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Special Alerts
Leukotriene Inhibitors: Potential Association with Neuropsychiatric Events - June 12, 2009; Updated August 2009
The Food and Drug Administration (FDA) is updating healthcare professionals regarding the possible association between leukotriene inhibitor use and neuropsychiatric events including agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide) and tremor. The FDA has requested that manufacturers of leukotriene inhibitors add a precaution regarding this potential risk to the drug prescribing information. In addition, the FDA recommends that both patients and healthcare providers are aware of the potential neuropsychiatric risks of taking these medications. Patients should be encouraged to report any neuropsychiatric effects to a healthcare provider. Healthcare professionals should consider discontinuing leukotriene inhibitors if a patient exhibits or reports a neuropsychiatric symptom.
In August, the respective manufacturers updated the prescribing information for Singulair® (montelukast), Accolate® (zafirlukast), and Zyflo CR®/Zyflo® (zileuton) to include information about neuropsychiatric events.
Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm166246.htm
Medication Safety Issues
Sound-alike/look-alike issues:
Singulair® may be confused with Sinequan®
Pronunciation
(mon te LOO kast)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Prophylaxis and chronic treatment of asthma; relief of symptoms of seasonal allergic rhinitis and perennial allergic rhinitis; prevention of exercise-induced bronchospasm
Use: Unlabeled/Investigational
Acute asthma
Pregnancy Risk Factor
B
Pregnancy Considerations
Montelukast was not teratogenic in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. Based on limited data, structural defects have been reported in neonates exposed to montelukast in utero; however, a specific pattern and relationship to montelukast has not been established. Healthcare providers should report any prenatal exposures to the montelukast pregnancy registry at (800) 986-8999.
Lactation
Excretion in breast milk unknown/use caution
Breast-Feeding Considerations
Zafirlukast, another leukotriene receptor antagonist, is excreted in breast milk and use while breast-feeding is not recommended.
Contraindications
Hypersensitivity to montelukast or any component of the formulation
Warnings/Precautions
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 Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. Healthcare providers should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast and these underlying conditions has not been established.
• Neuropsychiatric events: Postmarketing reports of behavioral changes (eg, agitation, aggression, depression, insomnia, tremor) have been noted in pediatric and adult patients. In a retrospective analysis performed by Merck, serious behavior-related events were rare (Philip G, 2009); assess patients for behavioral changes.
Concurrent drug therapy issues:
• Corticosteroids: Appropriate clinical monitoring and caution are recommended when systemic corticosteroid reduction is considered in patients receiving montelukast.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <6 months of age.
Dosage form specific issues:
• Chewable tablet: Contains phenylalanine.
Other warnings/precautions:
• Aspirin-sensitive asthmatics: Montelukast will not interrupt bronchoconstrictor response to aspirin or other NSAIDs. Patients with known aspirin sensitivity should continue to avoid these agents.
• Reversal of bronchospasm: Not FDA approved for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Some clinicians, however, support its use (Camargo, 2003; Cylly, 2003; Ferreira, 2001). Appropriate rescue medication should be available.
Adverse Reactions
(As reported in adults)
1% to 10%:
Central nervous system: Dizziness (2%), fatigue (2%), fever (2%), headache (?1%)
Dermatologic: Rash (2%)
Gastrointestinal: Dyspepsia (2%), dental pain (2%), gastroenteritis (2%)
Hepatic: AST increased (2%), ALT increased (2%)
Neuromuscular & skeletal: Weakness (2%)
Respiratory: Cough (1% to 3%), nasal congestion (2%), epistaxis (?1%), sinusitis (?1%), upper respiratory infection (?1%)
Postmarketing and/or case reports: Aggression, agitation, anaphylaxis, angioedema, anxiety, arthralgia, behavior/mood changes, bleeding tendency, bruising, cholestasis (rare), Churg-Strauss syndrome (rare), depression, diarrhea, dream abnormalities, drowsiness, edema, eosinophilia (systemic; rare), erythema nodosum, hallucinations, hepatic eosinophilic infiltration (rare); hepatitis (mixed pattern, hepatocellular, and cholestatic); hostility, hypersensitivity, hypoesthesia, insomnia, irritability, muscle cramps, myalgia, nausea, palpitation, pancreatitis (rare), paresthesia, pruritus, psychomotor hyperactivity, restlessness, seizure (rare), somnambulism, suicidal thinking/behavior (suicidality), suicide, tremor, urticaria, vasculitis (rare), vomiting
Metabolism/Transport Effects
Substrate (major) of CYP2C9, 3A4; Inhibits CYP2C8 (weak), 2C9 (weak)
Drug Interactions
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: St John's wort may decrease montelukast levels.
Storage
Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture and light.
Granules: Store in original package; use within 15 minutes of opening packet.
