Montelukast

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Montelukast
Clinical data
Pronunciationmon te loo' kast
Trade namesSingulair, others
AHFS/Drugs.comMonograph
MedlinePlusa600014
License data
Pregnancy
category
Leukotriene receptor antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63–73%
Protein binding99%
MetabolismLiver (CYP2C8-major, CYP3A4 and CYP2C9-minor)[3]
Elimination half-life2.7–5.5 hours [5]
ExcretionBiliary [5]
Identifiers
  • (E,Z)-2-(1-((1-(3-(2-(7-Chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetic acid
JSmol)
Melting point145 to 148 °C (293 to 298 °F)
  • O=C(O)CC1(CC1)CS[C@@H](c2cccc(c2)\C=C\c3nc4cc(Cl)ccc4cc3)CCc5ccccc5C(O)(C)C
  • InChI=1S/C35H36ClNO3S/c1-34(2,40)30-9-4-3-7-25(30)13-17-32(41-23-35(18-19-35)22-33(38)39)27-8-5-6-24(20-27)10-15-29-16-12-26-11-14-28(36)21-31(26)37-29/h3-12,14-16,20-21,32,40H,13,17-19,22-23H2,1-2H3,(H,38,39)/b15-10+/t32-/m1/s1 checkY
  • Key:UCHDWCPVSPXUMX-TZIWLTJVSA-N checkY
  (verify)

Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of

asthma attacks.[6] Other uses include allergic rhinitis and hives of long duration.[6] For allergic rhinitis it is a second-line treatment.[7]

Common side effects include abdominal pain, cough, and headache.

leukotriene receptor antagonist family of medications.[6] It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.[6]

Montelukast was approved for medical use in the United States in 1998.

generic medication.[8] In 2021, it was the fourteenth most commonly prescribed medication in the United States, with more than 30 million prescriptions.[9][10]

Medical uses

Montelukast is used for a number of conditions including

intravenous immunoglobulin. It may also be used as an adjunct therapy in symptomatic treatment of mastocytosis.[12] It is taken by mouth, as a tablet, chewable tablet, or as granules.[6]

Pharmacology

Main article:
Leukotriene receptor antagonist

Montelukast is in the

leukotriene receptor antagonist family of medications.[6] It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.[6]

Montelukast functions as a leukotriene

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

Two genes of interest are ALOX5 and LTC4S, which catalyze two major steps in the biosynthetic pathway of leukotrienes.[citation needed]

Montelukast may affect nerve remyelination in combination with Pexidartinib[14] and this may cause clinical benefits or side effects.[citation needed]

Adverse effects

Common

paresthesias and seizures, muscle cramps, and nose bleeds. Rare (may affect up to 1 in 10,000 people taking montelukast) but serious side effects include behavioral changes (including suicidal thoughts), angioedema, erythema multiforme, and liver problems.[3][15]

In 2019 and 2020, concerns for neuropsychiatric reactions were added to the label in the United Kingdom and United States where the most frequently suspected were nightmares, depression, insomnia (may affect between 1 in 100 to 1 in 1,000 people taking montelukast); aggression, anxiety and abnormal behaviour or changes in behaviour (may affect between 1 in 1,000 and 1 in 10,000 people taking montelukast).[16][17]

In 2024, following reports of night terrors, uncontrollable aggression, intrusive thoughts, depression and rare cases of hallucinations and suicidal behaviour in children, the UK Medicines and Healthcare products Regulatory Agency (MHRA) was reviewing the risks of montelukast after identifying "further concerns".[18]

FDA investigation

In June 2009, the U.S.

hallucinations, depression, irritability, restlessness, and tremor.[19]

In September 2019, the Pediatric Advisory Committee and the Drug Safety and Risk Management Advisory Committee met to discuss a pediatric-focused safety review of neuropsychiatric events with montelukast.[20]

