FDA Drug Approvals
New Indication for Singulair (montelukast sodium) Approved to Prevent Exercise-induced Bronchoconstriction
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Apr 25, 2007 - Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved a new indication for SINGULAIR(R) (montelukast sodium) to prevent exercise-induced bronchoconstriction (EIB; also known as exercise-induced asthma) in patients aged 15 years and older. SINGULAIR is the first and only oral tablet approved for this use.EIB is typically characterized by shortness of breath, cough, wheeze and chest tightness brought on by exercise. "EIB affects a broad spectrum of the asthma population. EIB limits the ability to participate in exercise or physical activities," said David S. Pearlman, M.D., Colorado Allergy and Asthma Centers, P.C. "This indication for SINGULAIR offers physicians a new and effective option to treat appropriate patients with EIB. Asthma is a complex disease, and a variety of treatment options are needed to manage different patients."
In clinical studies, a single tablet of SINGULAIR 10 mg prevented EIB when taken two hours before exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. SINGULAIR should not be taken for the immediate relief of asthma attacks. Patients should always have their inhaled rescue medicine available.
In addition to now being approved for use prior to exercise in appropriate patients with EIB, SINGULAIR continues to be an option for the prevention and chronic treatment of asthma in adults and pediatric patients 12 months of age and older. Patients already taking one tablet daily for another indication, including chronic asthma, should not take an additional dose to prevent EIB. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
SINGULAIR prevented EIB in clinical studies
The efficacy of SINGULAIR 10 mg when given as a single dose two hours before exercise for the prevention of EIB was evaluated in three randomized, double-blind, placebo-controlled crossover studies in 160 patients aged 15 years and older with EIB. In these studies, the primary endpoint was the mean maximum percent fall in FEV1 (Forced Expiratory Volume in the first second - an important measure of pulmonary function) following exercise at two hours after dosing.
In one study, patients exercised two hours, 8.5 hours, and 24 hours after taking either a single 10-mg dose of SINGULAIR or placebo. In this study, a single dose of SINGULAIR 10 mg demonstrated a statistically significant protective benefit against EIB when taken two hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. Results in this study were representative of the results from the other two studies.
The safety profile of SINGULAIR in these EIB studies was consistent with the safety profile previously described for SINGULAIR. In previous clinical studies, side effects in adults and children taking SINGULAIR were usually mild and generally did not cause patients to discontinue therapy. The most commonly reported side effects varied by age and included headache, ear infection, sore throat and upper respiratory infection.
Dosage and administration for EIB in patients 15 years of age and older
For prevention of EIB, a single dose of SINGULAIR should be taken at least two hours before exercise. An additional dose of SINGULAIR should not be taken within 24 hours of a previous dose. Patients already taking one tablet daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have inhaled rescue medication available. Safety and effectiveness of SINGULAIR for EIB in patients younger than 15 years of age have not been established. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
Important information about SINGULAIR
SINGULAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older, for the relief of symptoms of seasonal allergic rhinitis (SAR) in adults and children two years and older, and for the relief of symptoms of perennial allergic rhinitis (PAR) in adults and children six months and older. SINGULAIR is indicated for prevention of EIB in patients 15 years of age and older.
The use of SINGULAIR for chronic treatment of asthma may not eliminate the need for inhaled or oral corticosteroids. While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids. Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR. Patients should be advised to take SINGULAIR daily as prescribed for chronic treatment of asthma even when they have no symptoms, as well as during periods of worsening asthma, and to contact their physician if their asthma is not well controlled. Patients taking SINGULAIR daily for chronic asthma or allergic rhinitis should speak to their physician about treatment for their EIB.
About exercise-induced bronchoconstriction (EIB)
EIB is a condition typically found in patients with asthma. During bronchoconstriction induced by exercise, the smooth muscle that surrounds the airways in the lungs contracts, narrowing the airways and blocking the flow of air. This may be due to loss of heat, water or both from the lungs as breathing becomes deeper and faster during exercise. However, the underlying mechanism of EIB remains the subject of active scientific investigation. Typically, EIB starts after several minutes of physical activity and reaches peak five to 10 minutes after exercise, usually resolving spontaneously to some degree within an hour.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
SINGULAIR(R) (montelukast sodium) is a registered trademark of Merck & Co., Inc.
Prescribing information and patient product information for SINGULAIR are attached. -0-
9628409
SINGULAIR(R)
(Montelukast Sodium)
Tablets, Chewable Tablets, and Oral Granules
DESCRIPTION
Montelukast sodium, the active ingredient in SINGULAIR*, is a
selective and orally active leukotriene receptor antagonist that
inhibits the cysteinyl leukotriene CysLT1 receptor.
Montelukast sodium is described chemically as
(R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-
(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic
acid, monosodium salt.
The empirical formula is C35H35ClNNaO3S, and its molecular weight
is 608.18. The structural formula is:
(GRAPHIC OMITTED)
Montelukast sodium is a hygroscopic, optically active, white to
off-white powder. Montelukast sodium is freely soluble in ethanol,
methanol, and water and practically insoluble in acetonitrile.
Each 10-mg film-coated SINGULAIR tablet contains 10.4 mg
montelukast sodium, which is equivalent to 10 mg of montelukast, and
the following inactive ingredients: microcrystalline cellulose,
lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose,
and magnesium stearate. The film coating consists of: hydroxypropyl
methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric
oxide, yellow ferric oxide, and carnauba wax.
Each 4-mg and 5-mg chewable SINGULAIR tablet contains 4.2 and
5.2 mg montelukast sodium, respectively, which are equivalent to 4 and
5 mg of montelukast, respectively. Both chewable tablets contain the
following inactive ingredients: mannitol, microcrystalline cellulose,
hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium,
cherry flavor, aspartame, and magnesium stearate.
Each packet of SINGULAIR 4-mg oral granules contains 4.2 mg
montelukast sodium, which is equivalent to 4 mg of montelukast. The
oral granule formulation contains the following inactive ingredients:
mannitol, hydroxypropyl cellulose, and magnesium stearate.
