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    Systemic Leukotriene Antagonists

    BOXED WARNING

    Behavioral changes, depression, neurologic events, psychiatric event, suicidal ideation

    Behavioral changes consistent with a neuro-psychiatric event have been reported in adult, adolescent, and pediatric patients taking montelukast, and some of these events appear to be consistent with a drug-related effect. Be aware that some patients have reported neuropsychiatric events after discontinuation of montelukast.[29630] In March 2020, the FDA recommended that a Boxed Warning be added to the montelukast prescribing information because of serious mental health side effects and recommended that montelukast only be used to treat allergic rhinitis in patients who are not treated effectively with or cannot tolerate other allergy medicines.Postmarketing reports include psychiatric and neurologic events such as agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal ideation and behavior (including suicide), tic, and tremor. Available data are insufficient to characterize at-risk patients. Advise patients and their caregivers to report changes in mood or behavior immediately; consider alternate therapy if patients develop neuropsychiatric symptoms.[29630]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral leukotriene receptor antagonist (LRTA) class antiinflammatory
    Used orally for mild persistent asthma for age 1 year and older; for seasonal allergic rhinitis in those 2 years and older, perennial allergic rhinitis in those 6 months and older; and exercise-induced bronchoconstriction (EIB) prophylaxis in those 6 years and older
    Boxed warning regarding serious neuropsychiatric effects; only use in allergic rhinitis patients intolerant to or not responding to other treatments

    COMMON BRAND NAMES

    Singulair

    HOW SUPPLIED

    Montelukast Sodium/Singulair Oral Gran: 4mg
    Montelukast Sodium/Singulair Oral Tab Chew: 4mg, 5mg
    Montelukast Sodium/Singulair Oral Tab: 10mg

    DOSAGE & INDICATIONS

    For the chronic treatment and prevention of the symptoms of asthma, either as monotherapy or as add-on therapy in patients whose persistent mild-moderate asthma is inadequately controlled with inhaled corticosteroids.
    NOTE: Montelukast is not a rescue medication; it should not be used for the treatment of an acute asthmatic attack or acute bronchospasm. However, montelukast may be continued during the treatment of an acute asthmatic event.
    Oral dosage (regular tablets, 10 mg)
    Adults and Adolescents >= 15 years

    10 mg PO once daily in the evening. Although larger doses (e.g., 50—200 mg) have been studied, no additional benefit was seen beyond a dose of 10 mg/day. Daily administration for the chronic treatment of asthma has not been shown to prevent acute episodes of exercise-induced bronchoconstriction.

    Oral dosage (chewable tablets, 4 or 5 mg)
    Adolescents and Children 6—14 years

    5 mg PO once daily in the evening.

    Children 2—5 years

    4 mg PO once daily in the evening.

    Oral dosage (oral granules, 4 mg packet)
    Children 1—5 years

    4 mg PO once daily in the evening.

    For exercise-induced bronchospasm prophylaxis.
    Oral dosage
    Adults and Adolescents >= 15 years

    10 mg PO once, given at least 2 hours before exercise. Maximum: 1 dose/24 hours. Patients receiving daily montelukast for another indication should not take an additional dose to prevent exercise-induced bronchospasm (EIB). Rescue medications (e.g., beta-agonists) should be available. The American Thoracic Society recommends daily administration of a leukotriene receptor antagonist (LTRA) such as montelukast in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, LTRAs may be a first-line choice for a controller agent to be added to SABAs; inhaled corticosteroids may also be used. The choice between the 2 classes must be made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy.

    Adolescents < 15 years and Children >= 6 years

    5 mg PO once, given at least 2 hours before exercise. Maximum: 1 dose/24 hours. Patients receiving daily montelukast for another indication should not take an additional dose to prevent exercise-induced bronchospasm (EIB). Rescue medications (e.g., beta-agonists) should be available. The American Thoracic Society recommends daily administration of a leukotriene receptor antagonist (LTRA) such as montelukast in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, LTRAs may be a first-line choice for a controller agent to be added to SABAs; inhaled corticosteroids may also be used. The choice between the 2 classes must be made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy.

