Montelukast

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Montelukast
Montelukast.svg
Montelukast 3D ball-and-stick.png
Clinical data
Pronunciationmon te loo' kast
Trade names Singulair, others
AHFS/Drugs.com Monograph
MedlinePlus a600014
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Leukotriene receptor antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 63–73%
Protein binding 99%
Metabolism Liver (CYP2C8-major, CYP3A4 and CYP2C9-minor) [2]
Elimination half-life 2.7–5.5 hours [5]
Excretion Bile duct [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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.115.927 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C35H36ClNO3S
Molar mass 586.19 g·mol−1
3D model (JSmol)
Melting point 145 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 Yes check.svgY
  • Key:UCHDWCPVSPXUMX-TZIWLTJVSA-N Yes check.svgY
   (verify)

Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. [6] It is generally less preferred for this use than inhaled corticosteroids. [6] It is not useful for acute asthma attacks. [6] Other uses include allergic rhinitis and hives of long duration. [6] For allergic rhinitis it is a second-line treatment. [7]

Contents

Common side effects include abdominal pain, cough, and headache. [6] Severe side effects may include allergic reactions, such as anaphylaxis and eosinophilia. [6] Use in pregnancy appears to be safe. [6] 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 was approved for medical use in the United States in 1998. [6] It is available as a generic medication. [8] In 2022, it was the seventeenth most commonly prescribed medication in the United States, with more than 29 million prescriptions. [9] [10]

Medical uses

Montelukast is used for a number of conditions including asthma, exercise induced bronchospasm, allergic rhinitis, and urticaria. [11] 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. [12] It is taken by mouth, as a tablet, chewable tablet, or as granules. [6]

Pharmacology

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 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]

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 (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. [2] [14]

In 2019 and 2020, concerns for neuropsychiatric reactions were added to the prescription labels in the United Kingdom and the 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 behavior or changes in behavior (may affect between 1 in 1,000 and 1 in 10,000 people taking montelukast). [15] [16] [17] [18]

FDA investigation

In June 2009, the US Food and Drug Administration (FDA) concluded a review into the possibility of neuropsychiatric side effects with leukotriene modulator drugs. [19] Although clinical trials revealed only an increased risk of insomnia, post-marketing surveillance showed that the drugs were associated with a possible increase in suicidal behavior and other side effects such as agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, irritability, restlessness, and tremor. [19]

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. [20] [21] [16] 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. [20]

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. [21] 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." [21] "Treated outpatient depressive disorder" refers to patients who sought treatment specifically for depressive disorders in outpatient psychiatric settings. [21]

In 2024, following reports of night terrors, uncontrollable aggression, intrusive thoughts, depression and rare cases of hallucinations and suicidal behavior in children, the UK Medicines and Healthcare products Regulatory Agency (MHRA) was reviewing the risks of montelukast after identifying "further concerns". [22] The FDA has begun, as of 2020, an internal expert review of why the drug may cause "neuropsychiatric side effects". [23]

In a limited audience review of some findings of this internal group to the American College of Toxicology, on November 20, 2024 in Austin, TX, Jessica Oliphant, deputy director for FDA's National Center for Toxicological Research, said "that laboratory tests showed “significant binding” of montelukast to multiple receptors found in the brain" [23] and that "These data indicate that montelukast is highest in brain regions known to be involved in (psychiatric effects),”. [23] The FDA does not plan to update the box warning label. [23]

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. [24] [25] 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. [26]

Society and culture

Patents

Singulair was covered by US Patent No. 5,565,473 [27] which expired on 3 August 2012. [28] The same day, the FDA approved several generic versions of montelukast. [29]

The United States Patent and Trademark Office launched a reexamination of the patent covering Singulair on 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. [30] Seven months later the US 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. [31]

Use with loratadine

Schering-Plough and Merck sought permission to market a combined tablet with loratadine and montelukast. However, the FDA has found no benefit from a combined pill for seasonal allergies over taking the two drugs in combination, [32] and in April 2008, issued a not-approvable letter for the combination. [33]

Brand names

The Mont in montelukast stands for Montreal, the place where Merck (MSD) developed the drug. [34]

Montelukast is sold under a variety of brand names including Monalast (Ziska Pharmaceuticals Ltd) Montenaaf (NAAFCO Pharma) Montelon-10 (Apex), Montene (Square), Montair-10, Lukotas [35] , 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 [36] in South Africa, AirOn in Venezuela, and AirFast in Saudi Arabia.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Allergic rhinitis</span> Nasal inflammation due to allergens in the air

Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. The fluid from the nose is usually clear. Symptom onset is often within minutes following allergen exposure, and can affect sleep and the ability to work or study. Some people may develop symptoms only during specific times of the year, often as a result of pollen exposure. Many people with allergic rhinitis also have asthma, allergic conjunctivitis, or atopic dermatitis.

