Merck Announces US Label Change for SINGULAIR(R) (Montelukast Sodium): New Growth Data in Children; Clinical Study Shows Children Taking SINGULAIR Maintained Similar Growth Rates Compared with Children Taking Placebo.WHITEHOUSE Whitehouse may refer to:
An inhibitor that prevents leukotrienes from binding to cell receptors; taken over time, montelukast can reduce or prevent symptoms of asthma and allergies. (R) (montelukast sodium montelukast sodium Singulair Pharmacologic class: Leukotriene receptor antagonist Therapeutic class: Antiasthmatic Pregnancy risk category B Action), which includes new information from a 56-week clinical study that demonstrated that children with asthma asthma (ăz`mə, ăs`–), chronic inflammatory respiratory disease characterized by periodic attacks of wheezing, shortness of breath, and a tight feeling in the chest. A cough producing sticky mucus is symptomatic. (6-8 years of age) taking SINGULAIR 5 mg tablets once daily had similar growth rates Growth RatesThe compounded annualized rate of growth of a company's revenues, earnings, dividends, or other figures. Notes: Remember, historically high growth rates don't always mean a high rate of growth looking into the future. as children taking placebo placebo (pləsē`bō), inert substance given instead of a potent drug. Placebo medications are sometimes prescribed when a drug is not really needed or when one would not be appropriate because they make patients feel well taken care of. . In the same study, children taking the inhaled in·hale v. in·haled, in·hal·ing, in·hales v.tr. 1. To draw (air or smoke, for example) into the lungs by breathing; inspire. 2. steroid beclomethasone dipropionate bec·lo·meth·a·sone di·pro·pi·o·nate n. A corticosteroid usually used as an inhalant to treat asthma. beclomethasone dipropionate (bek´l 168 mcg twice daily had slower growth rates than children on either SINGULAIR or placebo. "The new label language provides physicians and patients with important new information on SINGULAIR that should prove helpful in furthering their understanding of the medicines used in the treatment of asthma," said Theodore Theodore. For Russian rulers thus named, use Feodor. F. Reiss REISS Research, Exchange and Impact for System Support , M.D., vice president, Clinical Research, Merck Research Laboratories. Study results Results from the 56 week, multi center, double-blind double blind n. A testing procedure, designed to eliminate biased results, in which the identity of those receiving a test treatment is concealed from both administrators and subjects until after the study is completed. , randomized ran·dom·ize tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es To make random in arrangement, especially in order to control the variables in an experiment. active and placebo controlled parallel group study of 360 patients with mild asthma showed that the differences in growth rates, expressed as least-squares (LS) mean (95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI)) in centimeters (cm)/year, for SINGULAIR minus placebo, beclomethasone beclomethasone /bec·lo·meth·a·sone/ (bek?lo-meth´ah-son) a glucocorticoid used in the dipropionate form in the treatment of bronchial asthma, seasonal and nonseasonal allergic rhinitis or other allergic or inflammatory nasal conditions, minus placebo, and SINGULAIR minus beclomethasone treatment groups were 0.03 (CI, -0.26, 0.31), -0.78 (CI, -1.06, -0.49); and 0.81 (CI, 0.53, 1.09), respectively. The primary comparison was the difference in growth rates between SINGULAIR and placebo groups. Growth rates, expressed as LS mean (95% CI) in cm/year, for the SINGULAIR, placebo, and beclomethasone treatment groups were 5.67 (CI, 5.46, 5.88), 5.64 (CI, 5.42, 5.86), and 4.86 (CI, 4.64, 5.08), respectively. Treatment groups included SINGULAIR 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. Important information about SINGULAIR for treatment of asthma The use of SINGULAIR for asthma may not eliminate the need for inhaled or oral corticosteroids Corticosteroids Definition Corticosteroids are group of natural and synthetic analogues of the hormones secreted by the hypothalamic-anterior pituitary-adrenocortical (HPA) axis, more commonly referred to as the pituitary gland. . Patients should be advised to take SINGULAIR daily as prescribed pre·scribe v. pre·scribed, pre·scrib·ing, pre·scribes v.tr. 1. To set down as a rule or guide; enjoin. See Synonyms at dictate. 2. To order the use of (a medicine or other treatment). even when they have no symptoms, as well as during periods of worsening wors·en tr. & intr.v. wors·ened, wors·en·ing, wors·ens To make or become worse. Noun 1. worsening - process of changing to an inferior state decline in quality, deterioration, declension asthma, and to contact their physician if their asthma is not well controlled. SINGULAIR should not be used for the fast relief of acute asthma attacks or used alone to treat and manage asthma made worse by exercise. Patients with known aspirin aspirin, acetyl derivative of salicylic acid (see salicylate) that is used to lower fever, relieve pain, reduce inflammation, and thin the blood. Common conditions treated with aspirin include headache, muscle and joint pain, and the inflammation caused by rheumatic sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory