T A B L E T S / C H E W A B L E T A B L E T S / O R A L G R A N U L E S Composition Each tablet/sachet contains: Active Ingredient Tablets: Each 10 mg Tablet contains 10.4 mg montelukast sodium, equivalent to 10mg free acid. Chewable Tablets: Each 5 mg chewable tablet contains 5.2 mg montelukast sodium, equivalent to 5 mg free acid. Each 4 mg chewable tablet contains 4.2 mg montelukast sodium, equivalent to 4 mg free acid. Oral Granules: Each sachet of 4 mg oral granules contains 4.2 mg montelukast sodium, equivalent to 4 mg free acid. Other Ingredients Tablets: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, red ferric oxide, yellow ferricoxide, and carnauba wax. Chewable Tablets: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, magnesium stearate. Oral granules: mannitol, hydroxypropyl cellulose, and magnesium stearate. Mechanism of Action Singulair (montelukast sodium, MSD), is a selective orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene CysLT1 receptor. Clinical Pharmacology Pharmacodynamics The cysteinyl leukotrienes (LTC4, LTD4, LTE4), are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is a potent, orally active compound that significantly improves parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or ß-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC4, LTD4, and LTE4 at the CysLT1 receptor without any agonist activity. In asthmatic patients, montelukast causes potent inhibition of airway cysteinyl leukotriene receptors, as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4. Doses as low as 5 mg, cause substantial blockage of LTD4- induced bronchoconstriction. Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the bronchodilation caused by a ß-agonist. Pharmacokinetics Absorption Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10-mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailiabilty is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. For the 5-mg chewable tablets, the Cmax is achieved 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73%. Food does not have a clinically important influence with chronic administration. For the 4-mg chewable tablet, Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The coadministration of applesauce or a standard meal with the oral granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC (1225.7 vs. 1223.1 ng.hr/mL with and without applesauce, respectively and 1191.8 vs. 1148.5 ng.hr/mL with and without a standard meal, respectively). Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable tablet, 5-mg chewable tablet, and 10- mg film-coated tablet were administered without regard to the timing of food ingestion. The safety of SINGULAIR was also demonstrated in a clinical study in which the 4-mg oral granules were administered without regard to the timing of food ingestion.
Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages
Compared with placebo, Singulair caused significant improvements in parameters of respiratory function (FEV1 and peak
8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier.
expiratory flow rate, PEFR) in each study and in the combined analysis (see Table 1 and Figure 1).
In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
Compared with placebo, Singulair significantly decreased the use of “as-needed” ß-agonist by 26.1% from baseline
Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of
compared with 4.6% in the placebo group, in the combined analysis. The decreases were also significant in each of the
montelukast are undetectable at steady state in adults and in pediatric patients. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4 and 2C9 are involved in the metabolismof montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of
Onset of Action and Maintenance of Benefits
montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
In each study and in the combined analysis, the treatment effect of Singulair, measured by daily dairy card parameters,including symptom scores, “as-needed” ß-agonist use, and PEFR measurements, was achieved after the first dose and was
maintained throughout the dosing interval (24 hours). Treatment effect also remained constant during continuous once-
The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast,
daily administration in extension studies for up to one year. Withdrawal of Singulair in asthmatic patients after 12 weeks
86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of
of continuous use did not cause rebound worsening of asthma (see also Effects on Exercise-induced Bronchoconstriction).
montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The
Effect Relative to Inhaled Corticosteroids
pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg.
