Serious neuropsychiatric (NP) events have been reported with the use of montelukast. The types of events reported were highly variable, and included, but were not limited to, agitation, aggression, depression, sleep disturbances, suicidal thoughts and behavior (including suicide). The mechanisms underlying NP events associated with montelukast use are currently not well understood.
Because of the risk of NP events, the benefits of montelukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of montelukast for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing montelukast.
Discuss the benefits and risks of montelukast with patients and caregivers when prescribing montelukast. Advise patients and/or caregivers to be alert for changes in behavior or new NP symptoms when taking montelukast. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue montelukast and contact a health care provider immediately.
Note: Due to risk of neuropsychiatric adverse effects, the benefits and risks of montelukast should be assessed prior to therapy initiation. Patients with both asthma and allergic rhinitis should take only 1 dose in the evening.
Allergic rhinitis:
Perennial:
Infants ≥6 months and Children <6 years: Oral: 4 mg once daily.
Children ≥6 years and Adolescents <15 years: Oral: 5 mg once daily.
Adolescents ≥15 years: Oral: 10 mg once daily.
Seasonal:
Children 2 to 5 years: Oral: 4 mg once daily.
Children ≥6 years and Adolescents <15 years: Oral: 5 mg once daily.
Adolescents ≥15 years: Oral: 10 mg once daily.
Asthma, maintenance therapy: Note: Not preferred therapy for any level of asthma severity; may be considered an alternative option for Step 2 or greater management; inhaled corticosteroids are preferred (GINA 2020).
12 months to 5 years: Oral: 4 mg once daily in the evening.
6 to 14 years: Oral: 5 mg once daily in the evening.
≥15 years: Oral: 10 mg once daily in the evening.
Exercise-induced bronchospasm, prevention:
Note: Additional doses should not be administered within 24 hours. Daily administration to prevent exercise-induced bronchospasm has not been evaluated. Patients receiving montelukast for another indication should not take an additional dose to prevent exercise-induced bronchoconstriction.
Children ≥6 years and Adolescents <15 years: Oral: 5 mg at least 2 hours prior to exercise.
Adolescents ≥15 years: Tablet: Oral: 10 mg at least 2 hours prior to exercise.
Urticaria (nonsteroidal anti-inflammatory drug-induced): Limited data available: Adolescents ≥15 years: Oral: 10 mg once daily (Pacor 2001).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No adjustment necessary.
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; has not been studied.
(For additional information see "Montelukast: Drug information")
Allergic rhinitis, perennial or seasonal (alternative agent):
Note: For use only in patients who have an inadequate response to or cannot tolerate other therapy options or in those with coexisting asthma; potential benefits of therapy may be outweighed by risk of adverse mood effects (AAAAI/ACAAI [Dykewicz 2020]; manufacturer's labeling).
Oral: 10 mg once daily.
Aspirin-exacerbated respiratory disease, including aspirin challenge/desensitization (adjunct) (off-label use):
Chronic management: Note: May be used as an adjunct to other first-line therapies regardless of symptom control or severity of asthma (GINA 2020; Laidlaw 2021).
Oral: 10 mg once daily in the evening (Dahlén 2002).
Aspirin challenge/desensitization procedures:
Oral: 10 mg once daily starting 3 days before challenge/desensitization or 10 mg twice daily the day before challenge/desensitization followed by 10 mg once daily on each day of the challenge/desensitization (AAAAI [Stevens 2021]; Simon 2021b).
Introduction of aspirin before cardiovascular interventions for myocardial infarction:
Note: If the cardiovascular intervention cannot be delayed for ≥3 to 5 hours or in patients with severe aspirin hypersensitivity, some experts use alternative antiplatelet agents instead of aspirin (Simon 2021a). Refer to local protocols; if used, administer as part of an appropriate premedication regimen. An example regimen is as follows:
Oral: 10 mg once ≥1 hour prior to the first aspirin dose (Simon 2021a; White 2013).
Asthma, persistent, maintenance therapy (alternative agent):
Note: In patients with mild persistent asthma, may be used as an alternative first-line controller therapy in those who cannot take an inhaled corticosteroid (ICS). In patients with moderate to severe asthma, may be used as an adjunctive controller therapy in those with inadequate symptom control on an ICS (GINA 2020).
Oral: 10 mg once daily in the evening. Some experts suggest waiting 1 to 2 months before assessing efficacy (Boyce 2021).
