MONTELUKAST SODIUM (Generic for SINGULAIR)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.
-In patients with asthma (with or without allergic rhinitis), administer montelukast in the evening. Although the pharmacokinetics of montelukast are similar when dosed in the morning or evening, there are no trials evaluating the efficacy of morning administration in asthma patients.
-In patients with allergic rhinitis (without asthma), administration time may be individualized to suit the patient's needs (e.g., morning or evening); administer at roughly the same time each day.
-In patients with exercise-induced bronchospasm (EIB), administer montelukast at least 2 hours before exercise. An additional dose should not be taken within 24 hours of a previous dose. Patients should have a short-acting beta-agonist (e.g., albuterol) readily available.
Oral Solid Formulations
-Oral 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, or ice cream. Do not dissolve in or mix with any other liquids or soft foods, other than those specified. Do not open the packet until ready to use. After opening the packet, the full dose should be administered within 15 minutes. Do not store unused granules or granules mixed with formula, breast milk, or food for future use. Liquids may be taken after administration.
-Chewable tablets: Chew tablet well prior to swallowing.
-Film-coated tablets: Swallow whole.

During initial clinical trials, montelukast was evaluated for safety in over 1,000 pediatric patients (ages 6 months to 14 years) and over 2,900 adolescent (>= 15 years) and adult patients, many of whom received the drug for at least 1 year. Overall, montelukast was well tolerated. The adverse reaction profile of montelukast is generally similar among pediatric and adult patients. Additionally, results from a 56-week multi-center, double-blind, randomized study did not suggest evidence of growth inhibition associated with montelukast use. Growth rates were similar in 360 asthmatic children (6 to 8 years old) receiving montelukast 5 mg per day or placebo; children receiving either montelukast or placebo had higher growth rates than those receiving inhaled beclomethasone. Post-marketing experience has produced a relatively high number of serious adverse event reports associated with montelukast use in pediatric patients. Of these reports, psychiatric effects (e.g., suicidal behaviors, aggression, and depressed mood) were predominant.

Neuropsychiatric events, including changes in mood or behavioral changes, have been reported in adolescent and pediatric patients taking montelukast. Postmarketing reports include, but are not limited to: agitation, aggressive behavior or hostility, anxiety, depression, disorientation (confusion), attention disturbance, abnormal dreams, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms (impulse control symptoms), restlessness, somnambulism, suicidal ideation and behavior (including suicide), drowsiness, seizures, tic, and tremor. Nightmares may be more common in children and typically resolve after drug discontinuation. In many cases, symptoms resolved after montelukast was discontinued, however, symptoms persisted after discontinuation in some cases. Although neuropsychiatric events were not commonly observed during clinical trials, the clinical details present in some of the postmarketing reports suggest a drug-induced effect, possibly related to the leukotriene pathway. Available data are insufficient to characterize at-risk patients. Advise patients to report changes in behavior and mood; consider alternate therapy if patients develop neuropsychiatric symptoms.

Upper respiratory tract infection, fever, pharyngitis, cough, otitis, otitis media, influenza, rhinorrhea, and sinusitis were among the most commonly reported adverse effects of montelukast in all populations during clinical trials, reported in >= 2% of pediatric patients. Viral infection, laryngitis, rhinitis (infective), varicella, acute bronchitis, otalgia, pneumonia, wheezing, and tonsillitis also occurred in >= 2% of pediatric patients. Nasal congestion (1.5%) and epistaxis (>= 1%) were reported in older patients (>= 15 years) during clinical trials for allergic rhinitis.

In rare cases, patients on montelukast may present with eosinophilia and clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition often treated with systemic corticosteroids. These events have sometimes been associated with systemic corticosteroid withdrawal. Patients presenting with eosinophilia, vasculitis with granulomas, worsening pulmonary symptoms, cardiac complications, and/or neuropathy may have this condition, which may be severe. Pulmonary eosinophilia has also been reported with post-marketing use. A causal relationship to montelukast has not been established; however, caution is advised when oral corticosteroid reduction is being considered in patients receiving montelukast.