CLINICAL PHARMACOLOGY
Mechanism of Action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of
arachidonic acid metabolism and are released from various cells,
including mast cells and eosinophils. These eicosanoids 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 airway
edema, smooth muscle contraction, and altered cellular activity
associated with the inflammatory process. 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.
SINGULAIR has not been assessed in intranasal challenge studies. The
clinical relevance of intranasal challenge studies is unknown.
Montelukast is an orally active compound that binds with high
affinity and selectivity to the CysLT1 receptor (in preference to
other pharmacologically important airway receptors, such as the
prostanoid, cholinergic, or (beta)-adrenergic receptor). Montelukast
inhibits physiologic actions of LTD4 at the CysLT1 receptor without
any agonist activity.
Pharmacokinetics
Absorption
Montelukast is rapidly absorbed following oral administration.
After administration of the 10-mg film-coated tablet to fasted adults,
the mean peak montelukast plasma concentration (Cmax) is achieved in 3
to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral
bioavailability and Cmax are not influenced by a standard meal in the
morning.
For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to
2.5 hours after administration to adults in the fasted state. The mean
oral bioavailability is 73% in the fasted state versus 63% when
administered with a standard meal in the morning.
For the 4-mg chewable tablet, the mean 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
co-administration of the oral granule formulation with applesauce did
not have a clinically significant effect on the pharmacokinetics of
montelukast. A high fat meal in the morning did not affect the AUC of
montelukast oral granules; however, the meal decreased Cmax by 35% and
prolonged Tmax from 2.3 +/- 1.0 hours to 6.4 +/- 2.9 hours.
The safety and efficacy of SINGULAIR in patients with asthma were
demonstrated in clinical trials in which the 10-mg film-coated tablet
and 5-mg chewable tablet formulations were administered in the evening
without regard to the time of food ingestion. The safety of SINGULAIR
in patients with asthma was also demonstrated in clinical trials in
which the 4-mg chewable tablet and 4-mg oral granule formulations were
administered in the evening without regard to the time of food
ingestion. The safety and efficacy of SINGULAIR in patients with
seasonal allergic rhinitis were demonstrated in clinical trials in
which the 10-mg film-coated tablet was administered in the morning or
evening without regard to the time of food ingestion.
The comparative pharmacokinetics of montelukast when administered
as two 5-mg chewable tablets versus one 10-mg film-coated tablet have
not been evaluated.
Distribution
Montelukast is more than 99% bound to plasma proteins. The steady
state volume of distribution of montelukast averages 8 to 11 liters.
Studies in rats with radiolabeled montelukast indicate minimal
distribution across the blood-brain barrier. In addition,
concentrations of radiolabeled material at 24 hours postdose were
minimal in all other tissues.
Metabolism
Montelukast is extensively metabolized. In studies with
therapeutic doses, plasma concentrations of metabolites of montelukast
are undetectable at steady state in adults and pediatric patients.
In vitro studies using human liver microsomes indicate that
cytochromes P450 3A4 and 2C9 are involved in the metabolism of
montelukast. Clinical studies investigating the effect of known
inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin)
or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not
been conducted. Based on further in vitro results in human liver
microsomes, therapeutic plasma concentrations of montelukast do not
inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug
Interactions). In vitro studies have shown that montelukast is a
potent inhibitor of cytochrome P450 2C8; however, data from a clinical
drug-drug interaction study involving montelukast and rosiglitazone (a
probe substrate representative of drugs primarily metabolized by
CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo,
and therefore is not anticipated to alter the metabolism of drugs
metabolized by this enzyme (see Drug Interactions).
Elimination
The plasma clearance of montelukast averages 45 mL/min in healthy
adults. Following an oral dose of radiolabeled montelukast, 86% of the
radioactivity was recovered in 5-day fecal collections and greater
than 0.2% was recovered in urine. Coupled with estimates of
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
pharmacokinetics of montelukast are nearly linear for oral doses up to
50 mg. During once-daily dosing with 10-mg montelukast, there is
little accumulation of the parent drug in plasma (14%).
Special Populations
Gender: The pharmacokinetics of montelukast are similar in males
and females.
Elderly: The pharmacokinetic profile and the oral bioavailability
of a single 10-mg oral dose of montelukast are similar in elderly and
younger adults. The plasma half-life of montelukast is slightly longer
in the elderly. No dosage adjustment in the elderly is required.
Race: Pharmacokinetic differences due to race have not been
studied.
Hepatic Insufficiency: Patients with mild-to-moderate hepatic
insufficiency and clinical evidence of cirrhosis had evidence of
decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%)
higher mean montelukast area under the plasma concentration curve
(AUC) following a single 10-mg dose. The elimination of montelukast
was 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 hepatic insufficiency. The pharmacokinetics of
SINGULAIR in patients with more severe hepatic impairment or with
hepatitis have not been evaluated.
Renal Insufficiency: Since montelukast and its metabolites are not
excreted in the urine, the pharmacokinetics of montelukast were not
evaluated in patients with renal insufficiency. No dosage adjustment
is recommended in these patients.
Adolescents and Pediatric Patients: Pharmacokinetic studies
evaluated the systemic exposure of the 4-mg oral granule formulation
in pediatric patients 6 to 23 months of age, the 4-mg chewable tablets
in pediatric patients 2 to 5 years of age, the 5-mg chewable tablets
in pediatric patients 6 to 14 years of age, and the 10-mg film-coated
tablets in young adults and adolescents (greater than or equal to) 15
years of age.
The plasma concentration profile of montelukast following
administration of the 10-mg film-coated tablet is similar in
adolescents (greater than or equal to) 15 years of age and young
adults. The 10-mg film-coated tablet is recommended for use in
patients (greater than or equal to) 15 years of age.
The mean systemic exposure of 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 is similar to the mean
systemic exposure of the 10-mg film-coated tablet in adults. The 5-mg
chewable tablet should be used in pediatric patients 6 to 14 years of
age and the 4-mg chewable tablet should be used in pediatric patients
2 to 5 years of age.
