Montelukast

Montelukast
Clinical data
Trade names Singulair
AHFS/Drugs.com Monograph
MedlinePlus a600014
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
    Routes of
    administration    		 Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 63–73%
    Protein binding 99%
    Metabolism Hepatic (CYP2C8-major, CYP3A4 and CYP2C9-minor)[1]
    Elimination half-life 2.7–5.5 hours
    Excretion Biliary
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.115.927 Edit this at Wikidata
    Chemical and physical data
    Formula C35H36ClNO3S
    Molar mass 586.184 g/mol
    3D model (JSmol)
    Melting point 145 to 148 °C (293 to 298 °F)
      (verify)

    Montelukast (trade name Singulair) is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.[2][3] Montelukast comes as a tablet, a chewable tablet, and granules to take by mouth.[4] Montelukast is usually taken once a day with or without food.[4] Montelukast is a CysLT1 antagonist; it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation.

    Because of its mechanism of action, it is not useful in the treatment of acute asthma attacks.

    The Mont in Montelukast stands for Montreal, the place where Merck (MSD) developed the drug.[5]

    Medical uses

    Montelukast is used for a number of conditions including asthma, exercise induced bronchospasm, allergic rhinitis, primary dysmenorrhoea (i.e. dysmenorrhoea not associated with known causes; see dysmenorrhea causes), and urticaria.[6] It is mainly used as a complementary therapy in adults in addition to inhaled corticosteroids, if they alone do not bring the desired effect. It is also used to prevent allergic reactions and asthma flare-ups during the administration of intravenous immunoglobulin. It may also be used as an adjunct therapy in symptomatic treatment of mastocytosis.[7]

    Montelukast is administered as montelukast sodium, with 5.2 mg of montelukast sodium being equivalent to 5 mg of montelukast.[8]

    Adverse effects

    Common side effects include diarrhea, nausea, vomiting, mild rashes, asymptomatic elevations in liver enzymes, and fever. Uncommon side effects include fatigue and malaise, behavioral changes, paresthesias and seizures, muscle cramps, and nose bleeds. Rare but sometimes serious side effects include severe behavioral changes (including suicidal thoughts), angioedema, erythema multiforme, and liver problems.[1]

    FDA investigation

    In March 2008, the U.S. Food and Drug Administration (FDA) announced that it would investigate whether mood changes and suicidal thoughts are possible side effects of drugs in this class, including the popular drug Singulair, which currently lists these side effects.[9]

    On June 12, 2009, the FDA concluded their review into the possibility of neuropsychiatric side effects with leukotriene modulator drugs. Although clinical trials only revealed an increased risk of insomnia, post-marketing surveillance showed that the drugs are associated with a possible increase in suicidal behavior and other side effects such as agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, irritability, restlessness, and tremor.[10]

    Drug interactions

    Montelukast has very few drug-drug interactions. This is due to the lack of off-target affinity towards other targets in the body where it might exert an effect. However, it is important to note that montelukast is an inhibitor of the drug metabolizing enzyme CYP2C8. Therefore, it is theoretically possible that the combination of montelukast with a CYP2C8 substrate (e.g. amodiaquine, an anti-malarial drug) could increase the plasma concentrations of the substrate.[11][12]

    Pharmacogenetics

    Two genes of interest are ALOX5 and LCT4S.

    Use with loratadine

    Schering-Plough and Merck sought permission to market a combined tablet with loratadine (Claritin) and montelukast (Singulair), as many patients combine the two themselves. However, the FDA has found no benefit from a combined pill for seasonal allergies over taking the two drugs in combination,[13] and on April 25, 2008, issued a not-approvable letter for the combination.[14]

    Uses under study

    Ludwig Aigner from Paracelsus Medical University in Austria presented findings at the October 2015 meeting of the Society for Neuroscience in Chicago which showed that administration of montelukast to older rats rejuvenated their brains, returning the same functionality as that of young rats. Human trials are planned, starting with Parkinson's disease patients.[15] The researchers conducted the experiment with montelukast because it reduces inflammation in the lungs and they thought it might also reduce inflammation in the brain. Some research has suggested that decline in memory skills may be associated with inflammation in the brain.[16]

    Dosage and administration

    The usual dose of montelukast in adults and teenagers is one 10 mg tablet taken orally a day. In children 6 to 14 years of age the usual dosage is one 5 mg chewable tablet a day. The dose is preferably taken in the evening.

