SINGULAIR^® 10 mg Tablets
SINGULAIR^® Pediatric 5 mg Chewable Tablets
SINGULAIR^® Pediatric 4 mg Chewable Tablets

10 mg tablet:
One film-coated tablet contains montelukast sodium, which is equivalent to 10 mg of montelukast.

5 mg chewable tablet:
One chewable tablet contains montelukast sodium, which is equivalent to 5 mg montelukast.

4 mg chewable tablet:
One chewable tablet contains montelukast sodium, which is equivalent to 4 mg montelukast.

For excipients, click here

10 mg film-coated tablet:
Beige, rounded square, film-coated (size 7.9 mm by 7.9 mm) with ‘SINGULAIR’ engraved on one side, ‘MSD 117’ on the other.

5 mg chewable tablet:
Pink, round, biconvex (diameter 9.5 mm), with ‘SINGULAIR’ engraved on one side, ‘MSD 275’ on the other.

4 mg chewable tablet:
Pink, oval, biconvex-shaped, ‘SINGULAIR’ engraved on one side, ‘MSD 711’ on the other.

‘Singulair’ 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 ?-agonists provide inadequate clinical control of asthma.
10 mg tablet ONLY:  In those asthmatic patients in whom ‘Singulair’ is indicated in asthma, ‘Singulair’ can also provide symptomatic relief of seasonal allergic rhinitis.

‘Singulair’ is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.

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10 mg tablet:
The dosage for adults 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.

5 mg chewable tablet:
The dosage for paediatric patients 6-14 years of age is one 5 mg chewable tablet daily to be taken in the evening. If taken in connection with food, ‘Singulair’ should be taken 1 hour before or 2 hours after food.  No dosage adjustment within this age group is necessary. 

4 mg chewable tablet:
The dosage for paediatric patients 2-5 years of age is one 4 mg chewable tablet daily to be taken in the evening. If taken in connection with food, ‘Singulair’ should be taken 1 hour before or 2 hours after food.  No dosage adjustment within this age group is necessary.  Experience in the paediatric population below 2 years of age is limited and use of montelukast is not recommended until further data become available.  Safety and efficacy have not yet been established in this age group.

General recommendations:  The therapeutic effect of ‘Singulair’ on parameters of asthma control occurs within one day.  ‘Singulair’ may be taken with or without food.  Patients should be advised to continue taking ‘Singulair’ even if their asthma is under control, as well as during periods of worsening asthma.
10 mg tablet: ‘Singulair’ 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 ‘Singulair’ in relation to other treatments for asthma.
‘Singulair’ can be added to a patient’s existing treatment regimen.

B-agonist therapy:  ‘Singulair’ can be added to the treatment regimen of patients who are not adequately controlled on ‘as-needed’ short-acting ?-agonist.  When a clinical response is evident (usually after the first dose), the patient may be able to decrease the use of ‘as-needed’ short-acting ?-agonist.

Inhaled corticosteroids:  Treatment with ‘Singulair’ can be used as add-on therapy in patients when other agents, such as inhaled corticosteroids provide inadequate clinical control.  ‘Singulair’ should not be substituted for inhaled corticosteroids (See Section 4.4).

10 mg tablets are available for adults 15 years of age and older.
5 mg chewable tablets are available for paediatric patients 6 to14 years of age.
4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.

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

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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 ?-agonist should be used.  Patients should seek their doctor’s advice as soon as possible if they need more inhalations of short-acting B-agonists than usual.

Montelukast should not be substituted for inhaled or oral corticosteroids.

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

In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy.  These cases usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy.  The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor 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.
10 mg tablet:
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.

5 mg chewable tablet:
‘Singulair’ contains aspartame, a source of phenylalanine. Patients with phenylketonuria should take into account that each 5 mg chewable tablet contains phenylalanine in an amount equivalent to 0.842 mg phenylalanine per dose.

4 mg chewable tablet:
Safety and efficacy have not yet been established in the paediatric population below 2 years of age.

‘Singulair’ contains aspartame, a source of phenylalanine.  Patients with phenylketonuria should take into account that each 4 mg chewable tablet contains phenylalanine in an amount equivalent to 0.674 mg phenylalanine per dose.

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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 drugs:  theophylline, prednisone, prednisolone, oral contraceptives (ethinyl oestradiol/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, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.

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Since there are no controlled studies in pregnant or nursing women, montelukast  should not be used during pregnancy or in nursing mothers unless it is considered to be clearly essential. (Click here to see section).

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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.

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Montelukast has been evaluated in clinical studies as follows:

• 10 mg film-coated tablets in approximately 4,000 adult asthmatic patients 15 years of age and older.
• 10 mg film-coated tablets in approximately 400 adult asthmatic patients with seasonal allergic rhinitis 15 years of age and older
• 5-mg chewable tablets in approximately 1,100 paediatric asthmatic patients 6 to 14 years of age, and
• 4 mg chewable tablets in 573 paediatric patients 2 to 5 years of age.

The following drug-related adverse reactions in placebo-controlled clinical studies were reported commonly (>1/100, <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo.

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 6 months for paediatric patients 6 to 14 years of age, the safety profile did not change.

Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least 3 months, 338 for 6 months or longer, and 256 patients for 12 months or longer.  With prolonged treatment, the safety profile did not change in these patients either.