In children 6 to 11 months of age, the systemic exposure to
montelukast and the variability of plasma montelukast concentrations
were higher than those observed in adults. Based on population
analyses, the mean AUC (4296 ng--hr/mL (range 1200 to 7153)) was 60%
higher and the mean Cmax (667 ng/mL (range 201 to 1058)) was 89%
higher than those observed in adults (mean AUC 2689 ng--hr/mL (range
1521 to 4595)) and mean Cmax (353 ng/mL (range 180 to 548)). The
systemic exposure in children 12 to 23 months of age was less
variable, but was still higher than that observed in adults. The mean
AUC (3574 ng--hr/mL (range 2229 to 5408)) was 33% higher and the mean
Cmax (562 ng/mL (range 296 to 814)) was 60% higher than those observed
in adults. Safety and tolerability of montelukast in a single-dose
pharmacokinetic study in 26 children 6 to 23 months of age were
similar to that of patients two years and above (see ADVERSE
REACTIONS). The 4-mg oral granule formulation should be used for
pediatric patients 12 to 23 months of age for the treatment of asthma,
or for pediatric patients 6 to 23 months of age for the treatment of
perennial allergic rhinitis. 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.
Drug Interactions
Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic
steady state:
-- did not cause clinically significant changes in the kinetics
of a single intravenous dose of theophylline (predominantly a
cytochrome P450 1A2 substrate).
-- did not change the pharmacokinetic profile of warfarin
(primarily a substrate of CYP 2C9, 3A4 and 1A2) or influence
the effect of a single 30-mg oral dose of warfarin on
prothrombin time or the INR (International Normalized Ratio).
-- did not change the pharmacokinetic profile or urinary
excretion of immunoreactive digoxin.
-- did not change the plasma concentration profile of terfenadine
(a substrate of CYP 3A4) or fexofenadine, its carboxylated
metabolite, and did not prolong the QTc interval following
co-administration with terfenadine 60 mg twice daily.
Montelukast at doses of (greater than or equal to) 100 mg daily
dosed to pharmacokinetic steady state:
-- did not significantly alter the plasma concentrations of
either component of an oral contraceptive containing
norethindrone 1 mg/ethinyl estradiol 35 mcg.
-- did not cause any clinically significant change in plasma
profiles of prednisone or prednisolone following
administration of either oral prednisone or intravenous
prednisolone.
Phenobarbital, which induces hepatic metabolism, decreased the AUC
of montelukast approximately 40% following a single 10-mg dose of
montelukast. No dosage adjustment for SINGULAIR is recommended. It is
reasonable to employ appropriate clinical monitoring when potent
cytochrome P450 enzyme inducers, such as phenobarbital or rifampin,
are co-administered with SINGULAIR.
Montelukast is a potent inhibitor of P450 2C8 in vitro. However,
data from a clinical drug-drug interaction study involving montelukast
and rosiglitazone (a probe substrate representative of drugs primarily
metabolized by CYP2C8) in 12 healthy individuals demonstrated that the
pharmacokinetics of rosiglitazone are not altered when the drugs are
coadministered, indicating that montelukast does not inhibit CYP2C8
in vivo. Therefore, montelukast is not anticipated to alter the
metabolism of drugs metabolized by this enzyme (e.g., paclitaxel,
rosiglitazone, and repaglinide.)
Pharmacodynamics
Montelukast causes inhibition of airway cysteinyl leukotriene
receptors as demonstrated by the ability to inhibit
bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as
5 mg cause substantial blockage of LTD4-induced bronchoconstriction.
In a placebo-controlled, crossover study (n=12), SINGULAIR inhibited
early- and late-phase bronchoconstriction due to antigen challenge by
75% and 57%, respectively.
The effect of SINGULAIR on eosinophils in the peripheral blood was
examined in clinical trials. In patients with asthma aged 2 years and
older who received SINGULAIR, a decrease in mean peripheral blood
eosinophil counts ranging from 9% to 15% was noted, compared with
placebo, over the double-blind treatment periods. In patients with
seasonal allergic rhinitis aged 15 years and older who received
SINGULAIR, a mean increase of 0.2% in peripheral blood eosinophil
counts was noted, compared with a mean increase of 12.5% in
placebo-treated patients, over the double-blind treatment periods;
this reflects a mean difference of 12.3% in favor of SINGULAIR. The
relationship between these observations and the clinical benefits of
montelukast noted in the clinical trials is not known (see CLINICAL
PHARMACOLOGY, Clinical Studies).
Clinical Studies
GENERAL
There have been no clinical trials in asthmatics to evaluate the
relative efficacy of morning versus evening dosing. The
pharmacokinetics of montelukast are similar whether dosed in the
morning or evening. Efficacy has been demonstrated for asthma when
montelukast was administered in the evening without regard to time of
food ingestion. Efficacy was demonstrated for seasonal allergic
rhinitis when montelukast was administered in the morning or the
evening without regard to time of food ingestion.
Clinical Studies - Asthma
ADULTS AND ADOLESCENTS 15 YEARS OF AGE AND OLDER
Clinical trials in adults and adolescents 15 years of age and
older demonstrated there is no additional clinical benefit to
montelukast doses above 10 mg once daily. This was shown in two
chronic asthma trials using doses up to 200 mg once daily and in one
exercise challenge study using doses up to 50 mg, evaluated at the end
of the once-daily dosing interval.
The efficacy of SINGULAIR for the chronic treatment of asthma in
adults and adolescents 15 years of age and older was demonstrated in
two (U.S. and Multinational) similarly designed, randomized, 12-week,
double-blind, placebo-controlled trials in 1576 patients (795 treated
with SINGULAIR, 530 treated with placebo, and 251 treated with active
control). The patients studied were mild and moderate, non-smoking
asthmatics who required approximately 5 puffs of inhaled
(beta)-agonist per day on an "as-needed" basis. The patients had a
mean baseline percent of predicted forced expiratory volume in
1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary
endpoints in these trials were FEV1 and daytime asthma symptoms.
Secondary endpoints included morning and evening peak expiratory flow
rates (AM PEFR, PM PEFR), rescue (beta)-agonist requirements,
nocturnal awakening due to asthma, and other asthma-related outcomes.