<span class="mw-page-title-main">Loratadine</span> Antihistamine medication

Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in which it is combined with pseudoephedrine, a nasal decongestant. It is taken orally.

<span class="mw-page-title-main">Ipratropium bromide</span> Type of anticholinergic

Ipratropium bromide, sold under the brand name Atrovent among others, is a type of anticholinergic medication which is applied by different routes: inhaler, nebulizer, or nasal spray, for different reasons.

<span class="mw-page-title-main">Desloratadine</span> Allergy medication

Desloratadine sold under the brand name Clarinex among others, is a tricyclic H1 inverse agonist that is used to treat allergies. It is an active metabolite of loratadine.

<span class="mw-page-title-main">Fexofenadine</span> Antihistamine medication

Fexofenadine, sold under the brand name Allegra among others, is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria.

<span class="mw-page-title-main">Zafirlukast</span> Chemical compound

Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headaches and stomach upset often occur. Some rare side effects can occur, which can be life-threatening, such as liver failure. eosinophilic granulomatosis with polyangiitis has been associated with zafirlukast, but the relationship isn't thought to be causative. Overdoses of zafirlukast tend to be self-limiting.

<span class="mw-page-title-main">Zileuton</span> Chemical compound

Zileuton (trade name Zyflo) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation, used for the maintenance treatment of asthma. Zileuton was introduced in 1996 by Abbott Laboratories and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names Zyflo and Zyflo CR. The original immediate-release formulation, Zyflo, is taken four times per day. The extended-release formulation, Zyflo CR, is taken twice daily.

<span class="mw-page-title-main">Allergen immunotherapy</span> Medical treatment for environmental allergies

Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response.

<span class="mw-page-title-main">Olopatadine</span> Chemical compound

Olopatadine, sold under the brand name Patanol among others, is an antihistamine medication used to decrease the symptoms of allergic conjunctivitis and allergic rhinitis. It is used as eye drops or as a nasal spray. The eye drops generally result in an improvement within half an hour.

<span class="mw-page-title-main">Fluticasone propionate</span> Medication

Fluticasone propionate, sold under the brand names Flovent and Flonase among others, is a glucocorticoid steroid medication. When inhaled it is used for the long term management of asthma and COPD. In the nose it is used for hay fever and nasal polyps. It can also be used for mouth ulcers. It works by decreasing inflammation.

<span class="mw-page-title-main">Levocetirizine</span> Antihistamine drug

Levocetirizine, sold under the brand name Xyzal, among others, is a second-generation antihistamine used for the treatment of allergic rhinitis and long-term hives of unclear cause. It is less sedating than older antihistamines. It is taken by mouth.

<span class="mw-page-title-main">Ketotifen</span> Antihistamine medication

Ketotifen is an antihistamine medication and a mast cell stabilizer used to treat allergic conditions such as conjunctivitis, asthma, and urticaria (hives). Ketotifen is available in ophthalmic and oral forms: the ophthalmic form relieves eye itchiness and irritation associated with seasonal allergies, while the oral form helps prevent systemic conditions such as asthma attacks and allergic reactions. In addition to treating allergies, ketotifen has shown efficacy in managing systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), which involve abnormal accumulation or activation of mast cells throughout the body. Ketotifen is also used for other allergic-type conditions like atopic dermatitis (eczema) and food allergies.

<span class="mw-page-title-main">Pranlukast</span> Chemical compound

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s montelukast (Singulair). It is widely used in Japan.

<span class="mw-page-title-main">Azelastine</span> Chemical compound

Azelastine, sold under the brand name Astelin among others, is a H1 receptor-blocking medication primarily used as a nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis. Other uses may include asthma and skin rashes for which it is taken by mouth. Onset of effects is within minutes when used in the eyes and within an hour when used in the nose. Effects last for up to 12 hours.

<span class="mw-page-title-main">Mometasone</span> Steroid medication

Mometasone, also known as mometasone furoate, is a steroid medication used to treat certain skin conditions, hay fever, and asthma. Specifically it is used to prevent rather than treat asthma attacks. It can be applied to the skin, inhaled, or used in the nose. Mometasone furoate, not mometasone, is used in medical products.

An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor or leukotriene receptor antagonist 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. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

<span class="mw-page-title-main">Fluticasone furoate</span> Corticosteroid

Fluticasone furoate, sold under the brand name Flonase Sensimist among others, is a corticosteroid for the treatment of non-allergic and allergic rhinitis administered by a nasal spray. It is also available as an inhaled corticosteroid to help prevent and control symptoms of asthma. It is derived from cortisol. Unlike fluticasone propionate, which is only approved for children four years and older, fluticasone furoate is approved in children as young as two years of age when used for allergies.

