Version December 2023
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.
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 (Ref). Some experts reserve use to those with coexisting asthma and intolerance to preferred therapies (Ref). Potential benefits of therapy may be outweighed by risk of adverse mood effects (Ref).
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 (Ref).
Oral: 10 mg once daily in the evening (Ref).
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 (Ref).
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 (Ref). 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 (Ref).
Asthma, persistent, maintenance therapy (alternative agent):
Note: In patients with mild persistent asthma, may be used as an alternative 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 (Ref).
Oral: 10 mg once daily in the evening. Some experts suggest waiting 1 to 2 months before assessing efficacy (Ref).
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) (Ref). 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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
Oral: 10 mg once daily (Ref). Some experts suggest waiting ≥4 weeks before assessing efficacy (Ref).
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 (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in manufacturer’s labeling; has not been studied.
Refer to adult dosing.
(For additional information see "Montelukast: Pediatric drug information")
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 (Ref).
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 (Ref).
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.
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.
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
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): $10.50
5 mg (per each): $10.50
Pack (Montelukast Sodium Oral)
4 mg (per each): $5.66 - $8.22
Pack (Singulair Oral)
4 mg (per each): $10.50
Tablets (Montelukast Sodium Oral)
10 mg (per each): $0.06 - $5.66
Tablets (Singulair Oral)
10 mg (per each): $10.50
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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
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 (Ref); 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.
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.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Allergic rhinitis (perennial or seasonal): Relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients ≥2 years of age and perennial allergic rhinitis in adults and pediatric patients ≥6 months of age. Because the benefits may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis, reserve use for patients who have had an inadequate response or intolerance to alternative therapies.
Asthma, persistent (maintenance therapy): Prophylaxis and chronic treatment of asthma in adults and pediatric patients ≥12 months of age.
Bronchoconstriction, exercise-induced (prevention): Prevention of exercise-induced bronchoconstriction in adults and pediatric patients ≥6 years of age.
Note: American Academy of Otolaryngology-Head and Neck Surgery and American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology guidelines recommend against montelukast use as first-line therapy for allergic rhinitis (except in patients with concurrent asthma) (AAAAI/ACAAI [Dykewicz 2020]; AAO-HNSF [Seidman 2015]). The Global Initiative for Asthma recommends montelukast in patients with concomitant allergic rhinitis or those who cannot take inhaled corticosteroids (GINA 2022).
Aspirin-exacerbated respiratory disease (including aspirin challenge/desensitization); Hypersensitivity reactions, rapid chemotherapy/biologics desensitization (premedication); Infusion-related reactions, daratumumab-based regimens (premedication); Urticaria, chronic and delayed pressure
Singulair may be confused with Oralair, SINEquan
Substrate of CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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
Outcome data following maternal use of montelukast during pregnancy are available (Bakhireva 2007; Cavero-Carbonell 2017; Hatakeyama 2022; Koren 2010; Nelsen 2012; Sarkar 2009; Van Zutphen 2015). Based on available data, an increased risk of teratogenic effects has not been observed with montelukast use during pregnancy (GINA 2022).
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 (ERS/TSANZ [Middleton 2020]; GINA 2022).
Pregnant patients adequately controlled on montelukast for asthma may continue therapy when conventional medications are not effective; initiating treatment during pregnancy is not recommended (Couillard 2021; ERS/TSANZ [Middleton 2020]).
Algorithms are available for the treatment of acute rhinitis and urticaria. Consider benefits and risks of treatment prior to use in pregnant patients (AAAAI/ACAAI [Dykewicz 2020]; EAACI [Zuberbier 2022])
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 patients in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS) (1-877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.
Montelukast is present in breast milk (Datta 2017).
Data related to the presence of montelukast in breast milk is available following chronic administration of oral montelukast 10 mg daily in 7 patients at 1.4 to 8.2 months' postpartum. All women were exclusively breastfeeding. Breast milk was sampled prior to and from 1 to 12 hours after the maternal dose. Using an average milk concentration of 5.3 ng/mL (average range: 2.87 to 9.12 ng/mL), authors of the study calculated the estimated exposure to the breastfeeding infant to be 0.798 mcg/kg/day (relative infant dose 0.68% based the weight-adjusted maternal dose). Adverse events were not reported in the mothers or breastfed infants (Datta 2017).
In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Some products may contain phenylalanine.
Neuropsychiatric events, 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.
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