In one of the two 12-week double-blind studies in adults (Multinational), Singulair was compared with inhaled
No difference in pharmacokinetics was noted between dosing in the morning or in the evening.
beclomethasone (200 µg twice daily with a spacer device). Singulair demonstrated a more rapid initial response although
During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%).
over the full duration of the study, beclomethasone provided a greater average treatment effect. However, a high percentof patients treated with Singulair achieved similar clinical responses compared with inhaled beclomethasone. Characteristics in PatientsGender: The pharmacokinetics of montelukast are similar in males and females. Pediatric Patients 6 to 14 Years of Age Elderly: The pharmacokinetic profile and the bioavailability of a single 10-mg oral dose of montelukast are similar in
The efficacy of Singulair in pediatric patients 6 to 14 years of age was demonstrated in one 8-week double-blind, placebo-
elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in
controlled study in 336 patients (201 treated with Singulair and 135 treated with placebo) using ß-agonist on an “as-
needed” basis. The mean baseline percent predicted FEV1 was 72% (approximate range, 45 to 90%) and approximately
Race: Pharmacokinetic differences due to race have not been studied. In clinical studies, there do not appear to be any
36% of the patients were on inhaled corticosteroids.
differences in clinically important effects.
Compared with placebo, Singulair, one 5-mg chewable tablet daily in the evening, significantly decreased the percent of
Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence
days asthma exacerbations occurred. Parents’ global asthma evaluations and the pediatric asthma-specific quality-of-life
of decreased metabolism of montelukast, resulting in approximately 41% higher mean montelukast area under the plasma
evaluations (in all domains, including normal daily activity and asthma symptoms) were significantly better with Singulair,
concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast is slightly prolonged compared
with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate
Compared with placebo, there was a significant improvement in morning FEV1 (8.7% versus 4.2% change from baseline
hepatic insufficiency. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score >9).
in the placebo group, p<0.001) and a significant decrease in total “as-needed” ß-agonist use (11.7% decrease from
Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast
baseline versus 8.2% increase from baseline in the placebo group, p≤0.050).
were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Adolescents and Pediatric Patients: The plasma concentration profile of montelukast following the 10-mg film-coated
tablet, is similar in adolescents 15 years of age and older and in young adults. The 10-mg film-coated tablet is
Effect of SINGULAIR, 10 mg Daily, on Parameters of Respiratory Function
recommended for use in patients 15 years of age and older. in Adults 15 Years and Older (Combined Analysis)
Pharmacokinetic studies show that the plasma profiles of the 4-mg oral granule formulation in pediatric patients 6 months
to 2 years of age, the 4-mg chewable tablet in pediatric patients 2 to 5 years of age, and the 5-mg chewable tablets in
pediatric patients 6 to 14 years of age were similar to the plasma profile of the 10-mg film-coated tablet in adults. Since
the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative
formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.
*Significantly better than placebo (p≤0.001)
Clinical Studies CLINICAL STUDIES - ASTHMA Adults 15 Years of Age and Older
The efficacy of Singulair for the chronic treatment of asthma in adults 15 years of age and older was demonstrated in two
Effect of SINGULAIR on Morning FEV1 in Adults Effect of SINGULAIR on “As-needed” (ß-agonist Use in
(US and Multinational) similarly designed 12-week double-blind, placebo-controlled studies in 1325 patients (795 treated
15 Years and Older (Combined Analysis) Adults 15 Years and Older (Combined Analysis)
with Singulair and 530 treated with placebo). Patients were symptomatic and using approximately 5 puffs of ß-agonistper day on an “as-needed” basis. The mean baseline percent of predicted forced expiratory volume in 1 second (FEV1 )
was 66% (approximate range, 40 to 90%). In these studies, asthma symptoms, asthma-related outcomes, respiratory
function, and “as-needed” ß-agonist use, were measured. Endpoints were analyzed in each study and in a combined
analysis, according to a prespecified data analysis plan.
The following clinical results were observed:
Asthma Symptoms and Asthma-related Outcomes
Singulair, 10 mg once daily in the evening, significantly improved measurements of patient-reported daytime symptoms
and nighttime awakenings in each study and in the combined analysis, compared with placebo. In patients with nocturnal
awakenings of at least 2 nights per week, Singulair reduced the nocturnal awakenings by 34% from baseline, significantly
better than the reduction of 14% for the placebo group (combined analysis).
