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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

Posted: April 2007


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