FDA Approves Merck's DULERA® (mometasone furoate and formoterol fumarate dihydrate) Inhalation Aerosol for the Treatment of Asthma in Patients 12 Years of Age and Older

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WHITEHOUSE STATION, N.J.--(Business Wire)--
Merck today announced that the U.S. Food and Drug Administration (FDA) has
approved DULERA® (mometasone furoate and formoterol fumarate dihydrate)
Inhalation Aerosol, a new fixed-dose combination asthma treatment for patients
12 years of age and older. DULERA is not indicated for the relief of acute
bronchospasm. DULERA combines an inhaled corticosteroid (mometasone furoate)
with a long-acting beta2-agonist (formoterol fumarate). The approval of DULERA
is based, in part, on Phase III studies that evaluated the safety and efficacy
of DULERA in patients 12 years of age and older with persistent asthma.

"Despite the advances made in the treatment of asthma in recent years, many
patients may still not be well-controlled on their current therapies," said
Michael S. Blaiss, M.D., clinical professor of pediatrics and medicine at the
University of Tennessee Health Science Center, Memphis, Tennessee. "Asthma
control is an important treatment goal and DULERA provides a new option for
physicians to help manage this chronic condition in appropriate patients."

DULERA is indicated for the treatment of asthma in patients 12 years of age and
older. DULERA is not indicated for the relief of acute bronchospasm.

Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the
active ingredients in DULERA, increase the risk of asthma-related death.
Available data from controlled clinical trials suggest that LABA increase the
risk of asthma-related hospitalization in pediatric and adolescent patients.
Therefore, when treating patients with asthma, DULERA should only be used for
patients not adequately controlled on a long-term asthma control medication,
such as an inhaled corticosteroid or whose disease severity clearly warrants
initiation of treatment with both an inhaled corticosteroid and LABA. Once
asthma control is achieved and maintained, assess the patient at regular
intervals and step down therapy (e.g., discontinue DULERA) if possible without
loss of asthma control, and maintain the patient on a long-term asthma control
medication, such as an inhaled corticosteroid. Do not use DULERA for patients
whose asthma is adequately controlled on low or medium dose inhaled
corticosteroids.

"As a leader in researching and developing new treatments for respiratory
diseases, including asthma, Merck is committed to bringing forth medicines that
help meet the needs of healthcare professionals and their patients," said James
E. Fish, M.D., executive director, Global Scientific Affairs, Merck Research
Laboratories. "DULERA represents an important part of this ongoing commitment."

DULERA is a pressurized metered-dose inhaler with a built-in numeric counter
that shows the number of remaining doses. DULERA will be available for patients
12 years of age and older in two strengths: DULERA 100 mcg/5 mcg and DULERA 200
mcg/5 mcg. Each inhalation contains 5 mcg of formoterol fumarate and either 100
mcg or 200 mcg of mometasone furoate. The recommended starting dose is based on
prior asthma therapy. The maximum daily recommended dose is two inhalations of
DULERA 200 mcg/5 mcg twice daily every day in the morning and evening. DULERA is
expected to be available in retail pharmacies nationwide by the end of July
2010.

Clinical Trials - Lung Function Measures

The approval of DULERA is supported, in part, by two randomized clinical trials
(Trial 1, Trial 2) lasting 12 to 26 weeks in duration. These trials involved a
total of 1,509 patients 12 years of age and older with persistent asthma
uncontrolled on medium or high dose inhaled corticosteroids. These studies
included a 2 to 3-week run-in period with mometasone furoate to establish a
certain level of asthma control.

Trial 1 compared DULERA 100 mcg/5 mcg (n=191) to its individual components,
mometasone furoate 100 mcg (n=192) and formoterol 5 mcg (n=202), and placebo
(n=196). Trial 2 compared DULERA 200 mcg/5 mcg (n=255) with DULERA 100 mcg/5 mcg
(n=233) and mometasone furoate 200 mcg (n=240). All medications were given as
two inhalations twice daily by metered dose inhalers.