an·ti-in·flam·ma·to·ry or an·ti·in·flam·ma·to·ry adj. Reducing inflammation by acting on body mechanisms. an agents while taking SINGULAIR. In clinical studies for asthma, side effects Side effects Effects of a proposed project on other parts of the firm. in adults and children taking SINGULAIR were usually mild and generally did not cause patients to discontinue dis·con·tin·ue v. dis·con·tin·ued, dis·con·tin·u·ing, dis·con·tin·ues v.tr. 1. To stop doing or providing (something); end or abandon: therapy. The most commonly reported side effects varied by age and included headache headache Pain in the upper portion of the head. Episodic tension headaches are the most common, usually causing mild to moderate pain on both sides. They result from sustained contraction of face and neck muscles, often due to fatigue, stress, or frustration. , ear infection, sore throat Sore Throat Definition Sore throat, also called pharyngitis, is a painful inflammation of the mucous membranes lining the pharynx. It is a symptom of many conditions, but most often is associated with colds or influenza. and upper respiratory infection Noun 1. upper respiratory infection - infection of the upper respiratory tract respiratory infection, respiratory tract infection - any infection of the respiratory tract . SINGULAIR is indicated for the prophylaxis prophylaxis (prō'fĭlăk`sĭs), measures designed to prevent the occurrence of disease or its dissemination. Some examples of prophylaxis are immunization against serious diseases such as smallpox or diphtheria; quarantine to confine and chronic treatment of asthma in adults and pediatric patients pediatric patient Child, see there 12 months of age and older. About Merck Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in over 20 therapeutic categories. The company devotes extensive efforts to increase access to medicines through far-reaching far-reach·ing adj. Having a wide range, influence, or effect: the far-reaching implications of a major new epidemic. 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 Not-for-profit An organization established for charitable, humanitarian, or educational purposes that is exempt from some taxes and in which no one in profits or losses. service. For more information, visit www.merck.com. Forward-looking statement forward-looking statement A projected financial statement based on management expectations. A forward-looking statement involves risks with regard to the accuracy of assumptions underlying the projections. This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act The Private Securities Litigation Reform Act of 1995 (PSLRA) implemented several significant substantive changes affecting certain cases brought under the federal securities laws, including changes related to pleading, discovery, liability, class representation and awards fees and 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 cautionary statements in Item 1 of Merck's Form 10-K Form 10-K A report required by the SEC from exchange-listed companies that provides for annual disclosure of certain financial information. Form 10-K See 10-K. for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q Form 10-Q See 10-Q. and Form 8-K Form 8-K The form required by the SEC when a publicly held company incurs any event that might affect its financial situation or the share value of its stock. Form 8-K See 8-K. , which the company incorporates by reference. Prescribing information and patient product information for SINGULAIR are attached. SINGULAIR(R) (montelukast sodium) is a registered trademark of Merck & Co., Inc.
9088825
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). However, in vitro studies have shown that montelukast
is a potent inhibitor of cytochrome P450 2C8 (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 less 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, but no in vivo drug
interaction studies have been conducted between montelukast and
cytochrome P450 2C8 substrates. Caution should be exercised when
concomitantly administering a cytochrome P450 2C8 substrate, such as
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 - Asthma and Allergic Rhinitis (Seasonal and
Perennial)
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 (0 to 6
scale) 2.43 -0.45* 2.45 -0.22
--------------------------------------------------------
(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
(#/week) 5.37 -1.84* 5.44 -0.79
--------------------------------------------------------
* p less 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 less than 0.001, compared with placebo
++ p less 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 less 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 less
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
(Multinational Trial) Patient Response
(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 less
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 less 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 less than or equal to
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 less than or equal to 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 less than or
equal to 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).
EFFECTS ON EXERCISE-INDUCED BRONCHOCONSTRICTION (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).
