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Montelukast Sodium

 

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: L-706631; MK-476; Montelukast sódico
BAN: Montelukast Sodium [BANM]
USAN: Montelukast Sodium
INN: Montelukast Sodium [rINNM (en)]
INN: Montelukast sódico [rINNM (es)]
INN: Montélukast Sodique [rINNM (fr)]
INN: Natrii Montelukastum [rINNM (la)]
INN: Натрий Монтелукаст [rINNM (ru)]
Chemical name: Sodium 1-[({(R)-m-[(E)-2-(7-chloro-2-quinolyl)-vinyl]-α[o-(1-hydroxy-1-methylethyl)phenethyl]-benzyl}thio)methyl] cyclopropaneacetate
Molecular formula: C35H35ClNNaO3S =608.2
CAS: 158966-92-8 (montelukast); 151767-02-1 (montelukast sodium)
ATC code: R03DC03

Adverse Effects and Precautions

As for Zafirlukast.

Suspected adverse effects reported to the UK CSM after the launch of montelukast included oedema, agitation and restlessness, allergy (including anaphylaxis, angioedema, and urticaria), chest pain, tremor, dry mouth, vertigo, and arthralgia. Further suspected adverse effects included nightmares, sedation, palpitations, and increased sweating. In March 2008 the FDA announced that it was investigating a possible association between the use of montelukast and behaviour/mood changes, suicidality, and suicide. Other postmarketing adverse events that had been incorporated into the US licensed product information in the previous year had included: tremor, depression, suicidality, and anxiousness.

Churg-Strauss syndrome. Churg-Strauss syndrome has been reported with the use of montelukast. Relapse has occurred in a patient with Churg-Strauss syndrome who was in complete remission when montelukast therapy was started. For discussion of the unresolved role of leukotriene antagonists in this disorder and precautions to be observed, see under Zafirlukast.

Hepatic impairment. Although there is evidence of effects on the liver in patients receiving montelukast, and although it is largely eliminated by hepatic metabolism, montelukast (unlike zafirlukast) is not considered by UK licensed product information to be contra-indicated in hepatic impairment, and no dose adjustment is considered necessary in mild to moderate hepatic impairment.

montelukast-sodium

Interactions

Licensed product information recommends caution when potent inducers of the cytochrome P450 isoenzyme CYP3 A4 such as phenytoin, phenobarbital, or rif-ampicin are given with montelukast.

Corticosteroids. For a report of peripheral oedema in a patient given montelukast and prednisone, see Leukotriene Antagonists.

Phenobarbital. Peak serum concentrations after a single dose of montelukast 10 mg were reduced by 20% in 14 healthy sub-j ects who took phenobarbital 100 mg daily for 14 days, and area under the serum concentration-time curve was reduced by 38%. However, it was not thought that montelukast doses would need adjustment if given with phenobarbital.

Pharmacokinetics

Peak plasma concentrations of montelukast are achieved in 3 to 4 hours after oral doses. The mean oral bioavailability is 64%. Montelukast is more than 99% bound to plasma proteins. It is extensively metabolised in the liver by cytochrome P450 isoenzymes CYP3 A4, CYP2A6, and CYP2C9, and is excreted principally in the faeces via the bile.

Uses and Administration

Montelukast is a selective leukotriene receptor antagonist with actions and uses similar to those of zafirlukast although it is reported to have a longer duration of action. It is used as the sodium salt, but doses are expressed in terms of the base montelukast sodium 10.38 mg is equivalentto about 10 mg of montelukast. In the management of chronic asthma (see below), allergic rhinitis (see below), and as prophylaxis for exercise-induced asthma, montelukast sodium is given in doses equivalent to 10 mg of montelukast once daily in the evening. It should not be used to treat an acute asthma attack. For details of doses in children, see below.

Administration in children. Montelukast sodium is available as oral granules and chewable tablets for use in children. Oral granules are suitable for infants as they may be given directly into the mouth or mixed with a small amount of soft food. UK licensed oral doses for the management of chronic asthma and as prophylaxis for exercise-induced asthma, expressed as montelukast, are as follows:

• 6 months to 5 years, 4 mg daily taken in the evening

• 6 to 14 years, 5 mg daily taken in the evening

• 15 years and over, use the adult dose, see above

In the USA these doses are licensed from 1 year of age in asthma and from 15 years in exercise-induced asthma. Montelukast is also licensed for use in allergic rhinitis (p.565) in the USA. The above doses can be given from 2 years of age in seasonal allergic rhinitis and from 6 months of age in perennial allergic rhinitis.

Asthma. Use of montelukast in asthma has been reviewed, (further general references for leukotriene antagonists can be found under Zafirlukast). Montelukast produced modest improvements compared with placebo in chronic asthma and exercise-induced asthma in both adults’ and children. In a systematic review of studies in adults and children comparing leukotriene receptor antagonists with inhaled corticosteroids for mild to moderate asthma, in which more than half of the studies used montelukast, leukotriene antagonists were found to be less effective in maintaining asthma control. A more recent study in children came to a similar conclusion, but another 12-month study in children with mild persistent asthma, reported that montelukast was not inferior to an inhaled corticosteroid (flutica-sone) similar numbers of days without rescue medication, the primary outcome in this study, were reported with both treatments. However, some of the conclusions drawn from the latter study have been questioned since patients who received inhaled fluticasone achieved better secondary outcomes such as fewer asthma attacks and less requirement for systemic corticosteroids.

Addition of montelukast to an inhaled corticosteroid has significantly improved asthma control in adults and children with mild to moderate asthma. Significant improvements in quality of life have also been reported, in association with a fall in the levels of exhaled inflammatory mediators leading the authors of this study to conclude that leukotriene receptor antagonists may provide a complementary effect to inhaled corticosteroids when suppression of inflammation is incomplete. Another study has reported that the use of montelukast did permit reduction in the dose of inhaled corticosteroid adding montelukast to an inhaled corticosteroid (budesonide) may be as effective as doubling the dose of the corticosteroid.