In both studies after 12 weeks, a random subset of patients receiving
SINGULAIR was switched to placebo for an additional 3 weeks of
double-blind treatment to evaluate for possible rebound effects. The
results of the U.S. trial on the primary endpoint, FEV1, expressed as
mean percent change from baseline, are shown in FIGURE 1.
FIGURE 1
FEV1 Mean Percent Change from Baseline
(U.S. Trial)
(GRAPHIC OMITTED)
The effect of SINGULAIR on other primary and secondary endpoints
is shown in TABLE 1 as combined analyses of the U.S. and Multinational
trials.
TABLE 1
Effect of SINGULAIR on Primary and Secondary Endpoints
in Placebo-controlled Trials
(Combined Analyses - U.S. and Multinational Trials)
SINGULAIR Placebo
----------------------------------------------------------------------
Endpoint Baseline Mean Baseline Mean
Change Change
from from
Baseline Baseline
----------------------------------------------------------------------
Daytime Asthma Symptoms 2.43 -0.45* 2.45 -0.22
(0 to 6 scale)
----------------------------------------------------------------------
(beta)-agonist (puffs per day) 5.38 -1.56* 5.55 -0.41
----------------------------------------------------------------------
AM PEFR (L/min) 361.3 24.5* 364.9 3.3
----------------------------------------------------------------------
PM PEFR (L/min) 385.2 17.9* 389.3 2.0
----------------------------------------------------------------------
Nocturnal Awakenings 5.37 -1.84* 5.44 -0.79
(#/week)
----------------------------------------------------------------------
* p greater than 0.001, compared with placebo
In adult patients, SINGULAIR reduced "as-needed" (beta)-agonist
use by 26.1% from baseline compared with 4.6% for placebo. In patients
with nocturnal awakenings of at least 2 nights per week, SINGULAIR
reduced the nocturnal awakenings by 34% from baseline, compared with
15% for placebo (combined analysis).
SINGULAIR, compared with placebo, significantly improved other
protocol-defined, asthma-related outcome measurements (see TABLE 2).
TABLE 2
Effect of SINGULAIR on Asthma-Related Outcome Measurements
(Combined Analyses - U.S. and Multinational Trials)
SINGULAIR Placebo
----------------------------------------------------------------------
Asthma Attack* (% of patients) 11.6+ 18.4
----------------------------------------------------------------------
Oral Corticosteroid Rescue (% of patients) 10.7+ 17.5
----------------------------------------------------------------------
Discontinuation Due to Asthma (% of patients) 1.4++ 4.0
----------------------------------------------------------------------
Asthma Exacerbations** (% of days) 12.8+ 20.5
----------------------------------------------------------------------
Asthma Control Days*** (% of days) 38.5+ 27.2
----------------------------------------------------------------------
Physicians' Global Evaluation (score)ss. 1.77+ 2.43
----------------------------------------------------------------------
Patients' Global Evaluation (score)ss.ss. 1.60+ 2.15
----------------------------------------------------------------------
+ p greater than 0.001, compared with placebo
++ p greater than 0.01, compared with placebo
----------------------------------------------------------------------
* Asthma Attack defined as utilization of health-care resources
such as an unscheduled visit to a doctor's office, emergency room, or
hospital; or treatment with oral, intravenous, or intramuscular
corticosteroid.
** Asthma Exacerbation defined by specific clinically important
decreases in PEFR, increase in (beta)-agonist use, increases in day or
nighttime symptoms, or the occurrence of an asthma attack.
*** An Asthma Control Day defined as a day without any of the
following: nocturnal awakening, use of more than 2 puffs of
(beta)-agonist, or an asthma attack.
ss. Physicians' evaluation of the patient's asthma, ranging from 0
to 6 ("very much better" through "very much worse", respectively).
ss.ss. Patients' evaluation of asthma, ranging from 0 to 6 ("very
much better" through "very much worse", respectively).
In one of these trials, a non-U.S. formulation of inhaled
beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg
ex-valve) twice daily with a spacer device was included as an active
control. Over the 12-week treatment period, the mean percentage change
in FEV1 over baseline for SINGULAIR and beclomethasone were 7.49% vs
13.3% (p greater than 0.001) respectively, see FIGURE 2; and the
change in daytime symptom scores was -0.49 vs -0.70 on a 0 to 6 scale
(p greater than 0.001) for SINGULAIR and beclomethasone, respectively.
The percentages of individual patients treated with SINGULAIR or
beclomethasone achieving any given percentage change in FEV1 from
baseline are shown in FIGURE 3.
FIGURE 2 FIGURE 3
FEV1 FEV1
Mean Percent Change From Baseline Distribution of Individual Patient
Response
(Multinational Trial) (Multinational Trial)
(GRAPHIC OMITTED) (GRAPHIC OMITTED)
Onset of Action and Maintenance of Benefits
In each placebo-controlled trial in adults, the treatment effect
of SINGULAIR, measured by daily diary card parameters, including
symptom scores, "as-needed" (beta)-agonist use, and PEFR measurements,
was achieved after the first dose and was maintained throughout the
dosing interval (24 hours). No significant change in treatment effect
was observed during continuous once-daily evening administration in
non-placebo-controlled extension trials for up to one year. Withdrawal
of SINGULAIR in asthmatic patients after 12 weeks of continuous use
did not cause rebound worsening of asthma.
PEDIATRIC PATIENTS 6 TO 14 YEARS OF AGE
The efficacy of SINGULAIR in pediatric patients 6 to 14 years of
age was demonstrated in one 8-week, double-blind, placebo-controlled
trial in 336 patients (201 treated with SINGULAIR and 135 treated with
placebo) using an inhaled (beta)-agonist on an "as-needed" basis. The
patients had a mean baseline percent predicted FEV1 of 72%
(approximate range, 45 to 90%) and a mean daily inhaled (beta)-agonist
requirement of 3.4 puffs of albuterol. Approximately 36% of the
patients were on inhaled corticosteroids.