Results from both clinical trials showed patients receiving DULERA (100 mcg/5
mcg or 200 mcg/5 mcg) experienced significant improvement from baseline in lung
function (mean area under the concentration-time curve for forced expiratory
volume in 1 second, measured from 0 to 12 hours [FEV1 AUC0-12h]) at week 12, a
primary efficacy endpoint in the trials, compared to mometasone furoate (Trial 1
and 2) and placebo (Trial 1). In Trial 1, these differences were maintained
through week 26.

The change in mean trough FEV1 from baseline to week 12 was assessed as another
endpoint in both trials. In Trial 1, a significantly greater increase in the
mean trough FEV1 was observed for DULERA 100 mcg/5 mcg compared to formoterol 5
mcg (the primary treatment comparison) as well as to placebo. In trial 2, a
greater numerical increase in the mean trough FEV1 were was observed for DULERA
200 mcg/5 mcg compared to DULERA 100 mcg/5 mcg and mometasone furoate 200 mcg.

Clinical Trials - Clinically Judged Deteriorations in Asthma or Reduction in
Lung Function

Clinically judged deteriorations in asthma or reductions in lung function were
assessed in Trial 1 as another primary endpoint to evaluate the contribution of
mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison
DULERA vs. formoterol). Deteriorations in asthma were defined as any of the
following: a 20 percent decrease in FEV1; a 30 percent decrease in peak
expiratory flow (PEF) on two or more consecutive days; emergency treatment,
hospitalization, or treatment with systemic corticosteroids or other asthma
medications not allowed per protocol. Fewer patients who received DULERA 100
mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg
(p<0.001).

In Trial 2, clinically judged deterioration in asthma or reduction in lung
function was also assessed as an additional endpoint. Fewer patients who
received DULERA 200 mcg/5 mcg or DULERA 100 mcg/5 mcg compared to mometasone
furoate 200 mcg alone reported an event, using the same definition as Trial 1.

Clinical Trials - Safety Data

The most common treatment-emergent adverse events were nasopharyngitis,
sinusitis and headache. These adverse events were reported at an incidence of
greater than or equal to 3.0 percent and more commonly than placebo. Oral
candidiasis has been reported in clinical trials at an incidence of 0.7 percent
in patients using DULERA 100 mcg/5 mcg, 0.8 percent in patients using DULERA 200
mcg/5 mcg and 0.5 percent in the placebo group. Similar safety outcomes were
observed in a long-term 52-week trial of patients 12 years of age and older
receiving DULERA (100 mcg/5 mcg or 200 mcg/5 mcg) or active comparator.
Dysphonia was observed at a higher frequency in the longer term treatment trial
at a reported incidence of 7/141 (5%) patients receiving DULERA 100 mcg/5 mcg
and 5/130 (3.8%) patients receiving DULERA 200 mcg/5 mcg.

Important Safety Information about DULERA®

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to
determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

When treating patients with asthma, prescribe DULERA only for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a
long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

DULERA is contraindicated in the primary treatment of status asthmaticus or
other acute episodes of asthma where intensive measures are required. DULERA is
contraindicated in patients with known hypersensitivity to any of the
ingredients in DULERA.

DULERA is NOT a rescue medication and does NOT replace fast-acting inhalers to
treat acute symptoms. Increasing use of inhaled, short-acting beta2-agonists is
a marker for deteriorating asthma. In this situation, the patient requires
immediate re-evaluation with reassessment of the treatment regimen.

Patients using DULERA should not use additional formoterol or other long-acting
inhaled beta2-agonists for any reason.

DULERA should be used with caution in patients with tuberculosis, fungal,
bacterial, viral (including chicken pox or measles), or parasitic infections; or
ocular herpes simplex infections because of the potential for worsening of these
infections. A more serious or even fatal course of chickenpox or measles can
occur in susceptible patients.

Particular care is needed for patients who are transferred from systemically
active corticosteroids to DULERA. Deaths due to adrenal insufficiency have
occurred in asthmatic patients during and after transfer from systemic
corticosteroids to less systemically available inhaled corticosteroids.