SINGULAIR should not be used as monotherapy for the treatment and
management of exercise-induced bronchospasm. Patients who have
exacerbations of asthma after exercise should continue to use their
usual regimen of inhaled (beta)-agonists as prophylaxis and have
available for rescue a short-acting inhaled (beta)-agonist (see
PRECAUTIONS, General and Information for Patients).
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 3.
TABLE 3
Effects of SINGULAIR on Daytime Nasal Symptoms Score* in a Placebo-
and Active-controlled Trial in Patients with Seasonal Allergic
Rhinitis
Baseline Mean Difference Between
Treatment Group (N) Mean Change Treatment and Placebo
Score from (95% CI)
Baseline 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 less than or equal to
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 4);
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 4
Effects of SINGULAIR on Daytime Nasal Symptoms Score** in a Placebo-
controlled Trial in Patients with Perennial Allergic Rhinitis
Baseline Mean Difference Between
Treatment Group (N) Mean Change Treatment and Placebo
Score from (95% CI)
Baseline 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 less than or equal to
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 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.
While the dose of inhaled corticosteroid may be reduced gradually
under medical supervision, SINGULAIR should not be abruptly
substituted for inhaled or oral corticosteroids.
SINGULAIR should not be used as monotherapy for the treatment and
management of exercise-induced bronchospasm. Patients who have
exacerbations of asthma after exercise should continue to use their
usual regimen of inhaled (beta)-agonists as prophylaxis and have
available for rescue a short-acting inhaled (beta)-agonist.
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 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 who have exacerbations of asthma after exercise
should be instructed to continue to use their usual regimen of
inhaled (beta)-agonists as prophylaxis unless otherwise
instructed by their physician. All patients should have
available for rescue a short-acting inhaled (beta)-agonist.
-- 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.
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 subjects in clinical studies of
montelukast, 3.5% were 65 years of age and over, and 0.4% were 75
years of age and over. No overall differences in safety or
effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Adults and Adolescents 15 Years of Age and Older with Asthma
SINGULAIR has been evaluated for safety in approximately 2600
adult and adolescent patients 15 years of age and older in clinical
trials. In placebo-controlled clinical trials, the following adverse
experiences reported with SINGULAIR occurred in greater than or equal
to 1% of patients and at an incidence greater than that in patients
treated with placebo, regardless of causality assessment:
Adverse Experiences Occurring in greater than or equal to 1% of
Patients with an Incidence Greater than that in Patients Treated with
Placebo, Regardless of Causality Assessment
SINGULAIR Placebo
10 mg/day
(%) (%)
(n=1955) (n=1180)
----------------------------------------------------
Body As A Whole
Asthenia/fatigue 1.8 1.2
Fever 1.5 0.9
Pain, abdominal 2.9 2.5
Trauma 1.0 0.8
Digestive System Disorders
Dyspepsia 2.1 1.1
Gastroenteritis,
infectious 1.5 0.5
Pain, dental 1.7 1.0
Nervous System/Psychiatric
Dizziness 1.9 1.4
Headache 18.4 18.1
Respiratory System Disorders
Congestion, nasal 1.6 1.3
Cough 2.7 2.4
Influenza 4.2 3.9
Skin/Skin Appendages Disorder
Rash 1.6 1.2
Laboratory Adverse Experiences*
ALT increased 2.1 2.0
AST increased 1.6 1.2
Pyuria 1.0 0.9
----------------------------------------------------
* Number of patients tested (SINGULAIR and placebo, respectively):
ALT and AST, 1935, 1170; pyuria, 1924, 1159.
The frequency of less common adverse events was comparable between
SINGULAIR and placebo.
Cumulatively, 569 patients were treated with SINGULAIR for at
least 6 months, 480 for one year, and 49 for two years in clinical
trials. With prolonged treatment, the adverse experience profile did
not significantly change.
Pediatric Patients 6 to 14 Years of Age with Asthma
SINGULAIR has been evaluated for safety in 476 pediatric patients
6 to 14 years of age. Cumulatively, 289 pediatric patients were
treated with SINGULAIR for at least 6 months, and 241 for one year or
longer in clinical trials. The safety profile of SINGULAIR in the
8-week, double-blind, pediatric efficacy trial was generally similar
to the adult safety profile. In pediatric patients 6 to 14 years of
age receiving SINGULAIR, the following events occurred with a
frequency greater than or equal to 2% and more frequently than in
pediatric patients who received placebo, regardless of causality
assessment: pharyngitis, influenza, fever, sinusitis, nausea,
diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The
frequency of less common adverse events was comparable between
SINGULAIR and placebo. With prolonged treatment, the adverse
experience profile did not significantly change.