    For the treatment of allergic rhinitis (seasonal allergies and perennial allergies).
    For perennial allergic rhinitis.
    Oral dosage (regular tablets, 10 mg)
    Adults

    10 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Adolescents 15 years and older

    10 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Oral dosage (chewable tablets, 4 or 5 mg or oral granules, 4 mg packet)
    Children and Adolescents 6 to 14 years

    5 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Children 2 to 5 years

    4 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Infants and Children 6 months to 2 years

    4 mg oral granules PO once daily (do not administer tablets). LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    For seasonal allergic rhinitis.
    Oral dosage (regular tablets, 10 mg)
    Adults

    10 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Adolescents 15 years and older

    10 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Oral dosage (chewable tablets, 4 or 5 mg or oral granules, 4 mg packet)
    Children and Adolescents 6 to 14 years

    5 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    Children 2 to 5 years

    4 mg PO once daily. LIMITS of USE: Montelukast should not be used for mild symptoms of allergic rhinitis, but should be reserved for patients who are not treated effectively with or cannot tolerate other allergy medication.

    For the treatment of aspirin-induced asthma†.
    Oral dosage
    Adults

    10 mg PO once daily at bedtime. Use with an established asthma treatment regimen that includes necessary medications such as bronchodilators and inhaled or systemic corticosteroids. The benefit of montelukast in aspirin-intolerant asthmatic patients was assessed in a randomized, double-blind, placebo-controlled trial. Patients qualified for inclusion based on asthma symptoms and the response of FEV1 to beta-agonists. Patients were randomized to receive montelukast 10 mg (n = 40) or placebo (n = 40) once daily at bedtime over 4 weeks. Glucocorticosteroids were used in 85% to 90% of patients and theophylline in 40% to 45% of patients at baseline. A 2-week washout period occurred prior to study entry during which no long-acting antihistamines, long-acting beta agonists, or inhaled antimuscarinics were used. Peak expiratory flow rate (PEFR) and asthma symptoms were recorded twice daily in addition to beta-agonist use. FEV1 was assessed once weekly. At study conclusion, montelukast significantly improved FEV1 and twice daily PEFR rates compared to placebo (p < 0.001), with mean differences in FEV1 of 10.2%, 28 L/minute (morning PEFR), and 23.1 L/minute (evening PEFR). Less rescue bronchodilator was used in patients treated with montelukast compared to placebo (decrease of 27.7% vs. 1.6% from baseline, p < 0.05), and the montelukast group had 54% fewer asthma exacerbations. Asthma quality of life improved; patients with nocturnal asthma slept 1.3 nights more per week compared to those treated with placebo. No significant adverse reactions were observed.

    For the treatment of atopic dermatitis†.
    Oral dosage
    Adults

    10 mg PO once daily. May be used concomitantly with emollients, antihistamines, or topical corticosteroids. Montelukast efficacy was evaluated in a randomized, double-blind, placebo-controlled crossover trial in 8 adults with mild to moderate atopic dermatitis (AD). Patients in 2 treatment groups were randomized to a regimen of montelukast 10 mg/day for 4 weeks, then placebo daily for 4 weeks after a 2-day washout period, or vice versa. Topical steroids, emollients, and antihistamines were used because of flaring during washout and initial blinded study periods. At study conclusion, a significant decrease in symptom severity was demonstrated by ADASI (atopic dermatitis area and severity index) scores, with scores with montelukast decreasing from approximately 8 to 6, and scores with placebo increasing from approximately 8 to 10 (p = 0.014). Improvements in scaling/dryness, lichenification, induration, erythema, erosions, and excoriation were noted. No patient completely cleared. In a single-blind study, adult patients with moderate to severe AD were randomized to treatment with montelukast 10 mg/day with placebo tablets 3 times daily or a combination of cetirizine, corticosteroids, and 10 days of clarithromycin. Placebo topical gel or topical emulsions containing urea or ammonium lactate were offered to those treated with montelukast or the combination regimen, respectively. After 6 weeks, the severity of AD, as estimated by the SCORAD (Scoring Atopic Dermatitis) tool, decreased in each treatment group, with mean scores of 25.5 for montelukast (baseline = 46.5) and 23.3 for the combination regimen (baseline = 47.3); the difference between groups was not statistically significant. Patients felt that reduction in pruritus was the most notable symptom improvement (in both treatment groups); montelukast did not improve xerosis. No adverse reactions to treatment were reported.