Mometasone furoate, a component of DULERA, will often help control asthma
symptoms with less suppression of HPA function than therapeutically equivalent
oral doses of prednisone. Since mometasone furoate is absorbed into the
circulation and can be systemically active at higher doses, the beneficial
effects of DULERA in minimizing HPA dysfunction may be expected only when
recommended dosages are not exceeded and individual patients are titrated to the
lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids,
patients treated with DULERA should be observed carefully for any evidence of
systemic corticosteroid effects. Particular care should be taken in observing
patients postoperatively or during periods of stress for evidence of inadequate
adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and
adrenal suppression (including adrenal crisis) may appear in a small number of
patients, particularly when mometasone furoate is administered at higher than
recommended doses over prolonged periods of time. If such effects occur, the
dosage of DULERA should be reduced slowly, consistent with accepted procedures
for reducing systemic corticosteroids and for management of asthma symptoms.

Caution should be exercised when considering the coadministration of DULERA with
long-term ketoconazole and other known strong CYP3A4 inhibitors, or in patients
being treated with MAO inhibitors or tricyclic antidepressants.

Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm
occurs.

Excessive beta-adrenergic stimulation has been associated with central nervous
system and cardiovascular effects. DULERA should be used with caution in
patients with cardiovascular disorders, especially coronary insufficiency,
cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term
administration of products containing inhaled corticosteroids, including
mometasone furoate, a component of DULERA.

Inhaled corticosteroids, including DULERA, may cause a reduction in growth
velocity when administered in pediatric patients.

Glaucoma, increased intraocular pressure, and cataracts have been reported
following the use of long-term inhaled corticosteroids, including mometasone
furoate, a component of DULERA.

DULERA, like other medications containing sympathomimetic amines, should be used
with caution in patients with convulsive disorders or thyrotoxicosis; and in
patients who are unusually responsive to sympathomimetic amines. Doses of the
related beta2-agonist albuterol, when administered intravenously, have been
reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Beta2-agonist medications may produce significant hypokalemia in some patients,
possibly through intracellular shunting, which has the potential to produce
adverse cardiovascular effects. The decrease in serum potassium is usually
transient, not requiring supplementation. Clinically significant changes in
blood glucose and/or serum potassium were seen infrequently during clinical
studies with DULERA at recommended doses.

The most common treatment-emergent adverse events reported in ≥ three percent of
patients and more common than placebo included nasopharyngitis, sinusitis, and
headache.

About Asthma

Asthma is a chronic lung disease characterized by inflammation of the air
passages, resulting in the temporary narrowing of the airways. Asthma symptoms
can be triggered by allergens or irritants and can include difficulty breathing,
wheezing, coughing, shortness of breath and chest tightness.

About Merck

Today's Merck is a global healthcare leader. Merck is known as MSD outside the
United States and Canada. Through our prescription medicines, vaccines, biologic
therapies, and consumer care and animal health products, we work with customers
and operate in more than 140 countries to deliver innovative health solutions.
We also demonstrate our commitment to increasing access to healthcare through
far-reaching policies, programs and partnerships. For more information, visit
www.merck.com.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of
the safe harbor provisions of the United States Private Securities Litigation
Reform Act of 1995. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and Schering-Plough,
including future financial and operating results, the combined company`s plans,
objectives, expectations and intentions and other statements that are not
historical facts. Such statements are based upon the current beliefs and
expectations of Merck`s management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in the
forward-looking statements.

The following factors, among others, could cause actual results to differ from
those set forth in the forward-looking statements: the possibility that the
expected synergies from the merger of Merck and Schering-Plough will not be
realized, or will not be realized within the expected time period; the impact of
pharmaceutical industry regulation and health care legislation; the risk that
the businesses will not be integrated successfully; disruption from the merger
making it more difficult to maintain business and operational relationships;
Merck`s ability to accurately predict future market conditions; dependence on
the effectiveness of Merck`s patents and other protections for innovative
products; the risk of new and changing regulation and health policies in the
U.S. and internationally and the exposure to litigation and/or regulatory
actions.