    Patents

    Singulair was covered by U.S. Patent No. 5,565,473[17] which expired on August 3, 2012.[18] The same day, the FDA approved several generic versions of montelukast.[19]

    The United States Patent and Trademark Office launched a reexamination of the patent covering Singulair on May 28, 2009. The decision was driven by the discovery of references that were not included in the original patent application process. The references were submitted through Article One Partners, an online research community focused on finding literature relating to existing patents. The references included a scientific article produced by a Merck employee on the active ingredient in Singulair. A previously filed patent had been submitted in the same technology area.[20] Seven months later the U.S. Patent and Trademark Office determined that the patent in question was valid based on the initial reexamination and new information provided, submitting their decision on December 17, 2009.[21]

    Brand names

    Montelukast is sold under a variety of brand names including Montelon-10 (Apex), Montene (Square), Montair-10, Montelo-10, Monteflo, and Tukast L in India, Reversair (ACI Bangladesh), Miralust, Montiva, Provair, Montril, Lumona, Lumenta, Arokast and Trilock in Bangladesh, Ventair in Nepal, Respicare in Pakistan, Montelair in Brazil, Zykast in the Philippines though combined with levocetrizine, Notta in Turkey, and AirOn in Venezuela.

    References

    1. 1 2 "EMC-Montelukast 10 mg film coated tablets".
    2. ↑ Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 178, ISBN 0-8160-4404-X
    3. ↑ "Asthma / Allergy " Archived 2012-06-14 at the Wayback Machine.. Mascothealth.com. Retrieved 9 April 2011.
    4. 1 2 Montelukast article on Medline Plus https://www.nlm.nih.gov/medlineplus/druginfo/meds/a600014.html "Montelukast comes as a tablet, a chewable tablet, and granules to take by mouth. Montelukast is usually taken once a day with or without food."
    5. ↑ Li, Jie Jack (2006). "8". Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use. Oxford University Press. p. 234. ISBN 978-0195300994. Retrieved 26 November 2017.
    6. ↑ "Montelukast Sodium". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
    7. ↑ Cardet, J. C; Akin, C; Lee, M. J (2013). "Mastocytosis: Update on pharmacotherapy and future directions". Expert Opinion on Pharmacotherapy. 14 (15): 2033–2045. doi:10.1517/14656566.2013.824424. PMC 4362676. PMID 24044484.
    8. ↑ Soni, Rajeev; Sagar, Gali Vidya; Sharma, Pankaj (2012). "Formulation, development and in-vitro evaluation of mucoadhesive bilayered buccal patches of montelukast sodium" (PDF). International Journal of Pharmacy and Pharmaceutical Studies. 4 (2).
    9. ↑ FDA Investigates Merck Drug-Suicide Link
    10. ↑ Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR). Food and Drug Administration. Published June 12, 2009. Accessed March 1, 2017.
    11. ↑ Artesunate Amodiaquine Winthrop (artesunate, amodiaquine) [summary of product characteristics]. Gentilly, France: Sanofi-aventis; August 2010. http://www.wipo.int/export/sites/www/research/en/data/sanofi/marketed_products/Artesunate_and_Amodiquine.pdf
    12. ↑ German P, Greenhouse B, Coates C, et al. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis. 2007;44(6):889-891. PID: 17304470
    13. ↑ Rubenstein, Sarah (April 28, 2008). "FDA Sneezes at Claritin-Singulair Combo Pill". The Wall Street Journal.
    14. ↑ Schering-Plough press release - Schering-Plough/MERCK Pharmaceuticals Receives Not-Approvable Letter from FDA for Loratadine/Montelukast
    15. ↑ Hamzelou, Jessica (23 October 2015). "Old rat brains rejuvenated and new neurons grown by asthma drug". New Scientist. Retrieved 28 October 2015.
    16. ↑ Yirka, Bob. "Asthma drug found to rejuvenate older rat brains". medicalxpress.com. Retrieved 3 November 2015.
    17. ↑ 5,565,473
    18. ↑ Singular patent details
    19. ↑ "FDA approves first generic versions of Singulair to treat asthma, allergies". 3 August 2012. Retrieved 15 August 2012.
    20. ↑ "U.S. Reexamines Merck's Singulair Patent". Thompson Reuters. May 28, 2009.
    21. ↑ "Merck Says U.S. Agency Upholds Singulair Patent". Thompson Reuters. December 17, 2009.
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