Compared with placebo, treatment with one 5-mg SINGULAIR chewable
tablet daily resulted in a significant improvement in mean morning
FEV1 percent change from baseline (8.7% in the group treated with
SINGULAIR vs 4.2% change from baseline in the placebo group, p greater
than 0.001). There was a significant decrease in the mean percentage
change in daily "as-needed" inhaled (beta)-agonist use (11.7% decrease
from baseline in the group treated with SINGULAIR vs 8.2% increase
from baseline in the placebo group, p greater than 0.05). This effect
represents a mean decrease from baseline of 0.56 and 0.23 puffs per
day for the montelukast and placebo groups, respectively. Subgroup
analyses indicated that younger pediatric patients aged 6 to 11 had
efficacy results comparable to those of the older pediatric patients
aged 12 to 14.
SINGULAIR, one 5-mg chewable tablet daily at bedtime,
significantly decreased the percent of days asthma exacerbations
occurred (SINGULAIR 20.6% vs placebo 25.7%, p(=)0.05). (See TABLE 2
for definition of asthma exacerbation.) Parents' global asthma
evaluations (parental evaluations of the patients' asthma, see TABLE 2
for definition of score) were significantly better with SINGULAIR
compared with placebo (SINGULAIR 1.34 vs placebo 1.69, p(=)0.05).
Similar to the adult studies, no significant change in the
treatment effect was observed during continuous once-daily
administration in one open-label extension trial without a concurrent
placebo group for up to 6 months.
PEDIATRIC PATIENTS 2 TO 5 YEARS OF AGE
The efficacy of SINGULAIR for the chronic treatment of asthma in
pediatric patients 2 to 5 years of age was explored in a 12-week,
placebo-controlled safety and tolerability study in 689 patients, 461
of whom were treated with SINGULAIR. While the primary objective was
to determine the safety and tolerability of SINGULAIR in this age
group, the study included exploratory efficacy evaluations, including
daytime and overnight asthma symptom scores, (beta)-agonist use, oral
corticosteroid rescue, and the physician's global evaluation. The
findings of these exploratory efficacy evaluations, along with
pharmacokinetics and extrapolation of efficacy data from older
patients, support the overall conclusion that SINGULAIR is efficacious
in the maintenance treatment of asthma in patients 2 to 5 years of
age.
EFFECTS IN PATIENTS ON CONCOMITANT INHALED CORTICOSTEROIDS
Separate trials in adults evaluated the ability of SINGULAIR to
add to the clinical effect of inhaled corticosteroids and to allow
inhaled corticosteroid tapering when used concomitantly.
One randomized, placebo-controlled, parallel-group trial (n=226)
enrolled stable asthmatic adults with a mean FEV1 of approximately 84%
of predicted who were previously maintained on various inhaled
corticosteroids (delivered by metered-dose aerosol or dry powder
inhalers). The types of inhaled corticosteroids and their mean
baseline requirements included beclomethasone dipropionate (mean dose,
1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day),
flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean
dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of
these inhaled corticosteroids were non-U.S.-approved formulations, and
doses expressed may not be ex-actuator. The pre-study inhaled
corticosteroid requirements were reduced by approximately 37% during a
5- to 7-week placebo run-in period designed to titrate patients toward
their lowest effective inhaled corticosteroid dose. Treatment with
SINGULAIR resulted in a further 47% reduction in mean inhaled
corticosteroid dose compared with a mean reduction of 30% in the
placebo group over the 12-week active treatment period (p(=)0.05).
Approximately 40% of the montelukast-treated patients and 29% of the
placebo-treated patients could be tapered off inhaled corticosteroids
and remained off inhaled corticosteroids at the conclusion of the
study (p=NS). It is not known whether the results of this study can be
generalized to asthmatics who require higher doses of inhaled
corticosteroids or systemic corticosteroids.
In another randomized, placebo-controlled, parallel-group trial
(n=642) in a similar population of adult patients previously
maintained, but not adequately controlled, on inhaled corticosteroids
(beclomethasone 336 mcg/day), the addition of SINGULAIR to
beclomethasone resulted in statistically significant improvements in
FEV1 compared with those patients who were continued on beclomethasone
alone or those patients who were withdrawn from beclomethasone and
treated with montelukast or placebo alone over the last 10 weeks of
the 16-week, blinded treatment period. Patients who were randomized to
treatment arms containing beclomethasone had statistically
significantly better asthma control than those patients randomized to
SINGULAIR alone or placebo alone as indicated by FEV1, daytime asthma
symptoms, PEFR, nocturnal awakenings due to asthma, and "as-needed"
(beta)-agonist requirements.
In adult asthmatic patients with documented aspirin sensitivity,
nearly all of whom were receiving concomitant inhaled and/or oral
corticosteroids, a 4-week, randomized, parallel-group trial (n=80)
demonstrated that SINGULAIR, compared with placebo, resulted in
significant improvement in parameters of asthma control. The magnitude
of effect of SINGULAIR in aspirin-sensitive patients was similar to
the effect observed in the general population of asthmatic patients
studied. The effect of SINGULAIR on the bronchoconstrictor response to
aspirin or other non-steroidal anti-inflammatory drugs in
aspirin-sensitive asthmatic patients has not been evaluated (see
PRECAUTIONS, General).
Clinical Studies - Exercise-Induced Bronchoconstriction
SINGLE-DOSE ADMINISTRATION (ADULTS AND ADOLESCENTS)
The efficacy of SINGULAIR, 10 mg, when given as a single dose 2
hours before exercise for the prevention of exercise-induced
bronchoconstriction (EIB) was investigated in three (U.S. and
Multinational), randomized, double-blind, placebo-controlled crossover
studies that included a total of 160 adult and adolescent patients 15
years of age and older with exercise-induced bronchoconstriction.
Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours,
and 24 hours following administration of a single dose of study drug
(SINGULAIR 10 mg or placebo). The primary endpoint was the mean
maximum percent fall in FEV1 following the 2 hours post-dose exercise
challenge in all three studies (Study A, Study B, and Study C). In
Study A, a single dose of SINGULAIR 10 mg demonstrated a statistically
significant protective benefit against EIB when taken 2 hours prior to
exercise. Some patients were protected from exercise-induced
bronchoconstriction at 8.5 and 24 hours after administration; however,
some patients were not. The results for the mean maximum percent fall
at each timepoint in Study A are shown in the TABLE 3 below and are
representative of the results from the other two studies.