Merck undertakes no obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or otherwise. Additional
factors that could cause results to differ materially from those described in
the forward-looking statements can be found in Merck`s 2009 Annual Report on
Form 10-K and the company`s other filings with the Securities and Exchange
Commission (SEC) available at the SEC`s Internet site (www.sec.gov).

# # #

Please see attached Full Prescribing Information including Boxed Warning for
DULERA. Full prescribing information is also available at
www.spfiles.com/pidulera.pdf

DULERA® is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DULERA safely
and effectively. See full prescribing information for DULERA.

DULERA 100 mcg/5 mcg (mometasone furoate 100 mcg and formoterol fumarate
dihydrate 5 mcg) Inhalation Aerosol

DULERA 200 mcg/5 mcg (mometasone furoate 200 mcg and formoterol fumarate
dihydrate 5 mcg) Inhalation Aerosol

FOR ORAL INHALATION
Initial U.S. Approval: 2010

WARNING: ASTHMA-RELATED DEATH
See full prescribing information for complete boxed warning.
-- Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to
determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.
-- When treating patients with asthma, prescribe DULERA only for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a
long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. (1.1, 5.1)

INDICATIONS AND USAGE

DULERA is a combination product containing a corticosteroid and a long-acting
beta2-adrenergic agonist indicated for:

* Treatment of asthma in patients 12 years of age and older. (1.1)

Important limitations:

* Not indicated for the relief of acute bronchospasm. (1.1)

DOSAGE AND ADMINISTRATION

For oral inhalation only.

Treatment of asthma in patients ≥12 years: 2 inhalations twice daily of DULERA
100 mcg/5 mcg or 200 mcg/5 mcg. Starting dosage is based on prior asthma
therapy. (2.2)

DOSAGE FORMS AND STRENGTHS

Inhalation aerosol containing a combination of mometasone furoate (100 or 200
mcg) and formoterol fumarate dihydrate (5 mcg) per actuation. (3)

CONTRAINDICATIONS

* Primary treatment of status asthmaticus or acute episodes of asthma requiring
intensive measures. (4.1)
* Hypersensitivity to any of the ingredients of DULERA. (4.2)

WARNINGS AND PRECAUTIONS

* Asthma-related death: Long-acting beta2-adrenergic agonists increase the risk.
Prescribe only for recommended patient populations. (5.1)
* Deterioration of disease and acute episodes: Do not initiate in acutely
deteriorating asthma or to treat acute symptoms. (5.2)
* Use with additional long-acting beta2-agonist: Do not use in combination
because of risk of overdose. (5.3)
* Localized infections: Candida albicans infection of the mouth and throat may
occur. Monitor patients periodically for signs of adverse effects on the oral
cavity. Advise patients to rinse the mouth following inhalation. (5.4)
* Immunosuppression: Potential worsening of existing tuberculosis, fungal,
bacterial, viral, or parasitic infection; or ocular herpes simplex infections.
More serious or even fatal course of chickenpox or measles can occur in
susceptible patients. Use with caution in patients with these infections because
of the potential for worsening of these infections. (5.5)
* Transferring patients from systemic corticosteroids: Risk of impaired adrenal
function when transferring from oral steroids. Taper patients slowly from
systemic corticosteroids if transferring to DULERA. (5.6)
* Hypercorticism and adrenal suppression: May occur with very high dosages or at
the regular dosage in susceptible individuals. If such changes occur,
discontinue DULERA slowly. (5.7)
* Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased
systemic corticosteroid effects. Exercise caution when used with DULERA. (5.8)
* Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy
if paradoxical bronchospasm occurs. (5.9)
* Patients with cardiovascular disorders: Use with caution because of
beta-adrenergic stimulation. (5.11)
* Decreases in bone mineral density: Monitor patients with major risk factors
for decreased bone mineral content. (5.12)
* Effects on growth: Monitor growth of pediatric patients. (5.13)
* Glaucoma and cataracts: Monitor patients with change in vision or with a
history of increased intraocular pressure, glaucoma, and/or cataracts closely.
(5.14)
* Coexisting conditions: Use with caution in patients with convulsive disorders,
thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15)
* Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia.
(5.16)

ADVERSE REACTIONS

Most common adverse reactions (reported in ≥3% of patients) included:

* Nasopharyngitis, sinusitis and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a
subsidiary of Merck & Co., Inc., at 1-800-526-4099 or FDA at 1-800-FDA-1088
orwww.fda.gov/medwatch.

