Singulair
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Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Other uses include
allergic rhinitis 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 a ...
and
hives Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
of long duration. For allergic rhinitis it is a second-line treatment. Common side effects include
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
,
cough A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and Microorganism, microbes. As a protective reflex, coughing can be repetitive with the cough reflex fol ...
, and
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
. Severe side effects may include allergic reactions, such as
anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...
and
eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 billion/ L (1,500/ μL). The hypereosinophilic syndrome ...
. Use in pregnancy appears to be safe. Montelukast is in the
leukotriene receptor antagonist An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor ( arachidonate 5-lipoxygenase) or leukotriene receptor antagonist ( cysteinyl leu ...
family of medications. It works by blocking the action of
leukotriene D4 Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released b ...
in the lungs resulting in decreased
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and relaxation of
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
. Montelukast was approved for medical use in the United States in 1998. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2022, it was the seventeenth most commonly prescribed medication in the United States, with more than 29million prescriptions.


Medical uses

Montelukast is used for a number of conditions including
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, exercise induced
bronchospasm Bronchospasm or a bronchial spasm is a sudden bronchoconstriction, constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylat ...
,
allergic rhinitis 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 a ...
, and
urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
. 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 Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinat ...
. It may also be used as an adjunct therapy in symptomatic treatment of
mastocytosis Mastocytosis, a type of mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from ...
. It is taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
, as a tablet, chewable tablet, or as granules.


Pharmacology

Montelukast is in the
leukotriene receptor antagonist An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor ( arachidonate 5-lipoxygenase) or leukotriene receptor antagonist ( cysteinyl leu ...
family of medications. It works by blocking the action of
leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...
D4 in the lungs resulting in decreased
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and relaxation of
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
. Montelukast functions as a leukotriene
receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
( cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
and serve to promote
bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bei ...
, inflammation, microvascular permeability, and mucus secretion in
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
and
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
.


Adverse effects

Common
side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...
include diarrhea, nausea, vomiting, mild rashes, asymptomatic elevations in
liver enzymes Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial t ...
, and
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
. Uncommon side effects include fatigue and malaise, behavioral changes,
paresthesias Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or chronic and has many possible underlying causes. Paresthesia is usually painless and can oc ...
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 Suicidal ideation, or suicidal thoughts, is the thought process of having ideas or ruminations about the possibility of dying by suicide.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal i ...
),
angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...
,
erythema multiforme Erythema multiforme (EM) is an immune-mediated inflammatory skin condition associated with several viral infections, that appears with red patches evolving into target lesions, typically on both hands. It is typically associated with infection ...
, and
liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
. 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).


FDA investigation

In June 2009, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) concluded a review into the possibility of
neuropsychiatric Neuropsychiatry is a branch of medicine that deals with psychiatry as it relates to neurology, in an effort to understand and attribute behavior to the interaction of neurobiology and social psychology factors. Within neuropsychiatry, the mind i ...
side effects with leukotriene modulator drugs. Although clinical trials revealed only an increased risk of
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
,
post-marketing surveillance Postmarketing surveillance (PMS), also known as post market surveillance, is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market and is an important part of the science of pharma ...
showed that the drugs were associated with a possible increase in
suicidal Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or acad ...
behavior and other side effects such as agitation,
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
, anxiousness,
dream A dream is a succession of images, ideas, emotions, and sensation (psychology), sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around ...
abnormalities,
hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
, depression,
irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...
, restlessness, and
tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
. In March 2020, the FDA required a
boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
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. 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. 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. 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." "Treated outpatient depressive disorder" refers to patients who sought treatment specifically for depressive disorders in outpatient psychiatric settings. 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 The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are accepta ...
(MHRA) was reviewing the risks of montelukast after identifying "further concerns". The FDA has begun, as of 2020, an internal expert review of why the drug may cause "neuropsychiatric side effects". 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" and that "These data indicate that montelukast is highest in brain regions known to be involved in (psychiatric effects),”. The FDA does not plan to update the box warning label.


Drug interactions

Montelukast is an
inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...
of the drug metabolizing enzyme
CYP2C8 Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsat ...
, part of the
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
system. Therefore, it is theoretically possible that the combination of montelukast with a CYP2C8 substrate (e.g.
amodiaquine Amodiaquine (ADQ) is a medication used to treat malaria, including ''Plasmodium falciparum'' malaria when uncomplicated. It is recommended to be given with artesunate to reduce the risk of resistance. Due to the risk of rare but serious side ef ...
, an anti-malarial drug) could increase the plasma concentrations of the substrate. 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 Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...
exhibited by montelukast.


Society and culture


Patents

Singulair was covered by US Patent No. 5,565,473 which expired on 3 August 2012. The same day, the FDA approved several generic versions of montelukast. The
United States Patent and Trademark Office The United States Patent and Trademark Office (USPTO) is an List of federal agencies in the United States, agency in the United States Department of Commerce, U.S. Department of Commerce that serves as the national patent office and trademark ...
launched a
reexamination In United States patent law, a reexamination is a process whereby anyone—third party or inventor—can have a U.S. patent reexamined by a patent examiner to verify that the subject matter it claims is patentable. To have a patent reexamined, ...
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 Article One Partners (AOP) is an online prior art search and intellectual property research crowdsourcing community. AOP was acquired by RWS Group in October 2017 and the AOP Connect crowdsourcing platform is now part of the IP Research group w ...
, 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. 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.


Use with loratadine

Schering-Plough Schering-Plough Corporation was an American pharmaceutical company. It was originally the U.S. subsidiary of the German company Schering AG, which was founded in 1851 by Ernst Christian Friedrich Schering. As a result of nationalization, it becam ...
and Merck sought permission to market a combined tablet with
loratadine Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis (hay fever) and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in whic ...
and montelukast. However, the FDA has found no benefit from a combined pill for seasonal allergies over taking the two drugs in combination, and in April 2008, issued a not-approvable letter for the combination.


Brand names

The ''Mont'' in montelukast stands for
Montreal Montreal is the List of towns in Quebec, largest city in the Provinces and territories of Canada, province of Quebec, the List of the largest municipalities in Canada by population, second-largest in Canada, and the List of North American cit ...
, where Merck (MSD) developed the drug. 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, Montelo-10, Monteflo, and Tukast L in
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
, 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 Levocetirizine, sold under the brand name Xyzal, among others, is a second-generation antihistamine used for the treatment of allergic rhinitis (hay fever) and long-term hives of unclear cause. It is less sedating than older antihistamines. ...
, Desmont, Levmont, Aircomb and Notta in Turkey, Topraz and Monte-Air in South Africa.


References

{{Authority control Alkene derivatives Chloroarenes Cyclopropanes CYP2C8 inhibitors Leukotriene antagonists Drugs developed by Merck & Co. Quinolines Thioethers Wikipedia medicine articles ready to translate Phenylene compounds Depressogens