During pre-marketing clinical trials, the incidence of elevated hepatic enzymes during montelukast treatment was not significantly different from patients taking placebo. ALT increased in 2.1% of montelukast-treated patients and 2% of placebo-treated patients; AST increased in 1.6% and 1.2% of patients, respectively. Increased ALT was also reported in >= 1% of patients in a clinical trial of adults and adolescents >= 15 years with perennial allergic rhinitis. According to the manufacturer, there are reports of eosinophilic infiltration of the liver (hypersensitivity hepatitis), and, in post-marketing experience, cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver-injury. Most of the post-marketing events occurred in patients who had underlying potential for liver disease.

Abdominal pain and diarrhea were among the most commonly reported adverse events in all populations during clinical trials of montelukast, occurring in >= 2% of pediatric patients. Nausea, dyspepsia, gastroenteritis, and dental caries also occurred in >= 2% of pediatric patients; dental pain (>= 1%) was reported in older patients (>= 15 years). Vomiting and pancreatitis have been reported during post-marketing use of montelukast; however, the frequency is unknown and causality to the drug has not been established.

Hypersensitivity reactions, including anaphylaxis (anaphylactoid reactions), angioedema, and pruritus have been reported during post-marketing use of montelukast; however, the frequency is unknown and causality to the drug has not been established. Urticaria has been reported during clinical trials of children with asthma aged 2 to 5 with an incidence rate >= 2%; it has also been reported post-marketing.

Rash (unspecified), atopic dermatitis, skin infection, and eczema have been reported at an incidence rate >= 2% during clinical trials of montelukast in pediatric patients. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, and ecchymosis have been reported during post-marketing use; however, the frequency is unknown and causality to the drug has not been established.

Asthenia (1.8%), fatigue (1.8%), and trauma (1%) have been reported in older adolescents (>= 15 years) and adults during clinical trials of montelukast for asthma. Arthralgia, myalgia, and muscle cramps have been reported with post-marketing use; however, the frequency is unknown and causality to the drug has not been established.

Myopia and conjunctivitis have been reported during clinical trials in pediatric patients taking montelukast with an incidence rate >= 2%.

Headache (2% or more) was one of the most commonly reported adverse effects in all populations during clinical trials of montelukast, occurring in 18% of older adolescents and adults. Dizziness (2%) was also reported in the older patient population. Paresthesias and hypoesthesia have been observed with postmarketing use; however, causality to the drug has not been established.

Pyuria was reported in 1% of older adolescents (>= 15 years) and adults during montelukast clinical trials for asthma. Increased bleeding tendency, thrombocytopenia, bruising, palpitations, edema, have been reported during post-marketing use; however, the frequency is unknown and causality to the drug has not been established.

Enuresis (night-time urinary incontinence) has been reported in children during post-marketing use of montelukast.

Montelukast is contraindicated in any patient with a known hypersensitivity to montelukast or any component of the product. The risk of allergic reaction is possible with any drug, although allergic reactions were uncommon in clinical trials of montelukast. Anaphylaxis, angioedema, rash, and urticaria have been reported in patients taking montelukast.

Montelukast is not effective for the treatment of acute asthma attacks, including status asthmaticus or acute bronchospasm. Thus, patients with asthma or exercise-induced bronchospasm (EIB) should be advised to have appropriate rescue medication (e.g., albuterol) available. 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 directed by their health care prescriber.

Montelukast is contraindicated for use in those patients with hypersensitivity to any product component. Montelukast chewable tablets contain phenylalanine and should be used with caution in patients with phenylketonuria. Before prescribing montelukast chewable tablets to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including montelukast.

Montelukast should be used cautiously in patients with hepatic disease. Though there are no recommended dose adjustments, pharmacokinetic studies in patients with mild to moderate hepatic impairment have demonstrated higher systemic exposure and a prolonged elimination half-life. Use caution in patients with severe hepatic impairment, jaundice, or hepatitis. Rarely, in patients with an underlying potential for hepatic disease (e.g., alcoholism or hepatitis), there have been post-marketing reports of cholestatic hepatitis, hepatocellular liver injury, or mixed pattern liver injury.

Use caution whenever oral corticosteroid withdrawal or dosage reduction is being considered in asthmatic patients. In rare cases, a systemic eosinophilic vasculitis consistent with Churg-Strauss syndrome has occurred in asthmatic patients receiving leukotriene-receptor antagonists. These events have sometimes been associated with oral corticosteroid dose reduction or corticosteroid withdrawal. Although a causal relationship to montelukast has not been established, prescribers should be alert to the presentation of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy in patients receiving montelukast. In addition, montelukast should not be abruptly substituted for inhaled or oral corticosteroids in asthma therapy. Corticosteroids may be gradually reduced; however, inhaled corticosteroids are the preferred treatment for persistent asthma.

