Adult and Adolescent Patients 15 years and older (two 12-week studies; n=795) | Paediatric Patients 6 to 14 years old (one 8-week study; n=201) (two 56-week studies; n=615) |
| Nervous system disorders | headache | headache |
| Gastro-intestinal disorders | abdominal pain |
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.
Tabulated list of Adverse Reactions
Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Reactions, in the table below. Frequency Categories were estimated based on relevant clinical trials.
| System Organ Class | Adverse Reactions | Frequency Category* |
| Infections and infestations | upper respiratory infection† | Very Common |
| Blood and lymphatic system disorders | increased bleeding tendency | Rare |
| Immune system disorders | hypersensitivity reactions including anaphylaxis | Uncommon |
| hepatic eosinophilic infiltration | Very Rare | |
| Psychiatric disorders | dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§) | Uncommon |
| disturbance in attention, memory impairment | Rare | |
| hallucinations, disorientation, suicidal thinking and behaviour (suicidality) | Very Rare | |
| Nervous system disorders | dizziness, drowsiness, paraesthesia/hypoesthesia, seizure | Uncommon |
| Cardiac disorders | palpitations | Rare |
| Respiratory, thoracic and mediastinal disorders | epistaxis | Uncommon |
| Churg-Strauss Syndrome (CSS) (see section 4.4) | Very Rare | |
| pulmonary eosinophilia | Very Rare | |
| Gastrointestinal disorders | diarrhoea‡, nausea‡, vomiting‡ | Common |
| dry mouth, dyspepsia | Uncommon | |
| Hepatobiliary disorders | elevated levels of serum transaminases (ALT, AST) | Common |
| hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury). | Very Rare | |
| Skin and subcutaneous tissue disorders | rash‡ | Common |
| bruising, urticaria, pruritus | Uncommon | |
| angiooedema | Rare | |
| erythema nodosum, erythema multiforme | Very Rare | |
| Musculoskeletal and connective tissue disorders | arthralgia, myalgia including muscle cramps | Uncommon |
| General disorders and administration site conditions | pyrexia‡ | Common |
| asthenia/fatigue, malaise, oedema | Uncommon | |
| * 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 (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000). † This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials. ‡ This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials. § Frequency Category: Rare | ||
4.9 Overdose
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 overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1,000 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 overdose reports.
Symptoms of overdose
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 of overdose
No specific information is available on the treatment of overdose with montelukast. It is not known whether montelukast is dialysable by peritoneal- or haemodialysis.
- Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Leukotriene receptor antagonist
Mechanism of action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (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 bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. 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.
5.2 Pharmacokinetic properties
Absorption
Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the Cmax is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
Distribution
Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.
Biotransformation
Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
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 faecal 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.
Characteristics in Patients
No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.
- Pharmaceutical particulars
6.1 List of excipients
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Hypromellose
Magnesium stearate
Film coating:
Hypromellose
Polyethylene glycol
Titanium dioxide
Talc, Iron oxide red
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in temperature not exceeding 30 o C in a dry place.Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Carton box containing 2 ( Aluminum / Aluminum ) Blisters each of 10 film coated tablets and an insert leaflet. 7.Marketing authorization holder
RamaPharma for pharmaceutical Industries.
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