DRUG INTERACTIONS

* Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May
cause increased systemic corticosteroid effects. (7.1)
* Adrenergic agents: Use with caution. Additional adrenergic drugs may
potentiate sympathetic effects. (7.2)
* Xanthine derivatives and diuretics: Use with caution. May potentiate ECG
changes and/or hypokalemia. (7.3, 7.4)
* MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc
interval: Use with extreme caution. May potentiate effect on the cardiovascular
system. (7.5)
* Beta-blockers: Use with caution and only when medically necessary. May
decrease effectiveness and produce severe bronchospasm. (7.6)

USE IN SPECIFIC POPULATIONS

* Hepatic impairment: Monitor patients for signs of increased drug exposure.
(8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 06/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ASTHMA-RELATED DEATH
1 INDICATIONS AND USAGE
1.1 Treatment of Asthma
2 DOSAGE AND ADMINISTRATION
2.1 General
2.2 Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Status Asthmaticus
4.2 Hypersensitivity
5 WARNINGS AND PRECAUTIONS
5.1 Asthma-Related Death
5.2 Deterioration of Disease and Acute Episodes
5.3 Excessive Use of DULERA and Use with Other Long-Acting Beta2-Agonists
5.4 Local Effects
5.5 Immunosuppression
5.6 Transferring Patients from Systemic Corticosteroid Therapy
5.7 Hypercorticism and Adrenal Suppression
5.8 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
5.9 Paradoxical Bronchospasm and Upper Airway Symptoms
5.10 Immediate Hypersensitivity Reactions
5.11 Cardiovascular and Central Nervous System Effects
5.12 Reduction in Bone Mineral Density
5.13 Effect on Growth
5.14 Glaucoma and Cataracts
5.15 Coexisting Conditions
5.16 Hypokalemia and Hyperglycemia
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Inhibitors of Cytochrome P450 3A4
7.2 Adrenergic agents
7.3 Xanthine derivatives
7.4 Diuretics
7.5 Monoamine oxidase inhibitors, tricyclic antidepressants, and drugs known to prolong the QTc interval
7.6 Beta-adrenergic receptor antagonists
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
10 OVERDOSAGE
10.1 Signs and Symptoms
10.2 Treatment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Asthma
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Asthma-Related Death
17.2 Not for Acute Symptoms
17.3 Do Not Use Additional Long-Acting Beta2-Agonists
17.4 Risks Associated With Corticosteroid Therapy
17.5 Risks Associated With Beta-Agonist Therapy

*Sections or subsections omitted from the full prescribing information are not
listed.

FULL PRESCRIBING INFORMATION

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently
available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on a long-term asthma control medication, such
as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium
dose inhaled corticosteroids. [See Warnings and Precautions (5.1)]

1INDICATIONS AND USAGE

1.1Treatment of Asthma

DULERA is indicated for the treatment of asthma in patients 12 years of age and
older.

Long-acting beta2-adrenergic agonists, such as formoterol, one of the active
ingredients in DULERA, increase the risk of asthma-related death. Available data
from controlled clinical trials suggest that LABA increase the risk of
asthma-related hospitalization in pediatric and adolescent patients [see
Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma,
DULERA should only be used for patients not adequately controlled on a long-term
asthma control medication, such as an inhaled corticosteroid or whose disease
severity clearly warrants initiation of treatment with both an inhaled
corticosteroid and LABA. Once asthma control is achieved and maintained, assess
the patient at regular intervals and step down therapy (e.g., discontinue
DULERA) if possible without loss of asthma control, and maintain the patient on
a long-term asthma control medication, such as an inhaled corticosteroid. Do not
use DULERA for patients whose asthma is adequately controlled on low or medium
dose inhaled corticosteroids.

Important Limitation of Use

* DULERA is NOT indicated for the relief of acute bronchospasm.