    For the adjunctive treatment of chronic urticaria† or chronic idiopathic urticaria†.
    Oral dosage
    Adults

    10 mg PO once daily in combination with a non-sedating antihistamine is recommended for refractory urticaria; montelukast should only be added to a treatment regimen after optimal dosing of a non-sedating antihistamine fails to control the urticaria. The efficacy and safety of montelukast for the treatment of chronic idiopathic urticaria was evaluated in a randomized, single-blind, placebo-controlled crossover study in adults with refractory urticaria (n = 30). Patients were randomized to receive montelukast 10 mg or placebo once daily at bedtime, with cetirizine 10 mg given as needed. Each treatment was given for 6 weeks with a 2-week washout period between crossover. Improvement was assessed by daily urticaria activity scores (UAS) completed by the patient, taking into account wheal numbers and itching severity, graded on a 0 to 3 severity scale (none to severe). A significant decrease in urticaria scores occurred with montelukast treatment (p < 0.001), and less cetirizine was used compared to the placebo group (p < 0.001). No significant adverse reactions were noted. Another randomized, double-blind, placebo-controlled trial evaluated the efficacy of montelukast in combination with desloratadine for the treatment of chronic urticaria. Patients (n = 81) received desloratadine 5 mg with montelukast 10 mg, desloratadine 5 mg with placebo, or placebo for 6 weeks following a 1 week single-blind placebo run-in period. A 1 week placebo washout period occurred following active treatment. Study outcomes included patient-reported symptoms of pruritus, size and number of wheals, and number of urticarial episodes graded on a 0 to 3 severity scale (none to severe). Quality of life questionnaires were assessed at each clinical visit. Significant improvement in overall urticaria symptoms was reported in each active treatment group compared to placebo (p < 0.05) and with desloratadine plus montelukast compared to desloratadine alone (p < 0.05). The montelukast combination regimen significantly reduced pruritus compared to desloratadine alone during active treatment (p < 0.05). The number of urticaria episodes did not significantly differ between the active treatment groups. Improvement in quality of life scores was greater with desloratadine plus montelukast vs. desloratadine alone throughout treatment and at follow-up after washout. No adverse reactions were reported.

    Children and Adolescents

    The addition of a leukotriene receptor antagonist, such as montelukast, to non-sedating antihistamine therapy is recommended if symptoms persist 1 to 4 weeks after optimal antihistamine dosing. Although specific dosing guidelines are not provided, use of typical age-adjusted doses should be considered (i.e., 4 mg/day for children aged 5 years or younger, 5 mg/day for children 6 to 14 years, and 10 mg/day for adolescents aged 15 years or older).

    For the treatment of mild to moderate obstructive sleep apnea†.
    Oral dosage
    Children 6 to 10 years

    5 mg PO once daily at bedtime.

    Children 2 to 5 years

    4 mg PO once daily at bedtime.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO.

    Geriatric

    10 mg/day PO.

    Adolescents

    15 years and older: 10 mg/day PO.
    13 to 14 years: 5 mg/day PO.

    Children

    6 to 12 years: 5 mg/day PO.
    1 to 5 years: 4 mg/day PO.

    Infants

    6 months and older: 4 mg/day PO for perennial allergic rhinitis only.
    Less than 6 months: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The mean elimination half-life of montelukast is only slightly prolonged in patients with mild-moderate hepatic insufficiency; therefore, no dosage adjustment is required. However, montelukast has not been evaluated in patients with severe hepatic impairment or hepatitis; no dosage guidelines are available for these patient populations.

    Renal Impairment

    It appears that no dosage adjustments are needed; montelukast is not significantly eliminated via the renal route (manufacturers recommendation).

    ADMINISTRATION

    Oral Administration

    For asthma, montelukast is administered in the evening without regard to meals; evening administration is recommended since the drug was given at bedtime during clinical trials. However, there are no studies evaluating the relative efficacy of morning versus evening dosing. For seasonal allergies, the time of daily administration may be adjusted to suit patient needs; administer at roughly the same time daily.

    Oral Solid Formulations

    Chewable tablets: Chew tablet well prior to swallowing.
    Oral granules: The 4 mg oral granules can be administered orally directly into the mouth, or mixed with a spoonful of cold or room temperature soft foods. Based on stability studies, only applesauce, carrots, rice or ice cream should be used. Do not open the packet until ready to use. After opening the packet, the full dose (with or without mixing with food) should be administered within 15 minutes. If mixed with food, the oral granules should not be stored for future use. Discard any unused portion. The oral granules are not intended to be dissolved in liquid for administration. However, liquids may be taken after administration.

    STORAGE

    Singulair:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The safety and efficacy of montelukast in children has been established. Additionally, in November 2005 the FDA approved revisions to the product labeling of montelukast oral formulations following the results of a 56 week study indicating that growth rates were similar among 6 to 8 year old asthmatic children receiving montelukast 5 mg per day or placebo. In addition, children receiving either montelukast or placebo had higher growth rates than those receiving inhaled beclomethasone 168 mcg twice daily.