In studies evaluating growth rate, the safety profile in these
pediatric patients was consistent with the safety profile previously
described for SINGULAIR. In a 56-week, double-blind study evaluating
growth rate in pediatric patients 6 to 8 years of age receiving
SINGULAIR, the following events not previously observed with the use
of SINGULAIR in this age group occurred with a frequency greater than
or equal to 2% and more frequently than in pediatric patients who
received placebo, regardless of causality assessment: headache,
rhinitis (infective), varicella, gastroenteritis, atopic dermatitis,
acute bronchitis, tooth infection, skin infection, and myopia.
Pediatric Patients 2 to 5 Years of Age with Asthma
SINGULAIR has been evaluated for safety in 573 pediatric patients
2 to 5 years of age in single- and multiple-dose studies.
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 one year or longer in clinical trials. SINGULAIR 4 mg
administered once daily at bedtime was generally well tolerated in
clinical trials. In pediatric patients 2 to 5 years of age receiving
SINGULAIR, the following events occurred with a frequency greater than
or equal to 2% and more frequently than in pediatric patients who
received placebo, regardless of causality assessment: fever, cough,
abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis,
influenza, rash, ear pain, gastroenteritis, eczema, urticaria,
varicella, pneumonia, dermatitis, and conjunctivitis.
Pediatric Patients 6 to 23 Months of Age with Asthma
Safety and effectiveness in pediatric patients younger than 12
months of age with asthma have not been established.
SINGULAIR has been evaluated for safety in 175 pediatric patients
6 to 23 months of age. The safety profile of SINGULAIR in a 6-week,
double-blind, placebo-controlled clinical study was generally similar
to the safety profile in adults and pediatric patients 2 to 14 years
of age. SINGULAIR administered once daily at bedtime was generally
well tolerated. In pediatric patients 6 to 23 months of age receiving
SINGULAIR, the following events occurred with a frequency greater than
or equal to 2% and more frequently than in pediatric patients who
received placebo, regardless of causality assessment: upper
respiratory infection, wheezing; otitis media; pharyngitis,
tonsillitis, cough; and rhinitis. The frequency of less common adverse
events was comparable between SINGULAIR and placebo.
Adults and Adolescents 15 Years of Age and Older with Seasonal
Allergic Rhinitis
SINGULAIR has been evaluated for safety in 2199 adult and
adolescent patients 15 years of age and older in clinical trials.
SINGULAIR administered once daily in the morning or in the evening was
generally well tolerated with a safety profile similar to that of
placebo. In placebo-controlled clinical trials, the following event
was reported with SINGULAIR with a frequency greater than or equal to
1% and at an incidence greater than placebo, regardless of causality
assessment: upper respiratory infection, 1.9% of patients receiving
SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week,
placebo-controlled clinical study, the safety profile was consistent
with that observed in 2-week studies. The incidence of somnolence was
similar to that of placebo in all studies.
Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic
Rhinitis
SINGULAIR has been evaluated in 280 pediatric patients 2 to 14
years of age in a 2-week, multicenter, double-blind,
placebo-controlled, parallel-group safety study. SINGULAIR
administered once daily in the evening was generally well tolerated
with a safety profile similar to that of placebo. In this study, the
following events occurred with a frequency greater than or equal to 2%
and at an incidence greater than placebo, regardless of causality
assessment: headache, otitis media, pharyngitis, and upper respiratory
infection.
Adults and Adolescents 15 Years of Age and Older with Perennial
Allergic Rhinitis
SINGULAIR has been evaluated for safety in 3357 adult and
adolescent patients 15 years of age and older with perennial allergic
rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical
studies. SINGULAIR administered once daily was generally well
tolerated, with a safety profile consistent with that observed in
patients with seasonal allergic rhinitis and similar to that of
placebo. In these two studies, the following events were reported with
SINGULAIR with a frequency greater than or equal to 1% and at an
incidence greater than placebo, regardless of causality assessment:
sinusitis, upper respiratory infection, sinus headache, cough,
epistaxis, and increased ALT. The incidence of somnolence was similar
to that of placebo.