TABLE 3
Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in
Study A (N=47)
Time of exercise Treatment
challenge following Mean Maximum percent difference % for
medication fall in FEV1* SINGULAIR versus
administration Placebo (95%CI)*
----------------------------------------------------------------------
SINGULAIR Placebo
----------------------------------------------------------------------
2 hours 13 22 -9 (-12, -5)
----------------------------------------------------------------------
8.5 hours 12 17 -5 (-9, -2)
----------------------------------------------------------------------
24 hours 10 14 -4 (-7, -1)
----------------------------------------------------------------------
*Least squares-mean
CHRONIC ADMINISTRATION (ADULTS AND PEDIATRIC PATIENTS)
In a 12-week, randomized, double-blind, parallel group study of
110 adult and adolescent asthmatics 15 years of age and older, with a
mean baseline FEV1 percent of predicted of 83% and with documented
exercise-induced exacerbation of asthma, treatment with SINGULAIR, 10
mg, once daily in the evening, resulted in a statistically significant
reduction in mean maximal percent fall in FEV1 and mean time to
recovery to within 5% of the pre-exercise FEV1. Exercise challenge was
conducted at the end of the dosing interval (i.e., 20 to 24 hours
after the preceding dose). This effect was maintained throughout the
12-week treatment period indicating that tolerance did not occur.
SINGULAIR did not, however, prevent clinically significant
deterioration in maximal percent fall in FEV1 after exercise (i.e.,
(greater than or equal to) 20% decrease from pre-exercise baseline) in
52% of patients studied. In a separate crossover study in adults, a
similar effect was observed after two once-daily 10-mg doses of
SINGULAIR.
In pediatric patients 6 to 14 years of age, using the 5-mg
chewable tablet, a 2-day crossover study demonstrated effects similar
to those observed in adults when exercise challenge was conducted at
the end of the dosing interval (i.e., 20 to 24 hours after the
preceding dose).
Daily administration of SINGULAIR for the chronic treatment of
asthma has not been established to prevent acute episodes of
exercise-induced bronchoconstriction.
Clinical Studies - Growth Rate in Pediatric Patients
A 56-week, multi-center, double-blind, randomized, active- and
placebo-controlled parallel group study was conducted to assess the
effect of SINGULAIR on growth rate in 360 patients with mild asthma,
aged 6 to 8 years. Treatment groups included SINGULAIR 5 mg once
daily, placebo, and beclomethasone dipropionate administered as 168
mcg twice daily with a spacer device. For each subject, a growth rate
was defined as the slope of a linear regression line fit to the height
measurements over 56 weeks. The primary comparison was the difference
in growth rates between SINGULAIR and placebo groups. Growth rates,
expressed as least-squares (LS) mean (95% CI) in cm/year, for the
SINGULAIR, placebo, and beclomethasone treatment groups were 5.67
(5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively.
The differences in growth rates, expressed as least-squares (LS) mean
(95% CI) in cm/year, for SINGULAIR minus placebo, beclomethasone minus
placebo, and SINGULAIR minus beclomethasone treatment groups were 0.03
(-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09),
respectively. Growth rate (expressed as mean change in height over
time) for each treatment group is shown in Figure 4.
FIGURE 4
Change in Height (cm) from Randomization Visit by Scheduled Week
(Treatment Group Mean +/- Standard Error+ of the Mean)
(GRAPHIC OMITTED)
+The standard errors of the treatment group means in change in height
are too small to be visible on the plot
Clinical Studies - Seasonal Allergic Rhinitis
The efficacy of SINGULAIR tablets for the treatment of seasonal
allergic rhinitis was investigated in 5 similarly designed,
randomized, double-blind, parallel-group, placebo- and
active-controlled (loratadine) trials conducted in North America. The
5 trials enrolled a total of 5029 patients, of whom 1799 were treated
with SINGULAIR tablets. Patients were 15 to 82 years of age with a
history of seasonal allergic rhinitis, a positive skin test to at
least one relevant seasonal allergen, and active symptoms of seasonal
allergic rhinitis at study entry.
The period of randomized treatment was 2 weeks in 4 trials and 4
weeks in one trial. The primary outcome variable was mean change from
baseline in daytime nasal symptoms score (the average of individual
scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as
assessed by patients on a 0-3 categorical scale.
Four of the five trials showed a significant reduction in daytime
nasal symptoms scores with SINGULAIR 10-mg tablets compared with
placebo. The efficacy results of one trial are shown below; the
remaining three trials that demonstrated efficacy showed similar
results. The mean changes from baseline in daytime nasal symptoms
score in the treatment groups that received SINGULAIR tablets,
loratadine and placebo are shown in TABLE 4.
TABLE 4
Effects of SINGULAIR on Daytime Nasal Symptoms Score* in a Placebo-
and Active-controlled Trial in Patients with Seasonal Allergic
Rhinitis
Difference Between
Treatment Group (N) Baseline Mean Change Treatment and
Mean Score from Baseline Placebo (95% CI)
Least-Squares Mean
----------------------------------------------------------------------
SINGULAIR 10 mg
(344) 2.09 -0.39 -0.13++ (-0.21, -0.06)
----------------------------------------------------------------------
Placebo
(351) 2.10 -0.26 N.A.
----------------------------------------------------------------------
Active Control+
(Loratadine 10 mg)
(599) 2.06 -0.46 -0.24++ (-0.31, -0.17)
----------------------------------------------------------------------
* Average of individual scores of nasal congestion, rhinorrhea,
nasal itching, sneezing as assessed by patients on a 0-3 categorical
scale.
+ The study was not designed for statistical comparison between
SINGULAIR and the active control (loratadine).
++ Statistically different from placebo (p(=)0.001).