There is some evidence that montelukast may be more effective than inhaled salmeterol for the chronic treatment of exercise-induced asthma, and although a later study found similar effects on lung function with the two drugs, a more favourable effect was seen on gas exchange during moderate exercise with the use of montelukast.

An intravenous form of montelukast is under investigation for the treatment of severe acute asthma.

Bronchiolitis. Bronchiolitis due to RSV infection is often followed by post-bronchiolitic reactive airways disease, characterised by asthma-like wheeze and other symptoms. In a pilot study, montelukast 5 mg orally daily was given for 4 weeks to infants who had been admitted for moderate to severe bronchiolitis. Symptom-free days and nights were increased, daytime cough was reduced, and exacerbations were delayed compared with placebo. The benefit of montelukast over placebo was only apparent after the first 2 weeks of treatment. Although the safety and efficacy of such treatment remains to be properly established, there is some interest in whether montelukast can prevent or modify more persistent asthma that has been associated with RSV.

Cystic fibrosis. A small study in children with cystic fibrosis found that montelukast reduced eosinophilic inflammation. A later study, reported improved lung function and a reduction in coughing and wheezing, and concluded that montelukast may have measurable anti-inflammatory activity in patients with cystic fibrosis. In a small group of adult patients with cystic fibrosis montelukast improved symptoms, in particular exercise tolerance and peak expiratory flow rates. The patients who benefited the most had positive Aspergillus serology, and the authors suggested that colonisation of the airways in cystic fibrosis by Aspergillus stimulates T helper cell inflammation and leukotriene synthesis. A review of leukotriene receptor antagonists in cystic fibrosis concluded that clinical benefit seemed likely in a subset of patients with cystic fibrosis who experience bronchial hyperresponsiveness similar to that seen in asthma. A study into the pharmacokinetics of montelukast in cystic fibrosis found that the dose of montelukast and the dosing interval do not need to be modified if the goal of therapy is to achieve similar serum concentrations as for asthma treatment however the effectiveness of these concentrations for the inflammatory lung disease of patients with cystic fibrosis was unknown.

Eczema. Despite early indications from some small clinical studies and case reports that montelukast might be of benefit in eczema larger, more recent studies have failed to show any improvement compared with placebo.

Gastrointestinal disorders. Benefit has been reported with the use of montelukast in patients with eosinophilic oesophagitis, a rare condition involving eosinophilic infiltration of the oesophagus with intermittent painful dysphagia. A systematic review with recommendations for the diagnosis and treatment of eosinophilic oesophagitis concluded that although leukotriene receptor antagonists had been shown to induce symptomatic relief at high doses, no significant improvements in histology were noted and their use for the treatment of eosinophilic oesophagitis is not supported by the current literature.

Graft-versus-host disease. A pilot study in refractory, chronic graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation, saw an improvement in 15 of 19 patients after montelukast was added to their standard immunosuppressive regimens in 4 patients signs of chronic GVHD were resolved, 2 showed significant improvement, and 9 showed moderate improvement.

Mastocytosis. Montelukast has been tried, with some success, in the treatment of systemic mastocytosis in an infant.

Rhinitis. Montelukast is used in allergic rhinitis, where large placebo-controlled studies have shown it to relieve symptoms in both seasonal allergic rhinitis, and perennial allergic rhinitis. However, a meta-analysis of leukotriene antagonists (mainly montelukast) for management of allergic rhinitis concluded that while leukotriene antagonists were modestly more effective than placebo and of similar efficacy to antihistamines, in reducing nasal symptoms and improving rhinoconjunctivitis, they were less effective than corticosteroids even when used with antihistamines. A later systematic review commented that some studies in allergic rhinitis using a combination of montelukast and an antihistamine had produced results comparable with intranasal corticosteroids. Also, in patients with both allergic rhinitis and asthma, montelukast had resulted in significant improvements in both when compared with placebo.

Sleep-disordered breathing. Montelukast with an intranasal corticosteroid has been reported to be beneficial in a small study in children with residual sleep-disordered breathing after tonsillectomy and adenoidectomy.

Urticaria. Montelukast has been investigated in the treatment of urticaria with variable results. However, urticaria has also been described as a suspected adverse effect of montelukast therapy (see above).

Montelukast has been reported to be more effective than placebo when used with the antihistamine desloratadine in the treatment of delayed pressure urticaria.

Preparations

Proprietary Preparations

 

Argentina: Singulair

Australia:: Singulair

Austria: Singulair

Belgium: Singulair

Brazil: Singulair

Canada: Singulair

Czech Republic: Singulair

Denmark: Singulair

Finland: Singulair

France: Singulair

Germany: Singulair

Greece: Singulair

Hong Kong: Singulair

Hungary: Singulair

India: Montair Montelast

Ireland: Singulair

Israel: Singulair

Italy: Lukasm Montegen Singulair

Japan: Kipres

Malaysia: Singulair

Mexico: Singulair

The Netherlands: Singulair

Norway: Singulair

New Zealand: Singulair

Philippines: Singulair

Poland: Singulair

Portugal: Lukair Singulair Singulergy Synglarin

Russia: Singulair

South Africa: Singulair

Singapore: Singulair

Spain: Singulair

Sweden: Singulair

Switzerland: Singulair

Thailand: Singulair

Turkey: Singulair

UK: Singulair

USA: Singulair

Venezuela: Airon Inuvic Monukast Singulair

Multi-ingredient

India: Montair Plus

 

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