Pediatric Patients 6 Months to 14 Years of Age with Perennial
Allergic Rhinitis
The safety in patients 2 to 14 years of age with perennial
allergic rhinitis is supported by the established safety in patients 2
to 14 years of age with seasonal allergic rhinitis. The safety in
patients 6 to 23 months of age is supported by data from
pharmacokinetic and safety and efficacy studies in asthma in this
pediatric population and from adult pharmacokinetic studies.
Post-Marketing Experience
The following additional adverse reactions have been reported in
post-marketing use: hypersensitivity reactions (including anaphylaxis,
angioedema, pruritus, urticaria, and very rarely, hepatic eosinophilic
infiltration); dream abnormalities and hallucinations, drowsiness,
irritability, agitation including aggressive behavior, restlessness,
insomnia, paraesthesia/hypoesthesia, and very rarely seizures;
arthralgia, myalgia including muscle cramps; increased bleeding
tendency, bruising; palpitations; edema; nausea, vomiting, dyspepsia,
diarrhea, and very rarely pancreatitis. Rare cases of cholestatic
hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury
have been reported in patients treated with SINGULAIR. Most of these
occurred in combination with other confounding factors, such as use of
other medications, or when SINGULAIR was administered to patients who
had underlying potential for liver disease such as alcohol use or
other forms of hepatitis.
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 PRECAUTIONS, Eosinophilic Conditions).
OVERDOSAGE
No mortality occurred following single oral doses of montelukast
up to 5000 mg/kg in mice (estimated exposure was approximately 335 and
210 times the AUC for adults and children, respectively, at the
maximum recommended daily oral dose) and rats (estimated exposure was
approximately 230 and 145 times the AUC for adults and children,
respectively, at the maximum recommended daily oral dose).
No specific information is available on the treatment of
overdosage with SINGULAIR. In chronic asthma studies, montelukast has
been 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 a week without clinically important adverse experiences.
In the event of overdose, it is reasonable to employ the usual
supportive measures; e.g., remove unabsorbed material from the
gastrointestinal tract, employ clinical monitoring, and institute
supportive therapy, if required.
There have been reports of acute overdosage in pediatric patients
in post-marketing experience and clinical studies of up to at least
150 mg/day with SINGULAIR. The clinical and laboratory findings
observed were consistent with the safety profile in adults and older
pediatric patients. There were no adverse experiences reported in the
majority of overdosage reports. The most frequent adverse experiences
observed were thirst, somnolence, mydriasis, hyperkinesia, and
abdominal pain.
It is not known whether montelukast is removed by peritoneal
dialysis or hemodialysis.
DOSAGE AND ADMINISTRATION
General Information
SINGULAIR should be taken once daily. For asthma, the dose should
be taken in the evening. For allergic rhinitis, the time of
administration may be individualized to suit patient needs.
Patients with both asthma and allergic rhinitis should take only
one tablet daily in the evening.
Adults and Adolescents 15 Years of Age and Older with Asthma or
Allergic Rhinitis
The dosage for adults and adolescents 15 years of age and older is
one 10-mg tablet daily.
Pediatric Patients 6 to 14 Years of Age with Asthma or Allergic
Rhinitis
The dosage for pediatric patients 6 to 14 years of age is one 5-mg
chewable tablet daily. No dosage adjustment within this age group is
necessary.
Pediatric Patients 2 to 5 Years of Age with Asthma or Allergic
Rhinitis
The dosage for pediatric patients 2 to 5 years of age is one 4-mg
chewable tablet or one packet of 4-mg oral granules daily.
Pediatric Patients 12 to 23 Months of Age with Asthma
The dosage for pediatric patients 12 to 23 months of age is one
packet of 4-mg oral granules daily to be taken in the evening.
Pediatric Patients 6 to 23 Months of Age with Perennial Allergic
Rhinitis
The dosage for pediatric patients 6 to 23 months of age is one
packet of 4-mg oral granules daily.
Safety and effectiveness in pediatric patients younger than 6
months of age with perennial allergic rhinitis and in patients less
than 12 months of age with asthma have not been established.
Administration of SINGULAIR Oral Granules
SINGULAIR 4-mg oral granules can be administered either directly
in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room
temperature baby formula or breast milk, or mixed with a spoonful of
cold or room temperature soft foods; based on stability studies, only
applesauce, carrots, rice, or ice cream should be used. The packet
should not be opened until ready to use. After opening the packet, the
full dose (with or without mixing with baby formula, breast milk, or
food) must be administered within 15 minutes. If mixed with baby
formula, breast milk, or food, SINGULAIR oral granules must not be
stored for future use. Discard any unused portion. SINGULAIR oral
granules are not intended to be dissolved in any liquid other than
baby formula or breast milk for administration. However, liquids may
be taken subsequent to administration. SINGULAIR oral granules can be
administered without regard to the time of meals.