Bronchoconstriction, exercise-induced (prevention):
Note: May be used as an adjunctive agent or alternative monotherapy in patients with persistent symptoms on or who cannot take a short-acting beta agonist or in patients who exercise frequently (eg, >3 hours/day or more than once per day) (ATS [Parsons 2013]; O’Byrne 2021). In patients receiving daily montelukast for another indication, additional montelukast should not be administered for exercise-induced bronchoconstriction.
Oral: 10 mg ≥2 hours prior to exercise; limit to 1 dose every 24 hours.
Hypersensitivity reactions, rapid chemotherapy/biologics desensitization (premedication) (off-label use):
Note: May be administered as part of an appropriate premedication regimen prior to the infusion of certain chemotherapy agents (eg, platinum-based agents) or biologics in patients who experienced respiratory symptoms during the initial reaction. Administer under close observation and ensure availability of trained clinicians during the procedure. An optimal premedication regimen has not been identified; refer to institutional protocols (Breslow 2009; Castells 2021).
Oral: 10 mg once daily for 1 to 2 days before the desensitization procedure, then 10 mg 1 hour before the start of the procedure (Breslow 2009; Castells 2021).
Infusion-related reactions, daratumumab-based regimens (premedication) (off-label use):
Oral: 10 mg administered 30 to 60 minutes prior to the first infusion; for split-dose infusion, administer 10 mg before start of daratumumab on day 1 and day 2; administer as part of an appropriate premedication regimen (Barr 2018; Hofmeister 2016; Mateos 2020; Moore 2020).
Urticaria, chronic and delayed pressure (adjunct) (off-label use):
Note: May be used as an adjunctive therapy in patients with persistent symptoms despite appropriately titrated antihistamine therapy (AAAAI/ACAAI [Bernstein 2014]; Kulthanan 2020; Maurer 2013; Zuberbier 2018).
Oral: 10 mg once daily (Di Lorenzo 2004; Nettis 2004; Nettis 2006). Some experts suggest waiting ≥4 weeks before assessing efficacy (Khan 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (manufacturer’s labeling).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): No supplemental dose or dosage adjustment necessary (expert opinion).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): No dosage adjustment necessary (expert opinion).
CRRT: No dosage adjustment necessary (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in manufacturer’s labeling; has not been studied.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet, Oral:
Singulair: 4 mg (30 ea)
Generic: 4 mg (1 ea, 30 ea)
Tablet, Oral:
Singulair: 10 mg
Generic: 10 mg
Tablet Chewable, Oral:
Singulair: 4 mg, 5 mg [contains aspartame]
Generic: 4 mg, 5 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet, Oral:
Singulair: 4 mg (30 ea)
Generic: 4 mg (30 ea)
Tablet, Oral:
Singulair: 10 mg
Generic: 10 mg
Tablet Chewable, Oral:
Singulair: 4 mg, 5 mg [contains aspartame]
Generic: 4 mg, 5 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Oral: May administer without regard to food or meals. When treating asthma, administer dose in the evening. Patients with allergic rhinitis may individualize administration time (morning or evening). Patients with both asthma and allergic rhinitis should take their dose in the evening.
Granules: May be administered directly into the mouth, dissolved in 5 mL of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature applesauce, carrots, rice, and ice cream; do not add to any other liquids or foods; administer within 15 minutes of opening the packet; liquids may be taken subsequent to administration.
Missed dose: The missed dose should be skipped and therapy resumed at next scheduled doses; two doses should not be administered at the same time to catch up.
Oral: In patients with asthma or who require chronic management of aspirin-exacerbated respiratory disease, administer dose in the evening regardless of the presence of other indications for montelukast (Dahlen 2002; manufacturer's labeling); for all other indications, may individualize administration time. May administer without regard to food or meals.
Granules: May be administered directly in the mouth or mixed with a spoonful of cold or room temperature applesauce, carrots, rice, or ice cream; do not add to any other liquids or foods. Administer within 15 minutes of opening packet.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in original package. Protect from moisture and light. Granules must be used within 15 minutes of opening packet.
Prophylaxis and chronic treatment of asthma (FDA approved in ages ≥12 months and adults); relief of symptoms of allergic rhinitis in patients who have had an inadequate response to or intolerance of alternative therapies (Seasonal: FDA approved in ages ≥2 years and adults; Perennial: FDA approved in ages ≥6 months and adults); prevention of exercise-induced bronchoconstriction (FDA approved in ages ≥6 years and adults); has also been used for nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria.