Clinical Studies - Perennial Allergic Rhinitis
The efficacy of SINGULAIR tablets for the treatment of perennial
allergic rhinitis was investigated in 2 randomized, double-blind,
placebo-controlled studies conducted in North America and Europe. The
two studies enrolled a total of 3357 patients, of whom 1632 received
SINGULAIR 10-mg tablets. Patients 15 to 82 years of age with perennial
allergic rhinitis as confirmed by history and a positive skin test to
at least one relevant perennial allergen (dust mites, animal dander,
and/or mold spores), who had active symptoms at the time of study
entry, were enrolled.
In the study in which efficacy was demonstrated, SINGULAIR 10-mg
tablets once daily was shown to significantly reduce symptoms of
perennial allergic rhinitis over a 6-week treatment period (TABLE 5);
in this study the primary outcome variable was mean change from
baseline in daytime nasal symptoms score (the average of individual
scores of nasal congestion, rhinorrhea, and sneezing).
TABLE 5
Effects of SINGULAIR on Daytime Nasal Symptoms Score** in a Placebo-
controlled Trial in Patients with Perennial Allergic Rhinitis
Difference Between
Treatment Group (N) Baseline Mean Change Treatment and
Mean Score from Baseline Placebo (95% CI)
Least-Squares Mean
----------------------------------------------------------------------
SINGULAIR 10 mg
(1000) 2.09 -0.42 -0.08++ (-0.12, -0.04)
----------------------------------------------------------------------
Placebo
(980) 2.10 -0.35 N.A.
----------------------------------------------------------------------
** Average of individual scores of nasal congestion, rhinorrhea,
sneezing as assessed by patients on a 0-3 categorical scale.
++ Statistically different from placebo (p(=)0.001).
The other 6-week study evaluated SINGULAIR 10 mg (n=626), placebo
(n=609), and an active-control (cetirizine 10 mg; n=120). The primary
analysis compared the mean change from baseline in daytime nasal
symptoms score for SINGULAIR vs. placebo over the first 4 weeks of
treatment; the study was not designed for statistical comparison
between SINGULAIR and the active-control. The primary outcome variable
included nasal itching in addition to nasal congestion, rhinorrhea,
and sneezing. The estimated difference between SINGULAIR and placebo
was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference
between the active-control and placebo was -0.10 with a 95% CI of
(-0.19, -0.01).
INDICATIONS AND USAGE
SINGULAIR is indicated for the prophylaxis and chronic treatment
of asthma in adults and pediatric patients 12 months of age and older.
SINGULAIR is indicated for prevention of exercise-induced
bronchoconstriction in patients 15 years of age and older.
SINGULAIR is indicated for the relief of symptoms of allergic
rhinitis (seasonal allergic rhinitis in adults and pediatric patients
2 years of age and older, and perennial allergic rhinitis in adults
and pediatric patients 6 months of age and older).
CONTRAINDICATIONS
Hypersensitivity to any component of this product.
PRECAUTIONS
General
SINGULAIR is not indicated for use in the reversal of bronchospasm
in acute asthma attacks, including status asthmaticus.
Patients should be advised to have appropriate rescue medication
available. Therapy with SINGULAIR can be continued during acute
exacerbations of asthma. Patients who have exacerbations of asthma
after exercise should have available for rescue a short-acting inhaled
(beta)-agonist.
While the dose of inhaled corticosteroid may be reduced gradually
under medical supervision, SINGULAIR should not be abruptly
substituted for inhaled or oral corticosteroids.
Patients with known aspirin sensitivity should continue avoidance
of aspirin or non-steroidal anti-inflammatory agents while taking
SINGULAIR. Although SINGULAIR is effective in improving airway
function in asthmatics with documented aspirin sensitivity, it has not
been shown to truncate bronchoconstrictor response to aspirin and
other non-steroidal anti-inflammatory drugs in aspirin-sensitive
asthmatic patients (see CLINICAL PHARMACOLOGY, Clinical Studies).
Eosinophilic Conditions
In rare cases, patients with asthma on therapy with SINGULAIR may
present with systemic eosinophilia, sometimes presenting with clinical
features of vasculitis consistent with Churg-Strauss syndrome, a
condition which is often treated with systemic corticosteroid therapy.
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 (see ADVERSE REACTIONS).
Information for Patients
-- Patients should be advised to take SINGULAIR daily as
prescribed, even when they are asymptomatic, as well as during
periods of worsening asthma, and to contact their physicians
if their asthma is not well controlled.
-- Patients should be advised that oral SINGULAIR is not for the
treatment of acute asthma attacks. They should have
appropriate short-acting inhaled (beta)-agonist medication
available to treat asthma exacerbations. Patients who have
exacerbations of asthma after exercise should be instructed to
have available for rescue a short-acting inhaled
(beta)-agonist. Daily administration of SINGULAIR for the
chronic treatment of asthma has not been established to
prevent acute episodes of exercise-induced
bronchoconstriction.
-- Patients should be advised that, while using SINGULAIR,
medical attention should be sought if short-acting inhaled
bronchodilators are needed more often than usual, or if more
than the maximum number of inhalations of short-acting
bronchodilator treatment prescribed for a 24-hour period are
needed.
-- Patients receiving SINGULAIR should be instructed not to
decrease the dose or stop taking any other anti-asthma
medications unless instructed by a physician.
-- Patients with known aspirin sensitivity should be advised to
continue avoidance of aspirin or non-steroidal
anti-inflammatory agents while taking SINGULAIR.
Chewable Tablets
-- Phenylketonurics: Phenylketonuric patients should be informed
that the 4-mg and 5-mg chewable tablets contain phenylalanine
(a component of aspartame), 0.674 and 0.842 mg per 4-mg and
5-mg chewable tablet, respectively.
Drug Interactions
SINGULAIR has been administered with other therapies routinely
used in the prophylaxis and chronic treatment of asthma with no
apparent increase in adverse reactions. In drug-interaction studies,
the recommended clinical dose of montelukast did not have clinically
important effects on the pharmacokinetics of the following drugs:
theophylline, prednisone, prednisolone, oral contraceptives
(norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin,
and warfarin.