2DOSAGE AND ADMINISTRATION

2.1General

DULERA should be administered only by the orally inhaled route (see Instructions
for Using DULERA in the Medication Guide). After each dose, the patient should
be advised to rinse his/her mouth with water without swallowing.

DULERA should be primed before using for the first time by releasing 4 test
sprays into the air, away from the face, shaking well before each spray. In
cases where the inhaler has not been used for more than 5 days, prime the
inhaler again by releasing 4 test sprays into the air, away from the face,
shaking well before each spray.

The DULERA canister should only be used with the DULERA actuator. The DULERA
actuator should not be used with any other inhalation drug product. Actuators
from other products should not be used with the DULERA canister.

2.2Dosing

DULERA should be administered as two inhalations twice daily every day (morning
and evening) by the orally inhaled route.

Shake well prior to each inhalation.

The recommended starting dosages for DULERA treatment are based on prior asthma
therapy.

Table 1: Recommended Dosages for DULERA
Previous Therapy Recommended Dose Maximum Recommended
Daily Dose
Inhaled medium dose DULERA 100 mcg/5 mcg, 2 400 mcg/20 mcg
corticosteroids inhalations twice daily
Inhaled high dose DULERA 200 mcg/5 mcg, 2 800 mcg/20 mcg
corticosteroids inhalations twice daily

The maximum daily recommended dose is two inhalations of DULERA 200 mcg/5 mcg
twice daily. Do not use more than two inhalations twice daily of the prescribed
strength of DULERA as some patients are more likely to experience adverse
effects with higher doses of formoterol. If symptoms arise between doses, an
inhaled short-acting beta2-agonist should be taken for immediate relief.

If a previously effective dosage regimen of DULERA fails to provide adequate
control of asthma, the therapeutic regimen should be reevaluated and additional
therapeutic options, e.g., replacing the current strength of DULERA with a
higher strength, adding additional inhaled corticosteroid, or initiating oral
corticosteroids, should be considered.

The maximum benefit may not be achieved for 1 week or longer after beginning
treatment. Individual patients may experience a variable time to onset and
degree of symptom relief. For patients ≥12 years of age who do not respond
adequately after 2 weeks of therapy, higher strength may provide additional
asthma control.

3DOSAGE FORMS AND STRENGTHS

DULERA is a pressurized metered dose inhaler that is available in 2 strengths.

DULERA 100 mcg/5 mcg delivers 100 mcg of mometasone furoate and 5 mcg of
formoterol fumarate dihydrate per actuation.

DULERA 200 mcg/5 mcg delivers 200 mcg of mometasone furoate and 5 mcg of
formoterol fumarate dihydrate per actuation.

4CONTRAINDICATIONS

4.1Status Asthmaticus

DULERA is contraindicated in the primary treatment of status asthmaticus or
other acute episodes of asthma where intensive measures are required.

4.2Hypersensitivity

DULERA is contraindicated in patients with known hypersensitivity to mometasone
furoate, formoterol fumarate, or any of the ingredients in DULERA [see Warnings
and Precautions (5.10)].

5WARNINGS AND PRECAUTIONS

5.1Asthma-Related Death

Long-acting beta2-adrenergic agonists, such as formoterol, one of the active
ingredients in DULERA, increase the risk of asthma-related death. Currently
available data are inadequate to determine whether concurrent use of inhaled
corticosteroids or other long-term asthma control drugs mitigates the increased
risk of asthma-related death from LABA. Available data from controlled clinical
trials suggest that LABA increase the risk of asthma-related hospitalization in
pediatric and adolescent patients. Therefore, when treating patients with
asthma, physicians should only prescribe DULERA for patients with asthma not
adequately controlled on a long-term asthma control medication, such as an
inhaled corticosteroid or whose disease severity clearly warrants initiation of
treatment with both an inhaled corticosteroid and LABA. Once asthma control is
achieved and maintained, assess the patient at regular intervals and step down
therapy (e.g., discontinue DULERA) if possible without loss of asthma control,
and maintain the patient on a long-term asthma control medication, such as an
inhaled corticosteroid. Do not use DULERA for patients whose asthma is
adequately controlled on low or medium dose inhaled corticosteroids.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with
placebo, each added to usual asthma therapy, showed an increase in
asthma-related deaths in patients receiving salmeterol (13/13,176 in patients
treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37,
95% CI 1.25, 15.34). This finding with salmeterol is considered a class effect
of the LABAs, including formoterol, one of the active ingredients in DULERA. No
study adequate to determine whether the rate of asthma-related death is
increased with DULERA has been conducted.

