Montelukast

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Montelukast quick reference

Montelukast
Montelukast general drug information
 Pronunciation mon te LOO kast (.wav file)
 Trade Name(s) Singulair
 How Supplied Tablets: 10 mg
Chewable tablets: 4 mg, 5 mg
Oral granules: 4 mg
 Generic Availability No generics available
 Patent Expiry Date February 3, 2012
 Classification Leukotriene receptor antagonist
 Schedule Rx
 Pregnancy Category B
 Breast-feeding Montelukast is excreted into breast milk. Use with caution.
Montelukast chemical information
 IUPAC Name (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl) ethenyl)
phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl) propyl)
thio) methyl) cyclopropaneacetic acid, monosodium salt
 Empirical Formula C35H35ClNNaO3S
 Molecular Weight 608.18 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) have been associated with airway edema, smooth muscle contraction, and inflammation. Inhibition of these physiologic actions with leukotriene receptor antagonists such as montelukast has been shown to be effective in the treatment of asthma. In addition, cysteinyl leukotrienes are released in the nasal mucosa by immune cells during an allergic response. Administration of leukotriene receptor antagonists to patients with seasonal and perennial allergies has been shown to decrease nasal airway resistance and nasal obstruction.

Comparative studies of montelukast and fluticasone have revealed that fluticasone is more effective and less expensive than montelukast for the treatment of asthma.[1][2][3][4] Therefore, montelukast is not considered first line therapy for the treatment of asthma. However, studies have shown that montelukast may be beneficial as an addition to inhaled cortisosteroid therapy.[5] Leukotriene receptor antagonists may also be useful in young asthmatic patients. While first-line therapy with inhaled corticosteroids carries a risk of decreased linear growth, chronic montelukast therapy has not been associated any growth changes.[6] Montelukast may also be preferred in patients with symptoms of both asthma and allergic rhinitis.

Montelukast may be preferred over zafirlukast (another leukotriene receptor antagonist) because montelukast has not been shown to inhibit CYP 3A4 or 2C9.[7]

Mechanism of Action

Leukotriene receptor antagonists exert their actions by binding to the active site of leukotriene receptors. Montelukast is a selective inhibitior of leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor CysLT1.

Pharmacokinetics

Absorption
Absorption of montelukast is rapid following administration. For the oral tablet form of montelukast, 64% of the total oral tablet dose is absorbed and tmax is achieved 3-4 hours post-dose. These values are not altered by coadministration with food. For the chewable tablet and oral granules forms, 73% of the total dose is absorbed and tmax is achieved 2-2.5 hours post dose. When these two forms of montelukast are administered with foods high in fat, bioavalibility decreases to 63%, tmax occurs in 6.4 hours, and Cmax is decreased by 35%. While no specific recommendations have been made concerning food administration with montelukast, patients should be counseled to keep the amount of food coadministered with montelukast constant. This is especially important if the patient is using the chewable tablets or the oral granules.[7]

Distribution
Montelukast is highly protein bound, with over 99% of the total absorbed dose bound to blood plasma proteins. The volume of distribution of montelukast is 8-11 L, suggesting that montelukast does not significantly accumulate in tissues and body fat. Montelukast has not been shown to significantly cross the blood brain barrier.[7]

Metabolism
Montelukast is hepatically metabolized by CYP 3A4 and CYP 2C9. In vitro studies have suggested that montelukast is a potent inhibitor of CYP 2C8. However, pharmacokinetic studies of montelukast and rosiglitazone coadministration have resulted in no significant interaction.[8] Therefore, montelukast may not be a clinically significant CYP 2C8 inhibitor in vivo.