HOW SUPPLIED
No. 3841 -- SINGULAIR Oral Granules, 4 mg, are white granules with
500 mg net weight, packed in a child-resistant foil packet. They are
supplied as follows:
NDC 0006-3841-30 unit of use carton with 30 packets.
No. 3796 --SINGULAIR Tablets, 4 mg, are pink, oval,
bi-convex-shaped chewable tablets, with code MRK 711 on one side and
SINGULAIR on the other. They are supplied as follows:
NDC 0006-0711-31 unit of use high-density polyethylene (HDPE)
bottles of 30 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0711-54 unit of use high-density polyethylene (HDPE)
bottles of 90 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0711-28 unit dose paper and aluminum foil-backed aluminum
foil peelable blister packs of 100.
No. 3760 -- SINGULAIR Tablets, 5 mg, are pink, round,
bi-convex-shaped chewable tablets, with code MRK 275 on one side and
SINGULAIR on the other. They are supplied as follows:
NDC 0006-0275-31 unit of use high-density polyethylene (HDPE)
bottles of 30 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0275-54 unit of use high-density polyethylene (HDPE)
bottles of 90 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0275-28 unit dose paper and aluminum foil-backed aluminum
foil peelable blister packs of 100.
No. 3761 -- SINGULAIR Tablets, 10 mg, are beige, rounded
square-shaped, film-coated tablets, with code MRK 117 on one side and
SINGULAIR on the other. They are supplied as follows:
NDC 0006-0117-31 unit of use high-density polyethylene (HDPE)
bottles of 30 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0117-54 unit of use high-density polyethylene (HDPE)
bottles of 90 with a polypropylene child-resistant cap, an aluminum
foil induction seal, and silica gel desiccant
NDC 0006-0117-28 unit dose paper and aluminum foil-backed aluminum
foil peelable blister pack of 100
NDC 0006-0117-80 bulk packaging high-density polyethylene (HDPE)
bottles of 8000 with a non-child-resistant white plastic closure with
a wax paper/pulp liner, an aluminum foil induction seal, and silica
gel desiccant.
Storage
Store SINGULAIR 4-mg oral granules, 4-mg chewable tablets, 5-mg
chewable tablets and 10-mg film-coated tablets at 25(degree)C
(77(degree)F), excursions permitted to 15-30(degree)C (59-86(degree)F)
(see USP Controlled Room Temperature). Protect from moisture and
light. Store in original package.
Storage for Bulk Bottles
Store bottle of 8000 SINGULAIR 10-mg film-coated tablets at
25(degree)C (77(degree)F), excursions permitted to 15-30(degree)C
(59-86(degree)F) (see USP Controlled Room Temperature). Protect from
moisture and light. Store in original container. When product
container is subdivided, repackage into a well-closed, light-resistant
container.
Issued November 2005
Printed in USA
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT (C) 1998-2005 MERCK & CO., Inc.
All rights reserved
9094219
Patient Information
SINGULAIR(R) (SING-u-lair) Tablets, Chewable Tablets, and Oral
Granules
Generic name: montelukast (mon-te-LOO-kast) sodium
Read this information before you start taking SINGULAIR(R). Also,
read the leaflet you get each time you refill SINGULAIR, since there
may be new information in the leaflet since the last time you saw it.
This leaflet does not take the place of talking with your doctor about
your medical condition and/or your treatment.
What is SINGULAIR*
-- SINGULAIR is a medicine called a leukotriene receptor
antagonist. It works by blocking substances in the body called
leukotrienes. Blocking leukotrienes improves asthma and
allergic rhinitis. SINGULAIR is not a steroid. Studies have
shown that SINGULAIR does not affect the growth rate of
children. (See the end of this leaflet for more information
about asthma and allergic rhinitis.)
SINGULAIR is prescribed for the treatment of asthma and allergic
rhinitis:
1. Asthma.
SINGULAIR should be used for the long-term management of
asthma in adults and children ages 12 months and older.
Do not take SINGULAIR for the immediate relief of an asthma
attack. If you get an asthma attack, you should follow the
instructions your doctor gave you for treating asthma attacks.