Singulair, compared with placebo, significantly improved asthma-related outcome measurements. In the combined
analysis, Singulair, compared with placebo, decreased asthma attacks by 37%, corticosteroid rescue by 39%,discontinuations due to worsening asthma by 65%, asthma exacerbations by 38% and increased asthma-free days by 42%.
Physicians’ and patients’ global asthma evaluations and asthma-specific quality-of-life evaluations (in all domains,
including normal daily activity and asthma symptoms) were significantly better with Singulair compared with placebo ineach study and in the combined analysis.
Similar to the adult studies, the treatment effect was achieved after the first dose and remained constant during continuous
pediatric patients 6 to 14 years of age Singulair also significantly decreased peripheral blood eosinophils 13% over the 8-
once-daily administration in clinical studies for up to 6 months.
week treatment period, compared with placebo. In a 4-week, randomized, parallel group study (n=40) in adults, Singulair significantly decreased airway eosinophils (as
assessed in sputum) by 48% from baseline compared with an increase of 23% from baseline with placebo. In this study,
Two controlled clinical studies have demonstrated that montelukast did not affect the growth rate in prepubertal pediatric
peripheral blood eosinophils significantly decreased, and clinical asthma endpoints improved with treatment with Singulair.
patients with asthma. In a study of children aged 6 to 11 years, growth rate as measured by lower leg length growth, wassimilar in patients treated with montelukast 5 mg once daily for 3 weeks compared with placebo, and was significantly
CLINICAL STUDIES - SEASONAL ALLERGIC RHINITIS
lower in patients treated with inhaled budesonide (200 µg twice daily) for 3 weeks, compared with placebo. In a 56-
The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis was investigated in similarly designed
week study in children aged 6 to 8 years, linear growth rate was similar in patients treated with montelukast 5 mg once
randomized, 2-week, double-blind, placebo-controlled trials including 4924 patients (1751 patients were treated with
daily and placebo (LS means for montelukast and placebo: 5.67 and 5.64 cm/year, respectively), and was significantly
SINGULAIR). Patients were 15 years of age and older with a history of seasonal allergic rhinitis, a positive skin test to at
lower (LS mean: 4.86 cm/year) in patients treated with inhaled beclomethasone (200 µg twice daily), compared with
least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study initiation.
placebo [difference in LS means (95% CI): -0.78 (-1.06, -0.49) cm/year]. Both montelukast and beclomethasone versus
In a combined analysis of three pivotal studies, SINGULAIR 10-mg tablets administered to 1189 patients once daily in the
placebo demonstrated significant benefit in rescue medication use in these patients with mild asthma.
evening resulted in a statistically significant improvement in the primary endpoint, daytime nasal symptoms score, andits individual components (nasal congestion, rhinorrhea, nasal itching, and sneezing); nighttime symptoms score, and its
Pediatric Patients 12 Months to 5 Years of Age
individual components (nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings); daytime
The efficacy of SINGULAIR, one 4-mg chewable tablet daily in the evening, in pediatric patients 2 to 5 years of age was
eye symptoms score, and its individual components (tearing, itchy, red, and puffy eyes); global evaluations of allergic
demonstrated in a 12-week double-blind, placebo-controlled study in 689 patients (461 treated with SINGULAIR and 228
rhinitis by patients and by physicians; and composite symptoms score (composed of the daytime nasal and nighttime
treated with placebo). SINGULAIR significantly improved multiple asthma efficacy endpoints and improved parameters
symptoms scores), compared with placebo.
In a separate 4-week study in which SINGULAIR was administered once daily in the morning, the efficacy over the initial
SINGULAIR was significantly better compared with placebo in the following caregiver asthma diary efficacy endpoints:
2 weeks was significantly different from placebo and consistent with the effect observed in studies using evening dosing.
days with daytime asthma symptoms, daytime asthma symptom score (including coughing, wheezing, trouble breathing,
Additionally, the effect over the entire 4 weeks was consistent with the 2-week results.
and child activities), beta-agonist use, corticosteroid rescue, days without asthma, and overnight asthma symptoms
In patients with seasonal allergic rhinitis aged 15 years and older who received SINGULAIR, a median decrease of 13%
(p<0.05). Additionally, there was a favorable trend in treatment effect for the efficacy endpoint, asthma attack (p=0.107).
in peripheral blood eosinophil counts was noted, compared with placebo, over the double-blind treatment periods.