    Acute bronchospasm, status asthmaticus

    Montelukast is not effective for the treatment of acute asthma attacks, including status asthmaticus or acute bronchospasm. Thus, patients should be advised to have appropriate rescue medication (e.g., inhaled beta-agonist) available. In addition, according to the manufacturer, montelukast should not be used as monotherapy for the management of exercise-induced bronchospasm. However, montelukast therapy may be continued during the treatment of an acute asthmatic event. Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting montelukast unless otherwise directed by their health care prescriber.

    Phenylketonuria

    Montelukast chewable tablets should be used with caution in patients with phenylketonuria. Each 4 mg and 5 mg chewable tablet contains 0.674 and 0.842 mg, respectively, of phenylalanine. Montelukast is contraindicated for use in those patients with hypersensitivity to any product component.

    Behavioral changes, depression, neurologic events, psychiatric event, suicidal ideation

    Behavioral changes consistent with a neuro-psychiatric event have been reported in adult, adolescent, and pediatric patients taking montelukast, and some of these events appear to be consistent with a drug-related effect. Be aware that some patients have reported neuropsychiatric events after discontinuation of montelukast.[29630] In March 2020, the FDA recommended that a Boxed Warning be added to the montelukast prescribing information because of serious mental health side effects and recommended that montelukast only be used to treat allergic rhinitis in patients who are not treated effectively with or cannot tolerate other allergy medicines.Postmarketing reports include psychiatric and neurologic events such as agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal ideation and behavior (including suicide), tic, and tremor. Available data are insufficient to characterize at-risk patients. Advise patients and their caregivers to report changes in mood or behavior immediately; consider alternate therapy if patients develop neuropsychiatric symptoms.[29630]

    Pregnancy

    Published data from prospective and retrospective cohort studies of montelukast use during human pregnancy have not established a drug-associated risk of major birth defects. Some of these studies did have limitations including small sample size, retrospective design, and inconsistent comparator groups. In animal reproduction studies, no adverse developmental effects were observed with montelukast administration to pregnant rats and rabbits during organogenesis at oral doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs.[29630] The National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group list leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy. The Working Group states that leukotriene receptor antagonists may be considered for use during pregnancy for patients who had a favorable response prior to becoming pregnant.[45934]

    Breast-feeding

    Montelukast may be used during breast-feeding when necessary. Montelukast is present in human milk. However, data available for infants exposed to montelukast either directly (for selected indications) or through breast milk do not suggest a significant risk of adverse effects. Montelukast is approved for use in infants 6 months and older and has been used in newborns in dosages that provide concentrations greater than the amounts in breastmilk. The effects of montelukast on human milk production are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for montelukast and any potential adverse effects on the breast-fed infant from montelukast or the underlying maternal condition.[29630] The National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group list leukotriene receptor antagonists, such as montelukast, as an alternative treatment option in the recommended stepwise management of asthma in lactating women.[45934]

    Infants, neonates

    Safety and effectiveness of montelukast have not been established in neonates and infants < 6 months of age. Montelukast is available in chewable tablets for use in children and oral granules for use in older infants and children.

    Alcoholism, hepatic disease, hepatitis, jaundice

    Montelukast should be used cautiously in patients with hepatic disease. Based on pharmacokinetic studies in mild-moderate stable cirrhosis, the manufacturer has recommended no specific dosage adjustments. However, use caution in patients with severe hepatic impairment, jaundice, or hepatitis. Rarely, in patients with hepatic disease (e.g., from alcoholism or hepatitis), there have been post-marketing reports of cholestatic hepatitis, hepatocellular liver injury, or mixed pattern liver injury.

    Corticosteroid withdrawal

    Caution is advised when oral corticosteroid withdrawal or a reduction in corticosteroid dose is being considered in patients taking montelukast. Although a causal relationship has not been established; in rare cases, reduction in oral corticosteroid dose in patients taking montelukast has resulted in Churg-Strauss syndrome, a systemic eosinophilic vasculitis. Symptoms may include eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy (see Adverse Reactions).

    Geriatric

    The clearance of montelukast is only slightly decreased in geriatric patients. Dosage reductions in this population are not needed; clinical responses and side effects of montelukast are similar for the elderly as for younger adults.