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Duration: >24 hours
Absorption: Rapid
Distribution: Vd: 8-11 L
Protein binding, plasma: >99%
Metabolism: Extensively hepatic via CYP3A4 and 2C9
Bioavailability: Tablet: 10 mg: Mean: 64%; 5 mg: 63% to 73%
Half-life elimination, plasma: Mean: 2.7-5.5 hours
Time to peak, serum: Tablet: 10 mg: 3-4 hours; 5 mg: 2-2.5 hours; 4 mg: 2 hours
Excretion: Feces (86%); urine (<0.2%)
Dosage
Oral:
Children:
6-11 months: Asthma (unlabeled use): 4 mg (oral granules) once daily, taken in the evening
6-23 months: Perennial allergic rhinitis: 4 mg (oral granules) once daily
12-23 months: Asthma: 4 mg (oral granules) once daily, taken in the evening
2-5 years: Asthma, seasonal or perennial allergic rhinitis: 4 mg (chewable tablet or oral granules) once daily, taken in the evening
6-14 years: Asthma, seasonal or perennial allergic rhinitis: 5 mg (chewable tablet) once daily, taken in the evening
Children ?15 years and Adults:
Asthma, seasonal or perennial allergic rhinitis: 10 mg/day, taken in the evening
Asthma, acute (unlabeled use): 10 mg as a single dose administered with first-line therapy
Bronchoconstriction, exercise-induced (prevention): 10 mg at least 2 hours prior to exercise; additional doses should not be administered within 24 hours. Daily administration to prevent exercise-induced bronchoconstriction has not been evaluated.
Dosing adjustment in renal impairment: No adjustment necessary
Dosing adjustment in hepatic impairment: Mild-to-moderate: No adjustment necessary. Patients with severe hepatic disease were not studied.
Administration: Oral
When treating asthma, administer dose in the evening. Patients with allergic rhinitis may individualize administration time. Granules may be administered directly in the mouth or mixed with a spoonful of applesauce, carrots, rice, ice cream, baby formula, or breast milk; do not add to any other liquids or foods. Administer within 15 minutes of opening packet. May administer without regard to meals.
Monitoring Parameters
Mood or behavior changes, including suicidal thinking/behavior
Dietary Considerations
Some products may contain phenylalanine.
Patient Education
Do not stop other asthma medication unless advised by prescriber. Chewable tablet contains phenylalanine. Take every evening on a continuous basis; do not discontinue even if feeling better (this medication may help reduce incidence of acute attacks). Granules may be administered directly in the mouth or mixed with applesauce, carrots, rice, ice cream, baby formula, or breast milk (do not add to any other liquids); administer within 15 minutes of opening packet. You may experience mild headache (mild analgesic may help); or fatigue or dizziness (use caution when driving). Report skin rash or itching, abdominal pain or persistent GI upset, unusual cough or congestion, behavior and mood changes including suicide thoughts, feeling of numbness in arms or legs, flu-like illness, or worsening of asthmatic condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
The pharmacokinetic profile in the elderly is similar to younger adults except the half-life is slightly longer in the elderly. Despite this difference, no adjustment in dose is necessary in the elderly. Elimination is mostly fecal and bile with insignificant amounts from renal elimination, which is an advantage for the elderly.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Dental pain.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause agitation, aggression, anxiousness, depression, dizziness, dream abnormalities, drowsiness, hallucinations, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide)
Mental Health: Effects on Psychiatric Treatment
Barbiturates may decrease the effects of montelukast; CYP3A4 substrate; nefazodone may increase effects
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor mental and mood status. Be alert to thoughts of suicide. Monitor effectiveness of therapy and adverse reactions at beginning of therapy and periodically with long-term use. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Granules:
Singulair®: 4 mg/packet (30s)
Tablet:
Singulair®: 10 mg
Tablet, chewable:
Singulair®: 4 mg [contains phenylalanine 0.674 mg; cherry flavor]; 5 mg [contains phenylalanine 0.842 mg; cherry flavor]
Pricing: U.S. (www.drugstore.com)
Chewable (Singulair)
4 mg (30): $123.71
5 mg (30): $125.95
Pack (Singulair)
4 mg (30): $131.00
Tablets (Singulair)
10 mg (30): $126.25
References
Bakhireva LN, Jones KL, and Chamber CD, “Safety of Leukotriene Receptor Antagonists in Pregnancy,” Birth Defects Res A Clin Mol Teratol, 2006, 76(5): 314. From “Abstracts of the 46th Teratology Society Annual Meeting, 30th Annual Meeting of the Neurobehavioral Teratology Society, 19th International Conference of the Organization of Teratology Information Specialists,” Birth Defects Res A Clin Mol Teratol, 2006, 76(5):313-428.
Camargo CA Jr, Smithline HA, Malice MP, et al, “A Randomized Controlled Trial of Intravenous Montelukast in Acute Asthma,” Am J Respir Crit Care Med, 2003, 167(4):528-33.
Cylly A, Kara A, Ozdemir T, et al, “Effects of Oral Montelukast on Airway Function in Acute Asthma,” Respir Med, 2003, 97(5):533-6.
Ferreira MB, Santos AS, Pregal AL, et al, “Leukotriene Receptor Antagonists (Montelukast) in the Treatment of Asthma Crisis: Preliminary Results of a Double-Blind Placebo Controlled Randomized Study,” Allerg Immunol (Paris), 2001, 33(8):315-8.
Philip G, Hustad CM, Malice MP, et al, “Analysis of Behavior-Related Adverse Experiences in Clinical Trials of Montelukast,” J Allergy Clin Immunol, 2009, 124(4):699-706.
Philip G, Hustad C, Noonan G, et al, “Reports Of Suicidality In Clinical Trials Of Montelukast,” J Allergy Clin Immunol, 2009, 124(4):691-6.
Sarkar M and Koren G, “Pregnancy Outcome Following Gestational Exposure to Montelukast: A Prospective Controlled Study,” Clin Pharmacol Ther, 2005, 77(2):30. From “Abstracts of the American Society for Clinical Pharmacology and Therapeutics Annual Meeting,” Clin Pharmacol Ther, 2005, 77(2):1-146.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2010
Content last modified January 2010
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