Singulair may be confused with Oralair, SINEquan
Various neuropsychiatric adverse reactions, which may lead to drug discontinuation, have been reported with montelukast in patients with and without a history of psychiatric illness (Benard 2017; FDA 2020). Reactions have been reported in adult and pediatric patients; however, reactions are more commonly reported in pediatric patients, possibly due to the increased use of the drug in this population (Perona 2016). Reactions include nervous system disorders (eg, disturbance in attention, memory impairment, stuttering, tic disorder, seizure), psychiatric disturbances (eg, agitation, aggressive behavior, anxiety, depression, disorientation, hallucination, irritability, obsessive compulsive disorder, restlessness, suicidal ideation, suicidal tendencies, and completed suicide), and sleep disturbances (eg, abnormal dreams, insomnia, somnambulism) (Benard 2017; Glockler-Lauf 2019; Law 2018). In most cases, these reactions were reversible upon discontinuation (Perona 2016). Time to resolution may depend on the reaction (Benard 2017). Alternatively, some data suggest no association between montelukast and neuropsychiatric reactions (Ali 2015; Sansing-Foster 2021).
Mechanism: Non–dose-related; idiosyncratic (Chen 2014; Glockler-Lauf 2019).
Onset: Varied; within hours to years after therapy initiation (Glockler-Lauf 2019; Perona 2016).
Risk factors (information from very limited observational data):
• Increased asthma severity (Glockler-Lauf 2019)
• Increased number of concurrent asthma medications (eg, corticosteroids [inhaled or systemic], long-acting beta agonists (Benard 2017; Glockler-Lauf 2019)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Dermatologic: Atopic dermatitis (children: ≥2%), dermatitis (children: ≥2%), eczema (children: ≥2%), skin infection (children: ≥2%), skin rash (2%), urticaria (children: ≥2%)
Gastrointestinal: Abdominal pain (children: ≥2%), diarrhea (children and adolescents: ≥2%), dyspepsia (2%), gastroenteritis (2%), nausea (children and adolescents: ≥2%), tooth infection (children: ≥2%), toothache (adolescents and adults: 2%)
Genitourinary: Pyuria (adolescents and adults: 1%)
Hepatic: Increased serum alanine aminotransferase (adolescents and adults: ≥1%), increased serum aspartate aminotransferase (adolescents and adults: 2%)
Infection: Influenza (children and adolescents: ≥2%), varicella zoster infection (children: ≥2%), viral infection (children and adolescents: ≥2%)
Nervous system: Dizziness (adolescents and adults: 2%), fatigue (adolescents and adults: ≤2%), headache (children and adolescents: ≥2%)
Neuromuscular & skeletal: Asthenia (adolescents and adults: ≤2%)
Ophthalmic: Conjunctivitis (children: ≥2%), myopia (children: ≥2%)
Otic: Otalgia (children: ≥2%), otitis (children and adolescents: ≥2%), otitis media (children and adolescents: ≥2%)
Respiratory: Acute bronchitis (children: ≥2%), cough (3%), epistaxis (adolescents and adults: ≥1%), laryngitis (children and adolescents: ≥2%), nasal congestion (adolescents and adults: 2%), pharyngitis (children: ≥2%), pneumonia (children: ≥2%), rhinitis (infective; children: ≥2%), rhinorrhea (children: ≥2%), sinus headache (adolescents and adults: ≥1%), sinusitis (≥1%), upper respiratory tract infection (≥1%)
Miscellaneous: Fever (2%), trauma (adolescents and adults: 1%)
Postmarketing:
Cardiovascular: Edema, eosinophilic granulomatosis with polyangiitis (Acoglu 2019; Calapai 2014; Lataifeh 2014; Nathani 2008), palpitations, vasculitis (Black 2009; Carlesimo 2011)
Dermatologic: Erythema multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis
Gastrointestinal: Pancreatitis, vomiting
Genitourinary: Urinary incontinence
Hematologic & oncologic: Bleeding tendency disorder, bruise, eosinophilia (systemic), thrombocytopenia
Hepatic: Hepatic eosinophilic infiltration, hepatitis (mixed pattern, hepatocellular, and cholestatic) (Russmann 2003)
Hypersensitivity: Anaphylaxis (Gerard 2009), angioedema (Sabbagh 2009)
Nervous system: Abnormal dreams (Benard 2017; Glockler-Lauf 2019; Law 2018), aggressive behavior (Benard 2017; Glockler-Lauf 2019; Law 2018), agitation (Benard 2017; Glockler-Lauf 2019; Law 2018), amnesia (Law 2018), anxiety (Benard 2017; Glockler-Lauf 2019; Law 2018), behavioral changes (Benard 2017), confusion (Law 2018), depression (Benard 2017; Glockler-Lauf 2019; Law 2018), disorientation (Law 2018), disturbance in attention (Law 2018), drowsiness (Benard 2017; Law 2018), hallucination (Law 2018), hostility, hyperactive behavior (Law 2018), hypoesthesia, insomnia (Law 2018), irritability (Benard 2017; Law 2018), lack of concentration (Law 2018), memory impairment (Law 2018), mood changes (Benard 2017; Glockler-Lauf 2019), nervousness (Law 2018), obsessive compulsive disorder, paresthesia, personality disorder (Law 2018), restlessness, seizure (Law 2018), somnambulism, stuttering, suicidal ideation (Glockler-Lauf 2019; Law 2018), suicidal tendencies (Glockler-Lauf 2019; Law 2018), tic disorder
Neuromuscular & skeletal: Arthralgia, muscle cramps, myalgia, tremor
Respiratory: Eosinophilic pneumonitis (Franco 1999)
Hypersensitivity to montelukast or any component of the formulation
Concerns related to adverse effects:
• Eosinophilia and vasculitis: In rare cases, patients may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss); these clinical features may include eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy. A causal association between montelukast and these underlying conditions has not been established.