In March 2020, the FDA required a boxed warning for montelukast to strengthen an existing warning about the risk of neuropsychiatric events associated with the drug in the wake of an increase in case reporting of neuropsychiatric events around the time of the initial communications about the concern from FDA in 2008.[21][22][17] The boxed warning advises health care providers to avoid prescribing montelukast to patients with mild symptoms, particularly those with allergic rhinitis, because there are many other allergy medicines that can safely and effectively manage this condition.[21]

In the FDA's data analysis, in comparison to case reports that based on people's self-reports, the propensity of developing neuropsychiatric disorders after montelukast use did not outpace that of inhaled corticosteroids; and there were no statistically significant risks of new-onset neuropsychiatric disorders among males, females, patients 12 years and older, patients with a psychiatric history, or after the 2008 FDA communication and prescribing information changes that first publicized the concern.[22] In addition, the FDA's analysis summary of its findings said "exposure to montelukast was significantly associated with a decreased risk of treated outpatient depressive disorder and the decreased risks were seen among patients with a history of a psychiatric disorder, in patients 12 to 17 years as well as 18 years and older, and in both females and males."[22] "Treated outpatient depressive disorder" refers to patients who sought treatment specifically for depressive disorders in outpatient psychiatric settings.[22]

Drug interactions

Montelukast is an inhibitor of the drug metabolizing enzyme CYP2C8, part of the cytochrome P450 system. 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.[23][24] However, clinical studies have shown minimal interactions between montelukast and other CYP2C8 substrate drugs, which is most likely due to the high plasma protein binding exhibited by montelukast.[25]

Society and culture

Patents

Singulair was covered by U.S. Patent No. 5,565,473[26] which expired on 3 August 2012.[27] The same day, the FDA approved several generic versions of montelukast.[28]

The United States Patent and Trademark Office launched a reexamination of the patent covering Singulair on 28 May 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.[29] 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 17 December 2009.[30]

Use with loratadine

not-approvable letter for the combination.[32]

Brand names

The Mont in montelukast stands for Montreal, the place where Merck (MSD) developed the drug.[33]

Montelukast is sold under a variety of brand names including Monalast (Ziska Pharmaceuticals Ltd) Montenaaf (NAAFCO Pharma) Montelon-10 (Apex), Montene (Square), Montair-10, Montelo-10, Monteflo, and Tukast L in India, Reversair (ACI Bangladesh), Monas, 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, Desmont, Levmont, Aircomb and Notta in Turkey, Topraz and Monte-Air[34]in South Africa, AirOn in Venezuela, and AirFast in Saudi Arabia.[citation needed]

