Montelukast

Montelukast, sold under the trade name Singulair among others, is a medication used in the maintenance treatment of asthma.[2] It is generally less preferred for this use than inhaled corticosteroids.[2] It is not useful for acute asthma attacks.[2] Other uses include allergic rhinitis and hives of long duration.[2] It is taken by mouth.[2]

Montelukast
Clinical data
Trade namesSingulair, others
AHFS/Drugs.comMonograph
MedlinePlusa600014
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
    Routes of
    administration    		By mouth
    Drug classLeukotriene receptor antagonist
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability63–73%
    Protein binding99%
    MetabolismLiver (CYP2C8-major, CYP3A4 and CYP2C9-minor)[1]
    Elimination half-life2.7–5.5 hours
    ExcretionBiliary
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.115.927
    Chemical and physical data
    FormulaC35H36ClNO3S
    Molar mass586.184 g/mol g·mol−1
    3D model (JSmol)
    Melting point145 to 148 °C (293 to 298 °F)
      (verify)

    Common side effects include abdominal pain, cough, and headache.[2] Severe side effects may include allergic reactions, such as anaphylaxis and eosinophilia.[2] Use in pregnancy appears to be safe.[2] Montelukast is in the leukotriene receptor antagonist family of medications.[2] It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.[2]

    Montelukast was approved for medical use in the United States in 1998.[2] It is available as a generic medication.[3] In the United States, the wholesale cost per dose is less than 0.15 USD as of 2018.[4] In the United Kingdom, it costs the NHS about a pound per dose.[3] In 2016, it was the 23rd most prescribed medication in the United States, with more than 25 million prescriptions.[5]

    Medical uses

    Montelukast is used for a number of conditions including asthma, exercise induced bronchospasm, allergic rhinitis, and urticaria.[6] It is mainly used as a complementary therapy in adults in addition to inhaled corticosteroids, if inhaled steroids 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 usually taken once a day with or without food.[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 serious side effects include behavioral changes (including suicidal thoughts), angioedema, erythema multiforme, and liver problems.[1]

    In 2019, concerns for neuropsychiatric reactions were added to the label in the United Kingdom where the most frequently suspected were nightmares, depression, insomnia, aggression, anxiety and abnormal behaviour or changes in behaviour.[9]

    FDA investigation

    In September 2019, the Pediatric Advisory Committee and the Drug Safety and Risk Management Advisory Committee will meet to discuss a pediatric-focused safety review of neuropsychiatric events with montelukast.[10]

    In June 2009, the FDA concluded a 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.[11]

    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.[12][13]

    Pharmacology
    Main article: Leukotriene receptor antagonist

    Montelukast is in the leukotriene receptor antagonist family of medications.[2] It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.[2]

    Montelukast functions as a leukotriene receptor antagonist (cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD.[14] Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

    Two genes of interest are ALOX5 and LCT4S.

    Society and culture

    Patents

    Singulair was covered by U.S. Patent No. 5,565,473[15] which expired on August 3, 2012.[16] The same day, the FDA approved several generic versions of montelukast.[17]

    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.[18] 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.[19]

    Use with loratadine

    Schering-Plough and Merck sought permission to market a combined tablet with loratadine and montelukast, as many people 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,[20] and on April 25, 2008, issued a not-approvable letter for the combination.[21]

    Names

    The Mont in montelukast stands for Montreal, the place where Merck (MSD) developed the drug.[22]

    Montelukast is sold under a variety of brand names including Montenaaf (NAAFCO Pharma) 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, Montika in Pakistan, Montelair in Brazil, Zykast in the Philippines though combined with levocetirizine, Notta in Turkey,Topraz in South Africa and AirOn in Venezuela.

    References
    1. "Montelukast 10 mg film coated tablets - Summary of Product Characteristics (SmPC) - (eMC)". Retrieved 23 December 2018.
    2. "Montelukast Sodium Monograph for Professionals". Drugs.com. AHFS. Retrieved 23 December 2018.
    3. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 269. ISBN 9780857113382.
    4. "NADAC as of 2018-12-19". Centers for Medicare and Medicaid Services. Retrieved 22 December 2018.
    5. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    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. 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."
    9. "Montelukast (Singulair): reminder of the risk of neuropsychiatric reactions". Retrieved 19 September 2019.
    10. FDA Joint Pediatric Advisory Committee and Drug Safety and Risk Management Advisory Committee; Notice of Meeting
    11. 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.
    12. 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
    13. 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
    14. Scott JP, Peters-Golden M (September 2013). "Antileukotriene agents for the treatment of lung disease". Am. J. Respir. Crit. Care Med. 188 (5): 538–544. doi:10.1164/rccm.201301-0023PP. PMID 23822826.
    15. 5,565,473
    16. Singular patent details
    17. "FDA approves first generic versions of Singulair to treat asthma, allergies". 3 August 2012. Retrieved 15 August 2012.
    18. "U.S. Reexamines Merck's Singulair Patent". Thompson Reuters. May 28, 2009.
    19. "Merck Says U.S. Agency Upholds Singulair Patent". Thompson Reuters. December 17, 2009.
    20. Rubenstein, Sarah (April 28, 2008). "FDA Sneezes at Claritin-Singulair Combo Pill". The Wall Street Journal.
    21. Schering-Plough press release - Schering-Plough/MERCK Pharmaceuticals Receives Not-Approvable Letter from FDA for Loratadine/Montelukast
    22. 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.
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