The physician's global assessment and the average of caregiver's and physician's global assessments of asthma were
The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age is supported
significantly better with SINGULAIR compared with placebo (p=0.007 and 0.015, respectively).
by extrapolation from the demonstrated efficacy in patients 15 years of age and older with seasonal allergic rhinitis as well as
A treatment effect was achieved after the first dose. In addition, total blood eosinophil counts were significantly decreased
the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.
(p=0.034). Efficacy of SINGULAIR is supported in pediatric patients 6 months to 2 years of age by extrapolation from the
demonstrated efficacy in patients 2 years of age and older with asthma, and is based on similar pharmacokinetic data, as
Singulair is indicated in adult and pediatric patients 12 months of age and older for the prophylaxis and chronic treatment
well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among
of asthma, including prevention of daytime and nighttime symptoms, the treatment of aspirin-sensitive asthmatic patients,
and the prevention of exercise-induced bronchoconstriction. Singulair is effective alone or in combination with other agents used in the maintenance treatment of chronic asthma. Effects in Patients on Concomitant Inhaled Corticosteroids
Singulair and inhaled corticosteroids may be used concomitantly with additive effects to control asthma or to reduce the
Separate studies in adults demonstrated the ability of Singulair to add to the clinical effect of inhaled corticosteroids, and
inhaled corticosteroid dose while maintaining clinical stability.
to allow steroid tapering when used concomitantly.
Singulair is indicated for the relief of daytime and nighttime symptoms of seasonal allergic rhinitis in adults and in
Three large studies demonstrated Singulair has additional benefits in patients taking corticosteroids.
pediatric patients 2 years of age and older.
In a randomized, placebo-controlled, parallel-group study (n=226), stable asthmatic patients on initial inhaledcorticosteroid doses of approximately 1600 mg per day, reduced their steroid use by approximately 37% during a placebo
run-in period. Singulair allowed a further 47% reduction in inhaled corticosteroid dose, compared with 30% for placebo,
Hypersensitivity to any component of this product.
over the 12-week active treatment period (p≤0.050). In another randomized, placebo-controlled, parallel-group study (n=642) in a similar population of patients maintained,
but not adequately controlled, on inhaled corticosteroids (beclomethasone 400 mg/day), Singulair provided additional
Use in Pregnancy
clinical benefit, compared with placebo. Complete abrupt removal of beclomethasone in patients receiving both
Singulair has not been studied in pregnant women. Singulair should be used during pregnancy only if clearly needed.
treatments caused clinical deterioration in some patients, suggesting that tapering inhaled corticosteroids as tolerated,
During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women
rather than abrupt removal of steroids, is preferred.
being treated with SINGULAIR during pregnancy. Most of these women were also taking other asthma medications during
In aspirin-sensitive asthmatic patients, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids,
their pregnancy. A causal relationship between these events and SINGULAIR has not been established.
a 4-week randomized, parallel-group study (n=80) demonstrated that Singulair, compared with placebo, resulted insignificant improvement in parameters of asthma control. Use in Breastfeeding It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution Effects on Exercise-induced Bronchoconstriction
should be exercised when Singulair is given to a nursing mother.
In a 12-week, parallel group study of 110 adult patients 15 years of age and older, Singulair, 10 mg, prevented exercise-induced bronchoconstriction (EIB) as demonstrated by significant inhibition of the following, compared with placebo:
Use in Pediatrics
Singulair has been studied in pediatric patients 6 months to 14 years of age (see Dosage and Administration). Safety and
1 over 60 minutes after exercise (as measured by the area under the % fall in
effectiveness in pediatric patients younger than 6 months of age have not been studied. Studies have shown that Singulair
1 versus time curve after exercise, AUC);
does not affect the growth rate of pediatric patients.