Although additional specific interaction studies were not
performed, SINGULAIR was used concomitantly with a wide range of
commonly prescribed drugs in clinical studies without evidence of
clinical adverse interactions. These medications included thyroid
hormones, sedative hypnotics, non-steroidal anti-inflammatory agents,
benzodiazepines, and decongestants.
Phenobarbital, which induces hepatic metabolism, decreased the AUC
of montelukast approximately 40% following a single 10-mg dose of
montelukast. No dosage adjustment for SINGULAIR is recommended. It is
reasonable to employ appropriate clinical monitoring when potent
cytochrome P450 enzyme inducers, such as phenobarbital or rifampin,
are co-administered with SINGULAIR.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of tumorigenicity was seen in carcinogenicity studies
of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral
gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The
estimated exposure in rats was approximately 120 and 75 times the area
under the plasma concentration versus time curve (AUC) for adults and
children, respectively, at the maximum recommended daily oral dose.
The estimated exposure in mice was approximately 45 and 25 times the
AUC for adults and children, respectively, at the maximum recommended
daily oral dose.
Montelukast demonstrated no evidence of mutagenic or clastogenic
activity in the following assays: the microbial mutagenesis assay, the
V-79 mammalian cell mutagenesis assay, the alkaline elution assay in
rat hepatocytes, the chromosomal aberration assay in Chinese hamster
ovary cells, and in the in vivo mouse bone marrow chromosomal
aberration assay.
In fertility studies in female rats, montelukast produced
reductions in fertility and fecundity indices at an oral dose of
200 mg/kg (estimated exposure was approximately 70 times the AUC for
adults at the maximum recommended daily oral dose). No effects on
female fertility or fecundity were observed at an oral dose of
100 mg/kg (estimated exposure was approximately 20 times the AUC for
adults at the maximum recommended daily oral dose). Montelukast had no
effects on fertility in male rats at oral doses up to 800 mg/kg
(estimated exposure was approximately 160 times the AUC for adults at
the maximum recommended daily oral dose).
Pregnancy, Teratogenic Effects
Pregnancy Category B:
No teratogenicity was observed in rats at oral doses up to
400 mg/kg/day (estimated exposure was approximately 100 times the AUC
for adults at the maximum recommended daily oral dose) and in rabbits
at oral doses up to 300 mg/kg/day (estimated exposure was
approximately 110 times the AUC for adults at the maximum recommended
daily oral dose). Montelukast crosses the placenta following oral
dosing in rats and rabbits. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, SINGULAIR should
be used during pregnancy only if clearly needed.
During worldwide marketing experience, congenital limb defects
have been rarely reported in the offspring of women being treated with
SINGULAIR during pregnancy. Most of these women were also taking other
asthma medications during their pregnancy. A causal relationship
between these events and SINGULAIR has not been established.
Merck & Co., Inc. maintains a registry to monitor the pregnancy
outcomes of women exposed to SINGULAIR while pregnant. Healthcare
providers are encouraged to report any prenatal exposure to SINGULAIR
by calling the Pregnancy Registry at (800) 986-8999.
Nursing Mothers
Studies in rats have shown that montelukast is excreted in milk.
It is not known if montelukast is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when
SINGULAIR is given to a nursing mother.
Pediatric Use
Safety and efficacy of SINGULAIR have been established in adequate
and well-controlled studies in pediatric patients with asthma 6 to
14 years of age. Safety and efficacy profiles in this age group are
similar to those seen in adults. (See Clinical Studies and ADVERSE
REACTIONS.)
The efficacy of SINGULAIR for the treatment of seasonal allergic
rhinitis in pediatric patients 2 to 14 years of age and for the
treatment of perennial allergic rhinitis in pediatric patients 6
months to 14 years of age is supported by extrapolation from the
demonstrated efficacy in patients 15 years of age and older with
allergic rhinitis as well as the assumption that the disease course,
pathophysiology and the drug's effect are substantially similar among
these populations.
The safety of SINGULAIR 4-mg chewable tablets in pediatric
patients 2 to 5 years of age with asthma has been demonstrated by
adequate and well-controlled data (see ADVERSE REACTIONS). Efficacy of
SINGULAIR in this age group is extrapolated from the demonstrated
efficacy in patients 6 years of age and older with asthma and is based
on similar pharmacokinetic data, as well as the assumption that the
disease course, pathophysiology and the drug's effect are
substantially similar among these populations. Efficacy in this age
group is supported by exploratory efficacy assessments from a large,
well-controlled safety study conducted in patients 2 to 5 years of
age.
The safety of SINGULAIR 4-mg oral granules in pediatric patients
12 to 23 months of age with asthma has been demonstrated in an
analysis of 172 pediatric patients, 124 of whom were treated with
SINGULAIR, in a 6-week, double-blind, placebo-controlled study (see
ADVERSE REACTIONS). Efficacy of SINGULAIR in this age group is
extrapolated from the demonstrated efficacy in patients 6 years of age
and older with asthma based on similar mean systemic exposure (AUC),
and that the disease course, pathophysiology and the drug's effect are
substantially similar among these populations, supported by efficacy
data from a safety trial in which efficacy was an exploratory
assessment.
The safety of SINGULAIR 4-mg and 5-mg chewable tablets in
pediatric patients aged 2 to 14 years with allergic rhinitis is
supported by data from studies conducted in pediatric patients aged 2
to 14 years with asthma. A safety study in pediatric patients 2 to 14
years of age with seasonal allergic rhinitis demonstrated a similar
safety profile (see ADVERSE REACTIONS). The safety of SINGULAIR 4-mg
oral granules in pediatric patients as young as 6 months of age with
perennial allergic rhinitis is supported by extrapolation from safety
data obtained from studies conducted in pediatric patients 6 months to
23 months of age with asthma and from pharmacokinetic data comparing
systemic exposures in patients 6 months to 23 months of age to
systemic exposures in adults.
The safety and effectiveness in pediatric patients below the age
of 12 months with asthma and 6 months with perennial allergic rhinitis
have not been established.
Geriatric Use
Of the total number of subje
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