    ADVERSE REACTIONS

    Severe

    Churg-Strauss syndrome / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known

    Moderate

    pyuria / Delayed / 1.0-1.0
    atopic dermatitis / Delayed / 2.0
    myopia / Delayed / 2.0
    wheezing / Rapid / 2.0
    gastritis / Delayed / 2.0
    conjunctivitis / Delayed / 2.0
    elevated hepatic enzymes / Delayed / 1.0
    eosinophilia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    bleeding / Early / Incidence not known
    depression / Delayed / Incidence not known
    confusion / Early / Incidence not known
    memory impairment / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    hostility / Early / Incidence not known
    dysphemia / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    urinary incontinence / Early / Incidence not known

    Mild

    dizziness / Early / 1.9-1.9
    fatigue / Early / 1.8-1.8
    asthenia / Delayed / 1.8-1.8
    nasal congestion / Early / 1.6-1.6
    nausea / Early / 2.0
    dyspepsia / Early / 2.0
    rash / Early / 1.6
    vomiting / Early / 2.0
    sinusitis / Delayed / 1.0
    fever / Early / 1.5
    laryngitis / Delayed / 2.0
    pharyngitis / Delayed / 2.0
    abdominal pain / Early / 2.0
    headache / Early / 1.0
    cough / Delayed / 1.0
    urticaria / Rapid / 2.0
    infection / Delayed / 1.9
    diarrhea / Early / 2.0
    rhinitis / Early / 2.0
    rhinorrhea / Early / 2.0
    epistaxis / Delayed / 1.0
    influenza / Delayed / 2.0
    myalgia / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    arthralgia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    somnambulism / Early / Incidence not known
    nightmares / Early / Incidence not known
    abnormal dreams / Early / Incidence not known
    tremor / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    agitation / Early / Incidence not known
    irritability / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    insomnia / Early / Incidence not known

    DRUG INTERACTIONS

    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Phenobarbital may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Phenobarbital is a strong CYP inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Phenobarbital may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Phenobarbital is a strong CYP inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Carbamazepine: (Minor) Carbamazepine may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Carbamazepine is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Enzalutamide: (Minor) Enzalutamide may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Enzalutamide is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Gemfibrozil: (Minor) Concentrations of montelukast may be increased with concomitant use of gemfibrozil; however, based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil. At clinically relevant concentrations, CYP2C8 is the primary isozyme involved in the metabolism of montelukast; the drug is also metabolized by CYP2C9 and CYP3A4. Data from a clinical drug interaction study involving montelukast and gemfibrozil (a CYP2C8 and 2C9 inhibitor) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. The addition of a potent CYP3A4 inhibitor did not further increase the inhibition of montelukast metabolism.
    Hydantoins: (Minor) Hydantoin anticonvulsants may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Hydantoin anticonvulsants are a strong CYP3A inducers. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Lumacaftor is a strong CYP3A inducer, and in vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C8 and CYP2C9. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Mitotane: (Minor) Mitotane may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Mitotane is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Phenobarbital: (Minor) Phenobarbital may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Phenobarbital is a strong CYP inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Primidone: (Minor) Primidione, which is metabolized to phenobarbital, may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Phenobarbital is a strong CYP inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Rifamycins: (Minor) Rifamycins may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. For example, rifampicin is a strong CYP3A and CYP2C8 inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    St. John's Wort, Hypericum perforatum: (Minor) St. John's Wort may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. St. John's Wort is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Warfarin: (Minor) Montelukast is reported by the manufacturer of warfarin to be a potential inducer of CYP1A2. The manufacturer of montelukast does not report an effect on CYP1A2 or on warfarin metabolism. As a precaution, monitor for clinical effectiveness and the international normalized ratio (INR) as per standard of care in a patient taking both drugs together.

    PREGNANCY AND LACTATION

    Pregnancy

    Published data from prospective and retrospective cohort studies of montelukast use during human pregnancy have not established a drug-associated risk of major birth defects. Some of these studies did have limitations including small sample size, retrospective design, and inconsistent comparator groups. In animal reproduction studies, no adverse developmental effects were observed with montelukast administration to pregnant rats and rabbits during organogenesis at oral doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs.[29630] The National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group list leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy. The Working Group states that leukotriene receptor antagonists may be considered for use during pregnancy for patients who had a favorable response prior to becoming pregnant.[45934]

    Montelukast may be used during breast-feeding when necessary. Montelukast is present in human milk. However, data available for infants exposed to montelukast either directly (for selected indications) or through breast milk do not suggest a significant risk of adverse effects. Montelukast is approved for use in infants 6 months and older and has been used in newborns in dosages that provide concentrations greater than the amounts in breastmilk. The effects of montelukast on human milk production are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for montelukast and any potential adverse effects on the breast-fed infant from montelukast or the underlying maternal condition.[29630] The National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group list leukotriene receptor antagonists, such as montelukast, as an alternative treatment option in the recommended stepwise management of asthma in lactating women.[45934]