- the time to recovery to within 5% of the pre-exercise FEV1. Protection was consistent throughout the 12-week treatment period, indicating that tolerance did not occur. In a separate
Use in the Elderly
cross-over study, protection was observed after two once-daily doses.
In clinical studies, there were no age-related differences in the efficacy or safety profiles of Singulair.
In pediatric patients 6 to 14 years of age, using the 5-mg chewable tablet, an identically designed cross-over studydemonstrated similar protection, and the protection was maintained throughout the dosing interval (24 hours). Mutagenicity Montelukast sodium was found to be neither genotoxic nor mutagenic. Montelukast sodium was negative in the in vitro Effects on Asthmatic Inflammation
microbial mutagenesis assay and the V-79 mammalian cell mutagenesis assays, with and without metabolic activation.
Several studies have shown Singulair inhibits parameters of asthmatic inflammation. In a placebo-controlled, cross-over study
There was no evidence of genotoxicity in the in vitro alkaline elution assay in rat hepatocytes and the in vitro
(n=12), Singulair inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75 and 57%, respectively.
chromosomal aberration assays in Chinese hamster ovary cells, with or without a microsomal enzyme activation system.
Because inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effects of Singulair on
Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice after the
eosinophils in the peripheral blood and airway were examined. In Phase Ilb/III clinical studies in adults, Singulair
administration of oral doses of up to 1200 mg/kg body weight (3600 mg/m2), which represent 6000 times the
significantly decreased peripheral blood eosinophils approximately 15% from baseline, compared with placebo. In
recommended daily adult dose, based on an adult patient weight of 50 kg. Carcinogenicity Pediatric Patients 2 to 5 Years of Age with Asthma
Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in a 106-week study
SINGULAIR has been evaluated in 573 pediatric patients 2 to 5 years of age. In a 12-week, placebo-controlled clinical study, the
in rats, or at oral doses of up to 100 mg/kg/day in a 92-week study in mice. These doses are equivalent to 1000 times
only adverse experience reported as drug related in > 1% of patients treated with SINGULAIR and at a greater incidence than in
and 500 times the recommended adult human dose respectively, based on an adult patient weight of 50 kg.
patients treated with placebo was thirst. The incidence of thirst was not significantly different in the two treatment groups. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months
or longer, and 63 patients for 12 months or longer. With prolonged treatment, the adverse experience profile did not change.
Fertility and reproductive performance were not affected in studies with male rats given oral doses of up to 800mg/kg/day or with female rats given doses of up to 100 mg/kg/day. These dosages provide margins of 4000-fold and
Pediatric Patients 6 Months to 2 Years of Age with Asthma
500-fold respectively above the recommended adult human dose, based on an adult patient weight of 50 kg.
SINGULAIR has been evaluated in 175 pediatric patients 6 months to 2 years of age. In a 6-week, placebo-controlledclinical study, the adverse experiences reported as drug related in > 1% of patients treated with SINGULAIR and at a
greater incidence than in patients treated with placebo were diarrhea, hyperkinesia, asthma, eczematous dermatitis and
In developmental toxicity studies, there were no treatment-related adverse effects at doses up to
rash. The incidences of these adverse experiences were not significantly different in the two treatment groups.
400 mg/kg/day in rats, and up to 100 mg/kg/day in rabbits. Fetal exposure of montelukast sodium in rats and rabbitsdoes occur and significant concentrations of drug were observed in milk of lactating rats. Adults 15 Years of Age and Older with Seasonal Allergic Rhinitis SINGULAIR has been evaluated in 2199 adult patients 15 years of age and older for the treatment of seasonal allergic Adverse Reactions
rhinitis in clinical studies. SINGULAIR administered once daily in the morning or in the evening was generally well
Singulair has been generally well tolerated. Side effects, which usually were mild, generally did not require
tolerated with a safety profile similar to that of placebo. In placebo-controlled clinical studies, no adverse experiences
discontinuation of therapy. The overall incidence of side effects reported with Singulair was comparable to placebo.
reported as drug related in ≥1% of patients treated with SINGULAIR and at a greater incidence than in patients treatedwith placebo were observed. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that
Adults 15 Years of Age and Older with Asthma
observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.
