Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than

inhaled corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

. It is not useful for acute

asthma attack Asthma is a 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 wheezing, cou ...

s. Other uses include allergic rhinitis and

hives Hives, also known as urticaria, is a kind of skin rash with red, 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 does not leave any long-lasti ...

of long duration. For allergic rhinitis it is a second-line treatment. Common side effects include abdominal pain, cough, and headache. Severe side effects may include allergic reactions, such as anaphylaxis 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 x 109/ L (i.e. 1,500/μL). The hypereosinophilic syndro ...

. 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 leuko ...

family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of

smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

. 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 2020, it was the fourteenth most commonly prescribed medication in the United States, with more than 31million prescriptions.

Medical uses

Montelukast is used for a number of conditions including asthma, exercise induced bronchospasm, allergic rhinitis, and urticaria. It is mainly used as a complementary therapy in adults in addition to

, 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 or NHIG) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory dem ...

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

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 Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and s ...

), angioedema, erythema multiforme, and liver problems. 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).

FDA investigation

In June 2009, the U.S. Food and Drug Administration (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 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 pharmac ...

showed that the drugs are associated with a possible increase in suicidal behavior and other side effects such as agitation,

aggression Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...

anxiousness Anxiety is an emotion which is characterized by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different than fear in that the former is defined as the anticipa ...

, dream abnormalities and

hallucinations A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

, depression, irritability, restlessness, and

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...

. 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. 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. The boxed warning advises health care providers to avoid prescribing montelukast for people with mild symptoms, particularly those with allergic rhinitis because there are many other effective, less-concerned allergy medicines that are also indicated for the mild cases. In the FDA's self-conducted data analysis in comparison to their received case reports which were dependent on people's self-claims, the propensity of developing neuropsychiatric disorders after montelukast use does 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, FDA's self-conducted data analysis also summarized their own findings, saying "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' actions of making an appointment with psychiatrists to contend with their depressions.

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 Inhibitor or inhibition may refer to: In 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 neurotra ...

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.

Pharmacology

Montelukast is in the

family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of

. 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 rece ...

( 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. Leukotriene receptor antagonists are sometimes colloquially referred to as ''leukasts''. Two genes of interest are ''ALOX5'' and ''LTC4S'', which catalyze two major steps in the biosynthetic pathway of leukotrienes. Montelukast may affect nerve remyelination in combination with Pexidartinib and this may cause clinical benefits or side effects.

Patents

Singulair was covered by U.S. 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 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. 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.

Use with loratadine

Schering-Plough and

Merck Merck refers primarily to the German Merck family and three companies founded by the family, including: * the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668 ** Merck Serono (known as EMD Serono in the Unite ...

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, and on 25 April 2008, issued a

not-approvable letter Approvable letters, and the related non-approvable letters (alternately not-approvable letters), were notifications sent out by the Food and Drug Administration (FDA) to drug manufacturers alerting them to the approval prospects of their drugs unde ...

for the combination.

Names

The ''Mont'' in montelukast stands for Montreal, the place 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, 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 in South Africa and AirOn in Venezuela.

References

External links

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