Excretion
Radioactive studies have shown that 86% of montelukast metabolites are recovered in the feces. This suggests that montelukast is excreted primarily via biliary routes. The average half life of montelukast is 2.7-5.5 hours in healthy adults.[7]

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Special Population Pharmacokinetics

  • Renal insufficiency: Montelukast is not excreted via renal mechanisms. Therefore, no dosage adjustments are required for patients with renal insufficiency.[7]
  • Hepatic insufficiency: The AUC of montelukast has been reported to be 41% higher in patients with mild-moderate hepatic insufficiency and/or cirrhosis when compared to healthy patients. The half-life of montelukast in these patients was also extended to 7.4 hours. However, no dosage adjustments are needed in patients with mild-moderate hepatic insufficiency due to the lack of toxicity associated with montelukast.[7]
  • Hemodialysis: No data has been gathered to determine if montelukast is removed by hemodialysis.
  • Geriatric: The half life of montelukast is "slightly longer" in elderly patients. No dosage adjustments are required.
  • Pediatric: The mean systemic exposure to montelukast is similar for adults and children ages 2-18 years. Pharmacokinetic studies in children 6-11 months of age have resulted in a mean AUC 60% higher and a mean Cmax 89% higher than seen in adults. Similar studies in children aged 12-23 months of age resulted in a mean AUC 33% higher and a mean Cmax 60% higher than seen in adults. However, safety and tolerability of montelukast was similar in the studied children compared to their adult counterparts.[7]
  • Gender: No gender variations in the pharmacokinetics of montelukast have been reported.[7]

Indications and Dosages

FDA Approved Indications

Allergic rhinitis (perennial and seasonal)[7][9][10]

  • Starting and maintenance dose:
    • Adults and adolescents >15 years: 10 mg once daily
    • Adolescents and children 6-14 years: 5 mg once daily
    • Children 2-5 years: 4 mg once daily
    • Children and infants 6 months-2 years (seasonal allergic rhinitis only): 4 mg oral granules once daily
    • NOTE: Chewable tablets should not be used in children younger than 2 years of age due to lack of safety and efficacy data.

Asthma (maintenance only)[7][11][12][13][14][15][16]

  • Starting and maintenance dose:
    • Adults and adolescents >15 years: 10 mg once daily in the evening
    • Adolescents and children 6-14 years: 5 mg once daily in the evening
    • Children 2-5 years': 4 mg once daily in the evening
    • Children and infants 1-2 years: 4 mg oral granules once daily in the evening
    • NOTE: Chewable tablets should not be used in children younger than 2 years of age due to lack of safety and efficacy data.

Bronchospasm prophylaxis[7][17]

Non-FDA Approved Indications

  • Cystic fibrosis[18]

Dosage Adjustment

Hepatic insufficiency: No adjustments needed for mild-moderate hepatic impairment. No recommendations exist for severe hepatic impairment.
Hemodialysis: No current recommendations.

Dosage Limits

  • Adults, elderly, and adolescents >15 years: 10 mg daily[7]
  • Adolescents and children 6-14 years: 5 mg daily
  • Children and infants 6 months to 5 years: 4 mg daily
  • Infants <6 months of age: safety and efficacy has not been established


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Administration

  • Route: Oral (tablet)
  • Method:
    • Take once daily as directed.
    • Administer in the evening if treating asthma.[7]
  • Route: Oral (chewable tablet)
  • Method:
    • Chew thoroughly before swallowing.
    • Administer in the evening if treating asthma.[7]
  • Route: Oral (granules)
  • Method:
    • Administer directly into the mouth or mix with a spoonful of cold or room temperature applesauce, carrots, rice, or ice cream.
    • The full dose must be given within 15 minutes of opening the package.
    • Administer in the evening if treating asthma.[7]

Monitoring Parameters

  • Monitor for efficacy by analyzing symptomatic improvement[7]

Contraindications/Precautions

Contraindications

  • Acute bronchospasm
  • Status asthmaticus
  • Known hypersensitivity to montelukast or to any inactive component of the preparation

Precautions

  • Patients with known alcoholism, jaundice, hepatitis, or other hepatic diseases.
  • Patients who are reducing their dose of oral corticosteroids has been associated with Churg-Strauss syndrome.
  • Use caution when administering chewable tablets in patients with phenylketonuria.
  • Safety and efficacy has not been established in infants younger than 6 months of age.

Pregnancy indications

Category B

Animal studies with AUCs over 100 times the expected human values have shown no teratogencity after montelukast dosing during pregnancy. However, the lack of human studies in pregnant women suggests that montelukast should be used with caution.[7]

Breast-feeding indications

Animal studies in rats have shown that montelukast is excreted into breast milk. While no studies of montelukast have been performed in human breast-feeding mothers, montelukast should only be used if medically necessary and only with caution.