Clinical studies with formoterol suggested a higher incidence of serious asthma
exacerbations in patients who received formoterol fumarate than in those who
received placebo. The sizes of these studies were not adequate to precisely
quantify the differences in serious asthma exacerbation rates between treatment
groups.

5.2Deterioration of Disease and Acute Episodes

DULERA should not be initiated in patients during rapidly deteriorating or
potentially life-threatening episodes of asthma. DULERA has not been studied in
patients with acutely deteriorating asthma. The initiation of DULERA in this
setting is not appropriate.

Increasing use of inhaled, short-acting beta2-agonists is a marker of
deteriorating asthma. In this situation, the patient requires immediate
re-evaluation with reassessment of the treatment regimen, giving special
consideration to the possible need for replacing the current strength of DULERA
with a higher strength, adding additional inhaled corticosteroid, or initiating
systemic corticosteroids. Patients should not use more than 2 inhalations twice
daily (morning and evening) of DULERA.

DULERA is not indicated for the relief of acute symptoms, i.e., as rescue
therapy for the treatment of acute episodes of bronchospasm. An inhaled,
short-acting beta2-agonist, not DULERA, should be used to relieve acute symptoms
such as shortness of breath. When prescribing DULERA, the physician must also
provide the patient with an inhaled, short-acting beta2-agonist (e.g.,
albuterol) for treatment of acute symptoms, despite regular twice-daily (morning
and evening) use of DULERA.

When beginning treatment with DULERA, patients who have been taking oral or
inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day)
should be instructed to discontinue the regular use of these drugs.

5.3Excessive Use of DULERA and Use with Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, DULERA should
not be used more often than recommended, at higher doses than recommended, or in
conjunction with other medications containing long-acting beta2-agonists, as an
overdose may result. Clinically significant cardiovascular effects and
fatalities have been reported in association with excessive use of inhaled
sympathomimetic drugs. Patients using DULERA should not use an additional
long-acting beta2-agonist (e.g., salmeterol, formoterol fumarate, arformoterol
tartrate) for any reason, including prevention of exercise-induced bronchospasm
(EIB) or the treatment of asthma.

5.4Local Effects

In clinical trials, the development of localized infections of the mouth and
pharynx with Candida albicans have occurred in patients treated with DULERA. If
oropharyngeal candidiasis develops, it should be treated with appropriate local
or systemic (i.e., oral) antifungal therapy while remaining on treatment with
DULERA therapy, but at times therapy with DULERA may need to be interrupted.
Advise patients to rinse the mouth after inhalation of DULERA.

5.5Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible
to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal
course in susceptible children or adults using corticosteroids. In such children
or adults who have not had these diseases or who are not properly immunized,
particular care should be taken to avoid exposure. How the dose, route, and
duration of corticosteroid administration affect the risk of developing a
disseminated infection is not known. The contribution of the underlying disease
and/or prior corticosteroid treatment to the risk is also not known. If exposed
to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or
pooled intravenous immunoglobulin (IVIG) may be indicated. If exposed to
measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be
indicated. (See the respective package inserts for complete VZIG and IG
prescribing information.) If chickenpox develops, treatment with antiviral
agents may be considered.