2. Allergic Rhinitis.
SINGULAIR is used to help control the symptoms of allergic
rhinitis (sneezing, stuffy nose, runny nose, itching of the
nose). SINGULAIR is used to treat seasonal allergic rhinitis
(outdoor allergies that happen part of the year) in adults and
children ages 2 years and older, and perennial allergic
rhinitis (indoor allergies that happen all year) in adults and
children ages 6 months and older.
Who should not take SINGULAIR?
Do not take SINGULAIR if you are allergic to SINGULAIR or any of
its ingredients.
The active ingredient in SINGULAIR is montelukast sodium.
See the end of this leaflet for a list of all the ingredients in
SINGULAIR.
What should I tell my doctor before I start taking SINGULAIR?
Tell your doctor about:
-- Pregnancy: If you are pregnant or plan to become pregnant,
SINGULAIR may not be right for you.
-- Breast-feeding: If you are breast-feeding, SINGULAIR may
be passed in your milk to your baby. You should consult
your doctor before taking SINGULAIR if you are
breast-feeding or intend to breast-feed.
-- Medical Problems or Allergies: Talk about any medical
problems or allergies you have now or had in the past.
-- Other Medicines: Tell your doctor about all the medicines
you take, including prescription and non-prescription
medicines, and herbal supplements. Some medicines may
affect how SINGULAIR works, or SINGULAIR may affect how
your other medicines work.
How should I take SINGULAIR?
For adults and children 12 months of age and older with asthma:
-- Take SINGULAIR once a day in the evening.
-- Take SINGULAIR every day for as long as your doctor
prescribes it, even if you have no asthma symptoms.
-- You may take SINGULAIR with food or without food.
-- If your asthma symptoms get worse, or if you need to
increase the use of your inhaled rescue medicine for
asthma attacks, call your doctor right away.
-- Do not take SINGULAIR for the immediate relief of an
asthma attack. If you get an asthma attack, you should
follow the instructions your doctor gave you for
treating asthma attacks.
-- Always have your inhaled rescue medicine for asthma
attacks with you.
-- Do not stop taking or lower the dose of your other
asthma medicines unless your doctor tells you to.
-- If your doctor has prescribed a medicine for you to
use before exercise, keep using that medicine unless
your doctor tells you not to.
For adults and children 2 years of age and older with seasonal
allergic rhinitis, or for adults and children 6 months of age and
older with perennial allergic rhinitis:
-- Take SINGULAIR once a day, at about the same time each
day.
-- Take SINGULAIR every day for as long as your doctor
prescribes it.
-- You may take SINGULAIR with food or without food.
How should I give SINGULAIR oral granules to my child?
Do not open the packet until ready to use.
SINGULAIR 4-mg oral granules can be given:
-- directly in the mouth;
-- dissolved in 1 teaspoonful (5 mL) of cold or room
temperature baby formula or breast milk;
-- mixed with a spoonful of one of the following soft
foods at cold or room temperature: applesauce, mashed
carrots, rice, or ice cream.
Be sure that the entire dose is mixed with the food, baby formula,
or breast milk and that the child is given the entire spoonful of the
food, baby formula, or breast milk mixture right away (within 15
minutes).
IMPORTANT: Never store any oral granules mixed with food, baby
formula, or breast milk for use at a later time. Throw away any unused
portion.
Do not put SINGULAIR oral granules in any liquid drink other than
baby formula or breast milk. However, your child may drink liquids
after swallowing the SINGULAIR oral granules.
What is the daily dose of SINGULAIR for asthma or allergic
rhinitis?
For Asthma (Take in the evening):
-- One 10-mg tablet for adults and adolescents 15 years of age
and older,
-- One 5-mg chewable tablet for children 6 to 14 years of age,
-- One 4-mg chewable tablet or one packet of 4-mg oral granules
for children 2 to 5 years of age, or
-- One packet of 4-mg oral granules for children 12 to 23 months
of age.
For Allergic Rhinitis (Take at about the same time each day):
-- One 10-mg tablet for adults and adolescents 15 years of age
and older,
-- One 5-mg chewable tablet for children 6 to 14 years of age,
-- One 4-mg chewable tablet for children 2 to 5 years of age, or
-- One packet of 4-mg oral granules for children 2 to 5 years of
age with seasonal allergic rhinitis, or for children 6 months
to 5 years of age with perennial allergic rhinitis.
What should I avoid while taking SINGULAIR?
