Montelukast

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Montelukast
Montelukast2DCSD.svg
Montelukast 3D ball-and-stick.png
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 Edit this at Wikidata
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)

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]

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[edit]

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[edit]

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[edit]

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[edit]

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]

Pharmacology[edit]

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.[13] Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

Two genes of interest are ALOX5 and LCT4S.[citation needed][clarification needed]

Society and culture[edit]

Patents[edit]

Singulair was covered by U.S. Patent No. 5,565,473[14] which expired on August 3, 2012.[15] The same day, the FDA approved several generic versions of montelukast.[16]

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.[17] 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.[18]

Use with loratadine[edit]

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,[19] and on April 25, 2008, issued a not-approvable letter for the combination.[20]

Names[edit]

The Mont in montelukast stands for Montreal, the place where Merck (MSD) developed the drug.[21]

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 levocetrizine, Notta in Turkey,Topraz in South Africa and AirOn in Venezuela.

References[edit]

  1. ^ a b "Montelukast 10 mg film coated tablets - Summary of Product Characteristics (SmPC) - (eMC)". Retrieved 23 December 2018.
  2. ^ a b c d e f g h i j k l m "Montelukast Sodium Monograph for Professionals". Drugs.com. AHFS. Retrieved 23 December 2018.
  3. ^ a b 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. ^ 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. ^ 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.
  14. ^ 5,565,473
  15. ^ Singular patent details
  16. ^ "FDA approves first generic versions of Singulair to treat asthma, allergies". 3 August 2012. Retrieved 15 August 2012.
  17. ^ "U.S. Reexamines Merck's Singulair Patent". Thompson Reuters. May 28, 2009.
  18. ^ "Merck Says U.S. Agency Upholds Singulair Patent". Thompson Reuters. December 17, 2009.
  19. ^ Rubenstein, Sarah (April 28, 2008). "FDA Sneezes at Claritin-Singulair Combo Pill". The Wall Street Journal.
  20. ^ Schering-Plough press release - Schering-Plough/MERCK Pharmaceuticals Receives Not-Approvable Letter from FDA for Loratadine/Montelukast
  21. ^ 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.

External links[edit]