    MECHANISM OF ACTION

    Montelukast is a potent and selective antagonist of leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1, found in the human airway. The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are important intermediaries of allergic airway disease. They are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils, in response to allergens. The binding of cysteinyl leukotrienes to CysLT has been associated with asthma pathophysiology, including chemoattraction of eosinophils, stimulation of inflammatory mediators, increased endothelial membrane permeability leading to airway edema, smooth muscle contraction, and enhanced secretion of thick, viscous mucus. In addition, the cysteinyl leukotrienes prepare the immune system for future allergic response through dendritic cell maturation and migration. In allergic rhinitis, the cysteinyl leukotrienes are released from nasal mucosa in response to allergen exposure during early- and late-phase reactions, producing symptoms of sneezing, nasal itching, and late-stage congestion. Montelukast improves the signs and symptoms of asthma and allergic rhinitis by inhibiting the physiologic actions of LTD4 at the CysLT1 receptor. Clinically, the drug has been shown to inhibit early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively. Montelukast does not have agonist properties at leukotriene receptors and it does not antagonize smooth muscle contractions due to LTC4, acetylcholine, histamine, prostaglandin, or serotonin.

    PHARMACOKINETICS

    Montelukast is administered orally. Montelukast is more than 99% bound to plasma proteins. The drug has a small volume of distribution; animal studies indicate minimal distribution across the blood-brain barrier. Montelukast undergoes extensive hepatic metabolism; hepatic isozymes CYP2C8, CYP2C9, and CYP3A4 are involved. At clinically relevant concentrations, CYP2C8 appears to play a significant role in the metabolism of montelukast. Plasma concentrations of metabolites of montelukast are undetectable at steady state. Montelukast and its metabolites are excreted almost exclusively via the bile; less than 0.2% of the drug is excreted in urine. Mean elimination half-life (half-life) of montelukast is 2.7 to 5.5 hours in healthy young adults. The pharmacokinetic profile of montelukast in age-appropriate doses is similar in children 2 years or older, adolescents, and adults.[29630]
     
    Affected cytochrome P450 isoenzymes: CYP2C8, CYP2C9, and CYP3A4
    In vitro studies indicate that the hepatic microsomal isoenzyme CYP2C8 plays a major role in montelukast's metabolism, with CYP2C9 and CYP3A4 also contributing to a lesser degree. However, even potent inhibitors of CYP2C8/9 and/or CYP3A4 do not result in appreciable clinical differences in montelukast pharmacokinetics despite increased exposure, and no dosage adjustments are recommended during coadministration of such inhibitors. Strong inducers also have little effect on the clinical effect of the drug, though the manufacturer recommends monitoring to ensure efficacy. While in vitro studies have shown that montelukast is a rather potent inhibitor of CYP2C8, human in vivo data against sensitive CYP2C8 substrates indicate that inhibition of CYP2C8 substrate metabolism does not occur, and thus interactions with CYP2C8 substrates is unlikely. Other hepatic CYP450 isozymes are not inhibited.[29630] [31034] [32856] [34499] A mild induction of CYP1A2 by montelukast may occur, but is likely only to be relevant for a drug like warfarin; such interactions are not established.[28549]

    Oral Route

    Oral absorption of montelukast is rapid, with peak plasma concentrations occurring 3 to 4 hours after administration of a 10-mg film-coated tablet. For the 5-mg chewable tablet, peak concentrations are achieved 2 to 2.5 hours after administration to fasting adults. For the 4-mg chewable tablet, the mean maximal concentration is obtained 2 hours after administration in children 2 to 5 years of age in the fasted state. In the fasted state, the mean oral bioavailability is 64% for the film-coated tablet and 73% for the chewable tablet. The 4-mg oral granules dosage unit is bioequivalent to the 4-mg chewable tablet, when administered to adults in the fasting state. The comparative pharmacokinetics of two 5-mg chewable tablets versus one 10-mg regular tablet has not been evaluated. A standard meal does not affect the peak concentration or oral bioavailability of the film-coated tablet; mean bioavailability of the chewable tablet is reduced to 63% with food. However, the clinical efficacy of the chewable tablet is not affected by taking the medication with food. Therefore, all oral forms of montelukast may be administered without regard to meals.