In clinical studies, Singulair has been evaluated for safety in approximately 2900 adult patients 15 years of age and older. In placebo-controlled clinical studies, the following adverse experiences reported with Singulair occurred in ≥1% of
Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis
patients and at an incidence greater than or equal to that in patients treated with placebo, regardless of drug relationship:
SINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age for the treatment of seasonal allergic rhinitisin a 2-week, placebo-controlled, clinical study. SINGULAIR administered once daily in the evening was generally well
Table 2: Adverse Experiences Occurring in ≥1% of Patients with an Incidence ≥ to that in Patients
tolerated with a safety profile similar to that of placebo. In this study, no adverse experiences reported as drug related in
Treated with Placebo, Regardless of Drug Relationship
≥1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo were observed. Churg-Strauss Syndrom - See Precautions Post Marketing Experience
The following side effects have been reported in post-marketing use: hypersensitivity reactions (including anaphylaxis,
angioedema, rash, pruritus, urticaria and, very rarely, hepatic eosinophilic infiltration), erythema nodosum; dream abnormalities
and hallucinations, drowsiness, dizziness, psychomotor hyperactivity (including irritability, agitation including aggressive
behavior, restlessness, and tremor), depression, suicidal thinking and behavior (suicidality), insomnia, paraesthesia/hypoesthesia,
and very rarely seizure; nausea, vomiting, dyspepsia, diarrhea, increased ALT and AST, and very rarely cholestatic hepatitis;
arthralgia, myalgia including muscle cramps; increased bleeding tendency, bruising; palpitations; and edema. Precautions
The efficacy of oral Singulair for the treatment of acute asthma attacks has not been established. Therefore, oral Singulair
should not be used to treat acute asthma attacks. Patients should be advised to have appropriate rescue medication available.
In the event Singulair is added to a patient’s existing treatment regimen of inhaled corticosteroid, the dosage of the
corticosteroid should be reduced gradually and under medical supervision. Singulair should not be abruptly substituted
for inhaled or oral corticosteroids. (See Dosage and Administration).
When Singulair is added to a bronchodilator therapy, the dosage of the bronchodilator can be reduced as tolerated
In rare cases, patients on therapy with Singulair may present with systemic eosinophilia, sometimes presenting with
clinical features of vasculitis consistent with the Churg-Strauss syndrome, a condition which is often treated with systemic
corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral
corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal association between Singulair and these
underlying conditions has not been established.
* Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. Drug Interactions
Cumulatively, 544 patients were treated with Singulair for at least 6 months, 253 for one year and 21 for 2 years, in clinical
Singulair may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma,
studies. With prolonged treatment, the adverse experience profile did not change.
and in the treatment of allergic rhinitis. In drug-interaction studies, the recommended clinical dose of montelukast didnot have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone,
Pediatric Patients 6 to 14 Years of Age with Asthma
prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
Singulair has been evaluated for safety in approximately 475 pediatric patients 6 to 14 years of age. The safety profile in
Although additional specific interaction studies were not performed, Singulair was used concomitantly with a wide range of
pediatric patients is generally similar to the adult safety profile and to placebo. In an 8-week, placebo-controlled clinical
commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included
study, the only adverse experience reported as drug-related in > 1% of patients treated with SINGULAIR and at a greater
thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents, benzodiazepines and decongestants.
incidence than in patients treated with placebo was headache. The incidence of headache was not significantly different
The area under the plasma concentration-time curve (AUC) for montelukast was decreased approximately 40% in subjects
with co-administration of phenobarbital. No dosage adjustment for Singulair is recommended.