Disease related concerns:
• Acute asthma/bronchospasm: Montelukast is not FDA approved for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Some studies, however, support its use as adjunctive therapy (Cylly 2003; Ferreira 2001; Harmancik 2006). Appropriate rescue medications should be available. Montelukast treatment should continue during acute asthma exacerbations.
Dosage form specific issues:
• Chewable tablet: Contains phenylalanine.
Substrate of CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Gemfibrozil: May increase the serum concentration of Montelukast. Risk C: Monitor therapy
Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combination
Lumacaftor and Ivacaftor: May decrease the serum concentration of Montelukast. Risk C: Monitor therapy
Some products may contain phenylalanine.
Based on available data, an increased risk of teratogenic effects has not been observed with montelukast use in pregnancy (GINA 2020).
Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low-birth-weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes). Maternal asthma symptoms should be monitored monthly during pregnancy. Montelukast should not be withheld during pregnancy when clinically indicated (ERS/TSANZ [Middleton 2020]; GINA 2020).
Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant females in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS) (877-311-8972 or http://mothertobaby.org). Patients may also enroll themselves.
Monitor asthma symptoms, FEV1, peak flow and/or other pulmonary function tests, mood or behavior changes, including suicidal thinking/behavior.
Selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Cysteinyl leukotrienes are also released from the nasal mucosa following allergen exposure leading to symptoms associated with allergic rhinitis (Jarvis, 2000).
Duration: >24 hours
Absorption: Rapid
Distribution: Vd: 8 to 11 L
Protein binding, plasma: >99%
Metabolism: Extensively hepatic via CYP3A4, 2C8, and 2C9
Bioavailability: Tablet: 10 mg, Mean: 64%; Chewable tablet: 5 mg: 73% (63% when administered with a standard meal)
Half-life elimination: 2.7 to 5.5 hours; Mild-to-moderate hepatic impairment: 7.4 hours
Time to peak: Tablet: 10 mg: 3 to 4 hours (fasting); Chewable tablet: 4 mg (children 2 to 5 years): 2 hours (fasting); Chewable tablet 5 mg: 2 to 2.5 hours (fasting); Granules: 2.3 ± 1 hours (fasting) and 6.4 ± 2.9 hours (with high-fat meal)
Excretion: Feces (86%); urine (<0.2%)
Hepatic function impairment: Following a single 10 mg dose, AUC increased 41% and half-life was prolonged to 7.4 hours in patients with mild-to-moderate hepatic impairment and cirrhosis. Patients with severe hepatic impairment or hepatitis have not been evaluated.
Pediatric: In children 6 to 23 months of age, the systemic exposure to montelukast is higher than in adults.
Chewable (Montelukast Sodium Oral)
4 mg (per each): $5.03 - $5.66
5 mg (per each): $5.03 - $5.66
Chewable (Singulair Oral)
4 mg (per each): $9.58
5 mg (per each): $9.58
Pack (Montelukast Sodium Oral)
4 mg (per each): $5.66 - $8.67
Pack (Singulair Oral)
4 mg (per each): $9.58
Tablets (Montelukast Sodium Oral)
10 mg (per each): $0.06 - $5.66
Tablets (Singulair Oral)
10 mg (per each): $9.58
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