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Montelukast is generally well tolerated. No adverse event was seen in more than 5% of the study population in phase III clinical trials.[7]

Montelukast Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All None
1-10% CNS Dizziness (2%), fatigue (2%), fever (2%)
Dermatologic Rash (2%)
GI Abdominal pain (3%), dyspepsia (2%), dental pain (2%), gastroenteritis (2%)
Neuromuscular/skeletal Weakness (2%)
Respiratory Cough (3%), nasal congestion (2%), upper respiratory infection (2%)
Miscellaneous Flu-like syndrome (4%)
<1% All Acute bronchitis (pediatric), atopic dermatitis (pediatric), agitation, anaphylaxis, angioedema, arthralgia, bleeding, bruising, cholestasis, Churg-Strauss syndrome, conjunctivitis (pediatric), cough (pediatric), dermatitis (pediatric), diarrhea (pediatric), drowsiness, ear pain (pediatric), eczema (pediatric), edema, elevated hepatic enzymes, eosinophilia, hallucinations, headache (pediatric), hepatic eosinophilis infiltration, hepatitis, hypoesthesia, infection (pediatric), insomnia, irritability, laryngitis (pediatric), myalgia, myopia (pediatric), nausea (pediatric), otitis (pediatric), palpitation, pancreatitis, paresthesia, pharyngitis(pediatric), pruritius, rhinitis (pediatric), rhinorrhea (pediatric), seizure, skin infection (pediatric), sinusitis (pediatric) tooth infection (pediatric), trauma, urticaria (pediatric), varicella (pediatric), vasculitis, vomitting (pediatric), weight loss

Leukotriene receptor antagonist use has been associated with rare reports of Churg-Strauss syndrome. This condition of eosinophilia and vasculitis usually occurs when a dose of concomitant oral corticosteroid therapy is reduced. Patients with this syndrome often complain initially of flu-like symptoms such as fever, myalgia, and weight loss. As the condition develops, patients can experience worsening pulmonary symptoms, cardiac compliactions, and neuropathy. This condition can be life-threatening. Treatment strategies often include oral corticosteroids. While a direct relationship has not been definitively shown, patients should be counseled to report flu-like symptoms to their physician while on montelukast therapy.[7]

Overdosage Measures

Overdosage studies have been performed in mice with AUCs of up to 335 times the normal expected human values. No mortalities were found in these studies. However, it is unknown if these results can be extrapolated to humans. No specific overdosage recommendations have been issued by the manufacturer. In the event of an overdose, symptomatic support, vital sign monitoring, and gastric lavage are reasonable approaches. Post-marketing reports of montelukast overdose suggest that most patients experience no adverse events after acute ingestion of up to 1000 mg.[7]

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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
4 mg chewable tablet pink oval SINGULAIR/MRK 711
5 mg chewable tablet pink round SINGULAIR/MRK 275
10 mg tablet beige rounded square SINGULAIR/MRK 117
4 mg oral granules white granules -
  • Inactive ingredients for tablets: carnauba wax, croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, red ferric oxide, titanium dioxide, yellow ferric oxide
  • Inactive ingredients for chewable tablets: aspartame, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, red ferric oxide
  • Inactive ingredients for oral granules: hydroxypropyl cellulose, magnesium stearate, mannitol

Patient Information

  • Do not stop other asthma medications unless directed by your physician.
  • Take as directed even if symptoms alleviate and you "feel better."
  • Montelukast will NOT stop an acute asthma attack. Continue to carry a rescue inhaler while on montelukast therapy.
  • Chewable tablets contain phenylalanine. Use caution in patients with phenylketonuria.
  • May cause headache. Use over the counter analgesic medications if this becomes troublesome.
  • May cause drowsiness or dizziness. Use caution when driving or operating heavy machinery.
  • Report worsening asthma symptoms, flu-like illness, numbness in the arms or legs, persistant GI upset, or skin rash to you health care provider.
  • Consult with your doctor if pregnancy occurs or if you wish to begin breast feeding.
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References