In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile
In vitro studies have shown that montelukast is an inhibitor of CYP 2C8. However, data from a clinical drug-drug
interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized
Cumulatively, 263 pediatric patients 6 to 14 years of age were treated with Singulair for at least 3 months, 164 for 6 months
by CYP2C8 demonstrated that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to
or longer, in clinical trials. With prolonged treatment, the adverse experience profile did not change.
alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, repaglinide). Information for Patients Patients should be advised to take Singulair daily as prescribed, even when they are asymptomatic, as well as during periods of asthma worsening, and to contact their physician if their asthma is not well controlled. Patients should be advised that Singulair is not intended for the treatment of acute asthma attacks, and that they should have appropriate rescue medication available. Dosage and Administration General Recommendations The therapeutic effect of Singulair on parameters of asthma control occurs within one day. Singulair may be taken with or without food. Patients should be advised to continue taking Singulair while their asthma is controlled, as well as during periods of worsening asthma. Note No dosage adjustment is necessary for pediatric patients, for the elderly, for patients with renal insufficiency or mild-to- moderate hepatic impairments or for patients of either gender. SINGULAIR should be taken once daily. For asthma, the dose should be taken in the evening. For seasonal allergic rhinitis, the time of administration may be individualized to suit patient needs. Patients with both asthma and seasonal allergic rhinitis should take only one tablet daily in the evening. Adults 15 Years of Age and Older with Asthma and/or Seasonal Allergic RhinitisThe dosage for adults 15 years of age and older is one 10-mg tablet daily.
Pediatric Patients 6 to 14 Years of Age with Asthma and/or Seasonal Allergic RhinitisThe dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily.
Pediatric Patients 2 to 5 Years of Age with Asthma and/or Seasonal Allergic RhinitisThe dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet daily or one sachet of 4-mg oral granules daily. Pediatric Patients 12 Months to 2 Years of Age with AsthmaThe dosage for pediatric patients 12 months to 2 years of age is one sachet of 4-mg oral granules daily. Administration of oral granules:SINGULAIR oral granules can be administered either directly in the mouth, mixed with a spoonful of cold or room temperaturesoft food (e.g., applesauce), or dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk. The sachet should not be opened until ready to use. After opening the sachet, the full dose of SINGULAIR oral granules mustbe administered immediately (within 15 minutes). If mixed with food, or dissolved in baby formula or breast milk, SINGULAIRoral granules must not be stored for future use. SINGULAIR oral granules are not intended to be dissolved in any liquid otherthan baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. Therapy with Singulair in Relation to Other Treatments for Asthma Singulair can be added to a patient’s existing treatment regimen. Reduction in Concomitant Therapy:Bronchodilators: Singulair can be added to the treatment regimen of patients who are not adequately controlled onbronchodilator therapy alone. When a clinical response is evident (usually after the first dose), the patient’sbronchodilator therapy can be reduced as tolerated. Inhaled Corticosteroids: Treatment with Singulair provides additional clinical benefit to patients treated with inhaledcorticosteroids. A reduction in the corticosteroid dose can be made as tolerated. The dose should be reduced graduallyand with medical supervision. In some patients, the dose of inhaled corticosteroids can be tapered off completely. Singulair should not be abruptly substituted for inhaled or oral corticosteroids. Overdosage No specific information is available on the treatment of overdosage with Singulair. In chronic asthma studies, Singulair was administered at doses up to 200 mg/day to adult patients for 22 weeks and in short-term studies up to 900 mg/day to patients for approximately one week, without clinically important adverse experiences. There have been reports of acute overdosage in postmarketing experience and clinical studies with SINGULAIR. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Singulair and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. It is not known whether montelukast is dialyzable by peritoneal-or hemodialysis.
Manufactured by Merck, Sharp & Dohme B.V., Haarlem, Netherlands
for Merck, Sharp & Dohme (Israel-1996) Company Ltd.,
P.O.Box 7121 Petah-Tikva, 49170, Israel.
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