<span class="mw-page-title-main">Mometasone/formoterol</span> Combination drug

Mometasone/formoterol, sold under the brand name Dulera among others, is a fixed-dose combination medication used in the long-term treatment of asthma. It contains mometasone a steroid and formoterol a long-acting beta agonist. It is only recommended in those for whom an inhaled steroid is not sufficient. It is used by inhalation.

Cysteinyl-leukotriene type 1 receptor antagonists Class of drugs that hinder the action of leukotriene

Cysteinyl-leukotriene type 1 receptor (CysLTR1) antagonists are a class of medications that block the action of cysteinyl leukotrienes, potent inflammatory mediators involved in various allergic and inflammatory conditions, particularly asthma and allergic rhinitis.

Anti-allergic agents are medications used to treat allergic reactions. Anti-allergic agents have existed since 3000 B.C in countries such as China and Egypt. It was not until 1933 when antihistamines, the first type of anti-allergic agents, were developed. Common allergic diseases include allergic rhinitis, allergic asthma and atopic dermatitis with varying symptoms, including runny nose, watery eyes, itchiness, coughing, and shortness of breath. More than one-third of the world's population is currently being affected by one or more allergic conditions.

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. 1 2 3 "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.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  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. 1 2 "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. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Montelukast Sodium Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 7 June 2019. Retrieved 23 December 2018.
  7. ↑ Grainger J, Drake-Lee A (October 2006). "Montelukast in allergic rhinitis: a systematic review and meta-analysis". Clinical Otolaryngology. 31 (5). Wiley: 360–367. doi:10.1111/j.1749-4486.2006.01276.x. PMID   17014443. S2CID   27200676.
  8. ↑ British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 269. ISBN   978-0-85711-338-2.
  9. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  10. ↑ "Montelukast Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  11. ↑ "Montelukast Sodium". The American Society of Health-System Pharmacists. Archived from the original on 7 June 2019. Retrieved 3 April 2011.
  12. ↑ Cardet JC, Akin C, Lee MJ (October 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.
  13. ↑ Scott JP, Peters-Golden M (September 2013). "Antileukotriene agents for the treatment of lung disease". American Journal of Respiratory and Critical Care Medicine. 188 (5): 538–544. doi:10.1164/rccm.201301-0023PP. PMID   23822826.
  14. ↑ 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.
  15. ↑ "Montelukast (Singulair): reminder of the risk of neuropsychiatric reactions". Archived from the original on 24 September 2019. Retrieved 19 September 2019.
  16. 1 2 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  17. ↑ "Montelukast: reminder of the risk of neuropsychiatric reactions". GOV.UK. 29 April 2024. Retrieved 24 November 2024.
  18. ↑ "Outcome of MHRA review of neuropsychiatric reactions with montelukast". GOV.UK (Press release). 29 April 2024. Retrieved 24 November 2024.
  19. 1 2 "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. 1 2 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  21. 1 2 3 4 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  22. ↑ Ungoed-Thomas J (3 March 2024). "Safety fears over asthma drug after young children suffer severe side effects". \The Observer.
  23. 1 2 3 4 Levine D, Dang S (22 November 2024). "Exclusive: US FDA finds widely used asthma drug impacts the brain". Reuters . Retrieved 24 November 2024.
  24. ↑ "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.
  25. ↑ German P, Greenhouse B, Coates C, Dorsey G, Rosenthal PJ, Charlebois E, et al. (March 2007). "Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz". Clinical Infectious Diseases. 44 (6): 889–891. doi: 10.1086/511882 . PMID   17304470.
  26. ↑ Backman JT, Filppula AM, Niemi M, Neuvonen PJ (January 2016). "Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions". Pharmacological Reviews. 68 (1): 168–241. doi: 10.1124/pr.115.011411 . PMID   26721703. S2CID   29099906.
  27. ↑ 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
  28. ↑ "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.
  29. ↑ "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.
  30. ↑ "U.S. Reexamines Merck's Singulair Patent". Thomson Reuters. 28 May 2009. Archived from the original on 16 May 2021. Retrieved 6 July 2021.
  31. ↑ "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.
  32. ↑ 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.
  33. ↑ "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.
  34. ↑ Li JK (2006). "8". Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use. Oxford University Press. p. 234. ISBN   978-0-19-530099-4 . Retrieved 26 November 2017.
  35. ↑ "Lukotas 10mg Tablet Price, substitutes, uses and composition". RxJinn.{{cite web}}: CS1 maint: url-status (link)
  36. ↑ "Monte-Air". 22 June 2022. Retrieved 19 February 2024.
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