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

Body as whole: asthenia/fatigue, malaise, oedema, hypersensitivity reactions including anaphylaxis, angioedema, urticaria, pruritus, rash and one isolated report of hepatic eosinophilic infiltration

Nervous system/psychiatric: dizziness, dream abnormalities including nightmares, hallucinations, drowsiness, insomnia, paraesthesia/hypoesthesia, irritability, agitation including aggressive behaviour, restlessness, seizure

Musculo-skeletal disorders: arthralgia, myalgia including muscle cramps

Digestive system disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.

Hepato-biliary disorders: elevated levels of serum transaminases (ALT, AST), cholestatic hepatitis.
Cardiovascular disorders: increased bleeding tendency, bruising, palpitations.

Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in asthmatic patients. (Click here to see section ).

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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 patients for 22 weeks and in short-term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.

There have been reports of acute overdosage in children in post-marketing experience and clinical studies of up to at least 150 mg/day with montelukast. The clinical and laboratory findings observed were consistent with the safety profile in adults and older paediatric patients. There were no adverse experiences reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain.

It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.

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Pharmacotherapeutic group: Anti-Asthmatics for systemic use, Leukotriene receptor antagonist

ATC Code: RO3D CO3

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.

Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor.  In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg.  Bronchodilation was observed within two hours of oral administration.  The bronchodilation effect caused by a B-agonist was additive to that caused by montelukast.  Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients.  In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.  In adult and paediatric patients 2 to 14 years of age, montelukast, compared with placebo, decreased peripheral blood eosinophils while improving clinical asthma control.

In studies in adults, montelukast 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total B-agonist use (-26.1% vs  4.6% change from baseline).  Improvement in patient-reported daytime and night time asthma symptoms scores was significantly better than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclomethasone, respectively for FEV1 : 5.43% vs 1.04%; B-agonist use: -8.70% vs 2.64%).  Compared with inhaled beclomethasone (200 ug twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided a greater average treatment effect (% change from baseline for montelukast vs beclomethasone, respectively for FEV1 : 7.49% vs 13.3%; B-agonist use: -28.28% vs -43.89%).  However, compared with beclomethasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g. 50% of patients treated with beclomethasone achieved an improvement in FEV1  of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

10 mg tablets:
A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis.  In this study, montelukast 10-mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score, compared with placebo.  The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhea, sneezing, nasal itching) and the Night-time Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and night-time awakenings scores).  Global evaluations of allergic rhinitis by patients and physicians, were significantly improved, compared with placebo.  The evaluation of asthma efficacy was not a primary objective of this study.

4 mg tablets:
In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once daily  improved parameters of asthma control compared with placebo, irrespective of concomitant controller therapy (inhaled/nebulised corticosteroids or inhaled/nebulised sodium cromoglycate). 60% of patients were not on any other controller therapy.  Montelukast improved daytime symptoms (including coughing, wheezing, trouble breathing and activity limitation) and night-time symptoms compared with placebo.  Montelukast also  decreased ‘as needed’ B-agonist use  and corticosteroid rescue for worsening asthma compared with placebo.  Patients receiving montelukast had more days without asthma than those receiving placebo.  A treatment effect was achieved after the first dose.

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased ‘as-needed’ B-agonist use (-11.7% vs +8.2% change from baseline).

Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min).  This effect was consistent throughout the 12-week study period.  Reduction in EIB was also demonstrated in a short term study in paediatric patients 6 to 14 years of age (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min).  The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline and decrease in total B-agonist use -27.78% vs 2.09% change from baseline).

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Absorption:  Montelukast is rapidly absorbed following oral administration.  For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved three 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 two hours after administration in adults in the fasted state.  The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted state, Cmax  is achieved 2 hours after administration.  The mean Cmax  is 66% higher while mean Cmin  is lower than in adults receiving a 10 mg tablet.

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.

In vitro studies using human liver microsomes indicate that cytochromes P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast.  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.  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 radiolabelled 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), a decrease in plasma theophylline concentration was observed.  This effect was not seen at the recommended dose of 10 mg once daily.

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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, gastro-intestinal 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 5000 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.

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10 mg tablet:
Microcrystalline cellulose, lactose monohydrate (89.3 mg), croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

Film coating:  hypromellose, hydroxypropyl cellulose, titanium dioxide (E171), red and yellow ferric oxide (E172) and carnauba wax.

5 mg and 4 mg chewable tablets:
Mannitol, microcrystalline cellulose, hydroxypropylcellulose, red ferric oxide (E172), croscarmellose sodium, cherry flavour, aspartame  and magnesium stearate.

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Not applicable

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10 mg tablet: 3 years.

5 mg and 4 mg chewable tablets: 2 years

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Store in the original package

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Packaged in polyamide/PVC/aluminium blister package in:
Blisters (with weekdays indicated), in packages of: 7, 14, 28, 56, 98 and 140 tablets.
Blisters (without weekdays indicated), in packages of: 10, 20, 28, 30, 50, 100 and 200 tablets.
Blisters (unit doses), in packages of: 49, 50 and 56 tablets.

Not all pack sizes may be marketed

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No special requirements.

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Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

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10 mg tablet: PL 0025/0358
5 mg chewable tablet: PL 0025/0357
4 mg chewable tablet: PL 0025/0412

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10 mg tablet UK: 15 January 1998/31 July 2002
5 mg chewable tablet UK: 15 January 1998/31 July 2002
4 mg chewable tablet UK: 24 January 2001/31 July 2002

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November 2004

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POM

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
© Merck Sharp & Dohme Limited 2004.  All rights reserved.

MSD
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

SPC.SGA.04.UK/IRL.1089 (W028&W029)

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