Behavioral changes consistent with a neuro-psychiatric event have been reported in adult, adolescent, and pediatric patients taking montelukast, and some of these psychiatric and neurologic events appear to be consistent with a drug-related effect. A Boxed Warning was added to the montelukast prescribing information because of serious neuropsychiatric events 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. In many cases, symptoms resolved after montelukast was discontinued, however, symptoms persisted after discontinuation in some cases. Available data are insufficient to characterize at-risk patients. Advise patients and their caregivers to report changes in mood or behavior immediately. Discontinue montelukast immediately if neuropsychiatric systems occur and continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting montelukast treatment.

Description: Montelukast is an oral leukotriene receptor antagonist (LTRA). Unlike zafirlukast, montelukast does not inhibit CYP2C9 or CYP3A4 and has not been found to affect the hepatic clearance of drugs metabolized by these enzymes. Montelukast is primarily used for the chronic maintenance treatment of asthma, to prevent exercise-induced bronchoconstriction (EIB), and for the treatment of perennial and seasonal allergic rhinitis. In general, montelukast is well tolerated; however, serious psychiatric effects (e.g., suicidal behaviors, aggression, depression) have been prevalent in postmarketing reports. A boxed warning exists in the product label because of serious neuropsychiatric effects. Montelukast has the most substantial evidence for seasonal and perennial allergies of the LRTAs. 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. Rhinitis guidelines suggest montelukast should only be used for allergic rhinitis if there has been an inadequate response or intolerance to alternative therapies due to the risk for neuropsychiatric events and the reduced efficacy of LRTAs when compared to other agents. However, in patients with allergic rhinitis and comorbid asthma, an LTRA could be an option after weighing the benefits of LTRA monotherapy for both conditions versus an inhaled corticosteroid for asthma plus the addition of an antihistamine or intranasal corticosteroid for allergic rhinitis; the modest efficacy of montelukast and the drug's potential risks must be carefully considered. For asthma maintenance therapy, LTRAs are less effective than inhaled corticosteroids (ICSs) and are not a preferred asthma treatment for persistent asthma; however, they may be of benefit in patients with mild persistent asthma who are unwilling or unable to use ICS, experience intolerable ICS side effects, or have concomitant allergic rhinitis. In adolescents with moderate to severe persistent asthma taking ICS, LTRAs are considered an alternative add-on therapy option. In young children with asthma, LTRA therapy reduces symptoms and the need for oral corticosteroids when compared with placebo; however, the potential for montelukast side effects in children make this agent less desirable for pediatric use for asthma. For the prevention of exercise-induced bronchoconstriction (EIB), montelukast may be considered a first-line choice to add as a controller agent to an inhaled short-acting beta-2 agonist (SABA) to control EIB symptoms in patients who cannot be controlled by an inhaled SABA alone. Montelukast is FDA-approved for use in patients as young as 1 year of age for the maintenance treatment of asthma, as young as 2 years of age for treatment of seasonal allergic rhinitis, and in infants as young as 6 months with perennial allergic rhinitis. Montelukast is also used for preventing exercise-induced bronchoconstriction (EIB) in patients 6 years and older.

For asthma maintenance treatment:
Oral dosage (oral granules):
Children 1 to 5 years: 4 mg PO once daily in the evening.
Oral dosage (chewable tablets):
Children 2 to 5 years: 4 mg PO once daily in the evening.
Children and Adolescents 6 to 14 years: 5 mg PO once daily in the evening.
Oral dosage (oral tablets):
Adolescents 15 to 17 years: 10 mg PO once daily in the evening.

For exercise-induced bronchospasm prophylaxis:
Oral dosage (tablets):
Adolescents 15 to 17 years: 10 mg PO as a single dose at least 2 hours before exercise. Max: 10 mg/24 hours. Persons receiving daily montelukast for another indication should not take an additional dose to prevent exercise-induced bronchospasm. Rescue medications (e.g., beta-agonists) should be available.
Oral dosage (chewable tablets):
Children and Adolescents 6 to 14 years: 5 mg PO as a single dose at least 2 hours before exercise. Max: 5 mg/24 hours. Persons receiving daily montelukast for another indication should not take an additional dose to prevent exercise-induced bronchospasm. Rescue medications (e.g., beta-agonists) should be available.