  1. ↑ Sorkness CA, Lemanske RF, Jr., Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. The Journal of allergy and clinical immunology. 2007 Jan;119(1):64-72.
  2. ↑ Stempel DA, Kruzikas DT, Manjunath R. Comparative efficacy and cost of asthma care in children with asthma treated with fluticasone propionate and montelukast. The Journal of pediatrics. 2007 Feb;150(2):162-7.
  3. ↑ Meltzer EO, Lockey RF, Friedman BF, Kalberg C, Goode-Sellers S, Srebro S, et al. Efficacy and safety of low-dose fluticasone propionate compared with montelukast for maintenance treatment of persistent asthma. Mayo Clinic proceedings. 2002 May;77(5):437-45.
  4. ↑ Ostrom NK, Decotiis BA, Lincourt WR, Edwards LD, Hanson KM, Carranza Rosenzweig JR, et al. Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma. The Journal of pediatrics. 2005 Aug;147(2):213-20.
  5. ↑ Kondo N, Katsunuma T, Odajima Y, Morikawa A. A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children. Allergol Int. 2006 Sep;55(3):287-93.
  6. ↑ Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, et al. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Ann Allergy Asthma Immunol. 2006 Jun;96(6):800-7.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 Singulair® (montelukast) package insert. Whitehouse Station, NJ: Merck & Co, Inc.; 2005 Sep.
  8. ↑ Kim KA, Park PW, Kim KR, Park JY. Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br J Clin Pharmacol. 2006 Sep 19.
  9. ↑ Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respiratory medicine. 2006 Nov;100(11):1952-9.
  10. ↑ Grainger J, Drake-Lee A. Montelukast in allergic rhinitis: a systematic review and meta-analysis. Clin Otolaryngol. 2006 Oct;31(5):360-7.
  11. ↑ Ghosh G, Manglik AK, Roy S. Efficacy and safety of montelukast as monotherapy in children with mild persistent asthma. Indian pediatrics. 2006 Sep;43(9):780-5.
  12. ↑ Athavale A, Souza GA, Avasthi R, Singh NP, Kale M, Taneja A, et al. A clinical trial of the efficacy and safety of montelukast as monotherapy in patients with chronic stable bronchial asthma. Journal of the Indian Medical Association. 2004 Feb;102(2):109-11
  13. ↑ van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss TF. Safety, tolerability, and exploratory efficacy of montelukast in 6- to 24-month-old patients with asthma. Current medical research and opinion. 2005 Jun;21(6):971-9.
  14. ↑ Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respiratory medicine. 2006 Nov;100(11):1952-9.
  15. ↑ Can M, Yuksel B, Demirtas S, Tomac N. The effect of montelukast on soluble interleukin-2 receptor and tumor necrosis factor alpha in pediatric asthma. Allergy Asthma Proc. 2006 Jul-Aug;27(4):383-6.
  16. ↑ Harmanci K, Bakirtas A, Turktas I, Degim T. Oral montelukast treatment of preschool-aged children with acute asthma. Ann Allergy Asthma Immunol. 2006 May;96(5):731-5.
  17. ↑ Hakim F, Vilozni D, Adler A, Livnat G, Tal A, Bentur L. The effect of montelukast on bronchial hyperreactivity in preschool children. Chest. 2007 Jan;131(1):180-6.
  18. ↑ Stelmach I, Korzeniewska A, Stelmach W, Majak P, Grzelewski T, Jerzynska J. Effects of montelukast treatment on clinical and inflammatory variables in patients with cystic fibrosis. Ann Allergy Asthma Immunol. 2005 Oct;95(4):372-80.