If you have asthma and if your asthma is made worse by aspirin,
continue to avoid aspirin or other medicines called non-steroidal
anti-inflammatory drugs while taking SINGULAIR.
What are the possible side effects of SINGULAIR?
The side effects of SINGULAIR are usually mild, and generally did
not cause patients to stop taking their medicine. The side effects in
patients treated with SINGULAIR were similar in type and frequency to
side effects in patients who were given a placebo (a pill containing
no medicine).
The most common side effects with SINGULAIR include:
-- stomach pain
-- stomach or intestinal upset
-- heartburn
-- tiredness
-- fever
-- stuffy nose
-- cough
-- flu
-- upper respiratory infection
-- dizziness
-- headache
-- rash
Less common side effects that have happened with SINGULAIR include
(listed alphabetically):
agitation including aggressive behavior, allergic reactions
(including swelling of the face, lips, tongue, and/or throat,
which may cause trouble breathing or swallowing), hives, and
itching, bad/vivid dreams, increased bleeding tendency, bruising,
diarrhea, drowsiness, hallucinations (seeing things that are not
there), hepatitis, indigestion, inflammation of the pancreas,
irritability, joint pain, muscle aches and muscle cramps, nausea,
palpitations, pins and needles/numbness, restlessness, seizures
(convulsions or fits), swelling, trouble sleeping, and vomiting.
Rarely, asthmatic patients taking SINGULAIR have experienced a
condition that includes certain symptoms that do not go away or that
get worse. These occur usually, but not always, in patients who were
taking steroid pills by mouth for asthma and those steroids were being
slowly lowered or stopped. Although SINGULAIR has not been shown to
cause this condition, you must tell your doctor right away if you get
one or more of these symptoms:
-- a feeling of pins and needles or numbness of arms or legs
-- a flu-like illness
-- rash
-- severe inflammation (pain and swelling) of the sinuses
(sinusitis)
These are not all the possible side effects of SINGULAIR. For more
information ask your doctor or pharmacist.
Talk to your doctor if you think you have side effects from taking
SINGULAIR.
General Information about the safe and effective use of SINGULAIR
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use SINGULAIR for a
condition for which it was not prescribed. Do not give SINGULAIR to
other people even if they have the same symptoms you have. It may harm
them. Keep SINGULAIR and all medicines out of the reach of children.
Store SINGULAIR at 25(degree)C (77(degree)F). Protect from
moisture and light. Store in original package.
This leaflet summarizes information about SINGULAIR. If you would
like more information, talk to your doctor. You can ask your
pharmacist or doctor for information about SINGULAIR that is written
for health professionals.
What are the ingredients in SINGULAIR?
Active ingredient: montelukast sodium
SINGULAIR chewable tablets contain aspartame, a source of
phenylalanine.
Phenylketonurics: SINGULAIR 4-mg and 5-mg chewable tablets contain
0.674 and 0.842 mg phenylalanine, respectively.
Inactive ingredients:
-- 4-mg oral granules: mannitol, hydroxypropyl cellulose, and
magnesium stearate.
-- 4-mg and 5-mg chewable tablets: mannitol, microcrystalline
cellulose, hydroxypropyl cellulose, red ferric oxide,
croscarmellose sodium, cherry flavor, aspartame, and magnesium
stearate.
-- 10-mg tablet: microcrystalline cellulose, lactose monohydrate,
croscarmellose sodium, hydroxypropyl cellulose, magnesium
stearate, hydroxypropyl methylcellulose, titanium dioxide, red
ferric oxide, yellow ferric oxide, and carnauba wax.
What is asthma?
Asthma is a continuing (chronic) inflammation of the bronchial
passageways which are the tubes that carry air from outside the body
to the lungs.
Symptoms of asthma include:
-- coughing
-- wheezing
-- chest tightness
-- shortness of breath
What is allergic rhinitis?
-- Seasonal allergic rhinitis, also known as hay fever, is
triggered by outdoor allergens such as pollens from trees,
grasses, and weeds.
-- Perennial allergic rhinitis may occur year-round and is
generally triggered by indoor allergens such as dust mites,
animal dander, and/or mold spores.
-- Symptoms of allergic rhinitis may include:
-- stuffy, runny, and/or itchy nose
-- sneezing
Rx only
Issued November 2005
MERCK & CO., INC.
Whitehouse Station, NJ 08889, USA
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT (C) 1998-2005 MERCK & CO., Inc.
All rights reserved
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