For the treatment of allergic rhinitis (seasonal allergies and perennial allergies):
Oral dosage (oral granules):
Infants and Children 6 months and up to 2 years: 4 mg PO once daily in patients with perennial allergic rhinitis. NOTE: Montelukast is not FDA-approved for use in patients aged younger than 2 years with seasonal allergic rhinitis. 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.
Oral dosage (chewable tablet):
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.
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.
Oral dosage (oral tablet):
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.

For the treatment of mild to moderate obstructive sleep apnea*:
Oral dosage:
Children 2 to 5 years: 4 mg PO once daily at bedtime.
Children 6 to 10 years: 5 mg PO once daily at bedtime.

For the adjunctive treatment of refractory chronic idiopathic urticaria*:
Oral dosage:
Children and Adolescents: The addition of a leukotriene receptor antagonist, such as montelukast, to nonsedating 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 for children aged 5 years or younger, 5 mg for children 6 to 14 years, and 10 mg for adolescents aged 15 years or older).

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
< 6 months: Safety and efficacy have not been established.
>= 6 months: 4 mg/day PO.
-Children
1-5 years: 4 mg/day PO.
6-12 years: 5 mg/day PO.
-Adolescents
13-14 years: 5 mg/day PO.
>= 15 years: 10 mg/day PO.

Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for mild to moderate hepatic impairment. Montelukast has not been evaluated in patients with severe hepatic impairment or hepatitis; no dosage guidelines are available for these patients.

Patients with Renal Impairment Dosing
No dosage adjustments are recommended; montelukast is not significantly eliminated via the renal route.

*non-FDA-approved indication

Monograph content under development

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.

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. 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.


-Route-Specific Pharmacokinetics
Oral Route
Absorption of montelukast is rapid after oral administration. All oral forms of montelukast may be taken without regard to meals.

Oral granules
The 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet when administered in the fasted state. Co-administration with applesauce does not have a clinically significant pharmacokinetic effect. Administration of the oral granules with a high fat meal decreases Cmax by 35% and prolongs Tmax from 2.3 hours to 6.4 hours. However, the clinical efficacy of the oral granules is not affected by taking the medication with food.

Chewable tablet
The mean oral bioavailability of the 5 mg chewable tablet is 73%. Bioavailability is reduced by approximately 10% when administered with food; however, the clinical efficacy of the chewable tablet is not affected by taking the medication with food. Maximum plasma concentrations are obtained 2-2.5 hours after oral administration. The comparative pharmacokinetics of two 5 mg chewable tablets vs. one 10 mg film-coated tablet have not been evaluated.

Film-coated tablet
The mean oral bioavailability of the film-coated tablet is 64%. Maximum plasma concentrations are obtained 3-4 hours after oral administration. A standard meal does not affect the Cmax or oral bioavailability.


-Special Populations
Pediatrics
Infants >= 6 months
The systemic exposure to montelukast and variability of montelukast plasma concentrations are higher in infants than in adults. In infants aged 6-11 months, the mean AUC (4296 ng x hr/ml [range: 1200-7153]) was 60% higher and mean Cmax (667 ng/ml [range: 201-1058) was 89% higher than those observed in adults (mean AUC: 2689 ng x hr/ml [range: 1521-4595]; mean Cmax: 353 ng/ml [range: 180-548]). Safety and tolerability of montelukast in pediatric patients 6-23 months of age is similar to that of pediatric patients >= 2 years.

Children < 2 years
The systemic exposure to montelukast in children < 2 years is higher than in adults; however, it is less variable compared to infants. Mean AUC (3574 ng x hr/ml) was 33% higher and mean Cmax (562 ng/ml) was 60% higher than those observed in adults (mean AUC: 2689 ng x hr/ml; mean Cmax: 353 ng/ml). Safety and tolerability of montelukast in pediatric patients 6-23 months of age is similar to that of pediatric patients >= 2 years.

Children >= 2 years and Adolescents < 15 years
The mean systemic exposure of the chewable tablets in children and young adolescents is similar to that of adults receiving the film-coated tablets.

Adolescents >= 15 years
The plasma concentration profile of montelukast is similar in adolescents >= 15 years and young adults after oral administration of the 10 mg film-coated tablet.