References

  1. ^ "Montelukast (Singulair) Use During Pregnancy". Drugs.com. 13 December 2019. Archived from the original on 7 August 2019. Retrieved 4 March 2020.
  2. FDA
    . Retrieved 22 October 2023.
  3. ^ a b c "Singulair 10 mg film-coated tablets - Summary of Product Characteristics (SmPC)". electronic medicines compendium (emc). Archived from the original on 1 October 2020. Retrieved 23 December 2018.
  4. ^ "Singulair- montelukast sodium granule Singulair- montelukast sodium tablet, chewable Singulair- montelukast sodium tablet, film coated". DailyMed. 29 April 2020. Archived from the original on 15 October 2020. Retrieved 12 October 2020.
  5. ^ a b "Elsevier – Drug Monograph │Montelukast". Elsevier's Healthcare Hub. 4 March 2020. Archived from the original on 27 January 2023. Retrieved 27 January 2023. Montelukast and its metabolites are excreted almost exclusively via the bile; less than 0.2% of the drug is excreted in urine. Mean elimination half-life (half-life) of montelukast is 2.7 to 5.5 hours in healthy young adults.
  6. ^ a b c d e f g h i j k l m "Montelukast Sodium Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 7 June 2019. Retrieved 23 December 2018.
  7. S2CID 27200676
    .
  8. ISBN 978-0-85711-338-2
    .
  9. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  10. ^ "Montelukast - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  11. ^ "Montelukast Sodium". The American Society of Health-System Pharmacists. Archived from the original on 7 June 2019. Retrieved 3 April 2011.
  12. PMID 24044484
    .
  13. PMID 23822826
    .
  14. ^ "New Strategies for Restoring Myelin on Damaged Nerve Cells". Neuroscience News. 6 November 2020. Archived from the original on 27 January 2022. Retrieved 27 January 2022.
  15. ^ Levine D, Respaut R, Cooke K, Spector M, Lesser B (26 June 2023). "A son died, his parents tried to sue. How U.S. courts protect Big Pharma". Reuters. Archived from the original on 26 June 2023. Retrieved 27 June 2023.
  16. ^ "Montelukast (Singulair): reminder of the risk of neuropsychiatric reactions". Archived from the original on 24 September 2019. Retrieved 19 September 2019.
  17. ^ a b "Singulair (montelukast) and All Generics: Strengthened Boxed Warning". U.S. Food and Drug Administration (FDA). 4 March 2020. Archived from the original on 4 March 2020. Retrieved 4 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  18. ^ Ungoed-Thomas J (3 March 2024). "Safety fears over asthma drug after young children suffer severe side effects". \The Observer.
  19. ^ a b "Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR)". U.S. Food and Drug Administration (FDA). 12 June 2009. Archived from the original on 14 November 2017. Retrieved 1 March 2017.
  20. ^ "Regulations.gov". www.regulations.gov. Archived from the original on 27 January 2022. Retrieved 27 January 2022.
  21. ^ a b "FDA Requires Stronger Warning About Risk of Neuropsychiatric Events Associated with Asthma and Allergy Medication Singulair and Generic Montelukast". U.S. Food and Drug Administration (FDA) (Press release). 4 March 2020. Archived from the original on 4 March 2020. Retrieved 4 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  22. ^ a b c d "FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis". U.S.Food and Drug Administration (FDA). 4 March 2020. Archived from the original on 4 March 2020. Retrieved 4 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  23. ^ "Artesunate Amodiaquine Winthrop (artesunate, amodiaquine) | summary of product characteristics. Gentilly, France: Sanofi-aventis; August 2010" (PDF). Archived from the original (PDF) on 24 October 2016. Retrieved 24 October 2016.
  24. PMID 17304470
    .
  25. S2CID 29099906
    .
  26. ^ US 5565473, Belley ML, Leger S, Labelle M, Roy P, Xiang YB, Guay D, "Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists", issued 15 October 1996, assigned to Merck Sharpe & Dohme  Archived 23 November 2023 at the Wayback Machine
  27. ^ "Drugs covered by patent 5,565,473. Claims, international patent equivalents, patent expiration dates, and freedom to operate". Deep knowledge on small-molecule drugs and the global patents covering them. Archived from the original on 27 January 2022. Retrieved 27 January 2022.
  28. ^ "FDA approves first generic versions of Singulair to treat asthma, allergies". 3 August 2012. Archived from the original on 6 August 2012. Retrieved 15 August 2012.
  29. ^ "U.S. Reexamines Merck's Singulair Patent". Thomson Reuters. 28 May 2009. Archived from the original on 16 May 2021. Retrieved 6 July 2021.
  30. ^ "Merck Says U.S. Agency Upholds Singulair Patent". Thomson Reuters. 17 December 2009. Archived from the original on 18 May 2021. Retrieved 6 July 2021.
  31. ^ Rubenstein S (28 April 2008). "FDA Sneezes at Claritin-Singulair Combo Pill". The Wall Street Journal. Archived from the original on 25 March 2017. Retrieved 4 August 2017.
  32. ^ "Schering-Plough/Merck Pharmaceuticals Receives Not-Approvable Letter from FDA for Loratadine/Montelukast". Schering-Plough (Press release). 25 April 2008. Archived from the original on 24 September 2008. Retrieved 17 March 2020.
  33. ISBN 978-0-19-530099-4
    . Retrieved 26 November 2017.
  34. ^ "Monte-Air". 22 June 2022. Retrieved 19 February 2024.
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