PUBMED References

Efficacy Trial Articles

  1. Athavale A, Souza GA, Avasthi R, Singh NP, Kale M, Taneja A, et al. A clinical trial of the efficacy and safety of montelukast as monotherapy in patients with chronic stable bronchial asthma. Journal of the Indian Medical Association. 2004 Feb;102(2):109-11.
  2. Can M, Yuksel B, Demirtas S, Tomac N. The effect of montelukast on soluble interleukin-2 receptor and tumor necrosis factor alpha in pediatric asthma. Allergy Asthma Proc. 2006 Jul-Aug;27(4):383-6.
  3. Ghosh G, Manglik AK, Roy S. Efficacy and safety of montelukast as monotherapy in children with mild persistent asthma. Indian pediatrics. 2006 Sep;43(9):780-5.
  4. Grainger J, Drake-Lee A. Montelukast in allergic rhinitis: a systematic review and meta-analysis. Clin Otolaryngol. 2006 Oct;31(5):360-7.
  5. Hakim F, Vilozni D, Adler A, Livnat G, Tal A, Bentur L. The effect of montelukast on bronchial hyperreactivity in preschool children. Chest. 2007 Jan;131(1):180-6.
  6. Harmanci K, Bakirtas A, Turktas I, Degim T. Oral montelukast treatment of preschool-aged children with acute asthma. Ann Allergy Asthma Immunol. 2006 May;96(5):731-5.
  7. Stelmach I, Korzeniewska A, Stelmach W, Majak P, Grzelewski T, Jerzynska J. Effects of montelukast treatment on clinical and inflammatory variables in patients with cystic fibrosis. Ann Allergy Asthma Immunol. 2005 Oct;95(4):372-80.
  8. van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss TF. Safety, tolerability, and exploratory efficacy of montelukast in 6- to 24-month-old patients with asthma. Current medical research and opinion. 2005 Jun;21(6):971-9.
  9. Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respiratory medicine. 2006 Nov;100(11):1952-9.
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Therapeutic Class Comparison Articles

  1. Sorkness CA, Lemanske RF, Jr., Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. The Journal of allergy and clinical immunology. 2007 Jan;119(1):64-72.
  2. Stempel DA, Kruzikas DT, Manjunath R. Comparative efficacy and cost of asthma care in children with asthma treated with fluticasone propionate and montelukast. The Journal of pediatrics. 2007 Feb;150(2):162-7.
  3. Kondo N, Katsunuma T, Odajima Y, Morikawa A. A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children. Allergol Int. 2006 Sep;55(3):287-93.
  4. Martin BG, Andrews CP, van Bavel JH, Hampel FC, Klein KC, Prillaman BA, et al. Comparison of fluticasone propionate aqueous nasal spray and oral montelukast for the treatment of seasonal allergic rhinitis symptoms. Ann Allergy Asthma Immunol. 2006 Jun;96(6):851-7.
  5. Meltzer EO, Lockey RF, Friedman BF, Kalberg C, Goode-Sellers S, Srebro S, et al. Efficacy and safety of low-dose fluticasone propionate compared with montelukast for maintenance treatment of persistent asthma. Mayo Clinic proceedings. 2002 May;77(5):437-45.
  6. Ostrom NK, Decotiis BA, Lincourt WR, Edwards LD, Hanson KM, Carranza Rosenzweig JR, et al. Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma. The Journal of pediatrics. 2005 Aug;147(2):213-20.

Pharmacokinetics Articles

  1. Knorr B, Maganti L, Ramakrishnan R, Tozzi CA, Migoya E, Kearns G. Pharmacokinetics and safety of montelukast in children aged 3 to 6 months. Journal of clinical pharmacology. 2006 Jun;46(6):620-7.
  2. Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, Hendeles L, et al. Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol. 2006 Jul;97(1):98-104.
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Drug Interaction Articles

  1. Kim KA, Park PW, Kim KR, Park JY. Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br J Clin Pharmacol. 2006 Sep 19.

Adverse Effects Articles

  1. Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, et al. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Ann Allergy Asthma Immunol. 2006 Jun;96(6):800-7.
  2. Boccagni C, Tesser F, Mittino D, Terazzi E, Naldi P, Colombi S, et al. Churg-Strauss syndrome associated with the leukotriene antagonist montelukast. Neurol Sci. 2004 Apr;25(1):21-2.
  3. Geller M, Geller M. Marked peripheral edema associated with montelukast and prednisone. Annals of Internal Medicine. 2000 Jun 6;132(11):924.
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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources


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