DULERA should be used with caution, if at all, in patients with active or
quiescent tuberculosis infection of the respiratory tract, untreated systemic
fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.6Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who are transferred from systemically
active corticosteroids to DULERA because deaths due to adrenal insufficiency
have occurred in asthmatic patients during and after transfer from systemic
corticosteroids to less systemically available inhaled corticosteroids. After
withdrawal from systemic corticosteroids, a number of months are required for
recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of
prednisone (or its equivalent) may be most susceptible, particularly when their
systemic corticosteroids have been almost completely withdrawn. During this
period of HPA suppression, patients may exhibit signs and symptoms of adrenal
insufficiency when exposed to trauma, surgery, or infection (particularly
gastroenteritis) or other conditions associated with severe electrolyte loss.
Although DULERA may improve control of asthma symptoms during these episodes, in
recommended doses it supplies less than normal physiological amounts of
corticosteroid systemically and does NOT provide the mineralocorticoid activity
necessary for coping with these emergencies.

During periods of stress or severe asthma attack, patients who have been
withdrawn from systemic corticosteroids should be instructed to resume oral
corticosteroids (in large doses) immediately and to contact their physicians for
further instruction. These patients should also be instructed to carry a medical
identification card indicating that they may need supplementary systemic
corticosteroids during periods of stress or severe asthma attack.

Patients requiring systemic corticosteroids should be weaned slowly from
systemic corticosteroid use after transferring to DULERA. Lung function (FEV1 or
PEF), beta-agonist use, and asthma symptoms should be carefully monitored during
withdrawal of systemic corticosteroids. In addition to monitoring asthma signs
and symptoms, patients should be observed for signs and symptoms of adrenal
insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and
hypotension.

Transfer of patients from systemic corticosteroid therapy to DULERA may unmask
allergic conditions previously suppressed by the systemic corticosteroid
therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic
conditions.

During withdrawal from oral corticosteroids, some patients may experience
symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or
muscular pain, lassitude, and depression, despite maintenance or even
improvement of respiratory function.

5.7Hypercorticism and Adrenal Suppression

Mometasone furoate, a component of DULERA, will often help control asthma
symptoms with less suppression of HPA function than therapeutically equivalent
oral doses of prednisone. Since mometasone furoate is absorbed into the
circulation and can be systemically active at higher doses, the beneficial
effects of DULERA in minimizing HPA dysfunction may be expected only when
recommended dosages are not exceeded and individual patients are titrated to the
lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids,
patients treated with DULERA should be observed carefully for any evidence of
systemic corticosteroid effects. Particular care should be taken in observing
patients postoperatively or during periods of stress for evidence of inadequate
adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and
adrenal suppression (including adrenal crisis) may appear in a small number of
patients, particularly when mometasone furoate is administered at higher than
recommended doses over prolonged periods of time. If such effects occur, the
dosage of DULERA should be reduced slowly, consistent with accepted procedures
for reducing systemic corticosteroids and for management of asthma symptoms.

5.8Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of DULERA with
ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir,
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir,
saquinavir, telithromycin) because adverse effects related to increased systemic
exposure to mometasone furoate may occur [see Drug Interactions (7.1) and
Clinical Pharmacology (12.3)].

5.9Paradoxical Bronchospasm and Upper Airway Symptoms

DULERA may produce inhalation induced bronchospasm with an immediate increase in
wheezing after dosing that may be life-threatening. If inhalation induced
bronchospasm occurs, it should be treated immediately with an inhaled,
short-acting inhaled bronchodilator. DULERA should be discontinued immediately
and alternative therapy instituted.

5.10Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of DULERA,
as demonstrated by cases of urticaria, flushing, allergic dermatitis, and
bronchospasm.

5.11Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina,
hypertension or hypotension, tachycardia with rates up to 200 beats/min,
arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness,
fatigue, malaise, and insomnia. Therefore, DULERA should be used with caution in
patients with cardiovascular disorders, especially coronary insufficiency,
cardiac arrhythmias, and hypertension.

Formoterol fumarate, a component of DULERA, can produce a clinically significant
cardiovascular effect in some patients as measured by pulse rate, blood
pressure, and/or symptoms. Although such effects are uncommon after
administration of DULERA at recommended doses, if they occur, the drug may need
to be discontinued. In addition, beta-agonists have been reported to produce ECG
changes, such as flattening of the T wave, prolongation of the QTc interval, and
ST segment depression. The clinical significance of these findings is unknown.
Fatalities have been reported in association with excessive use of inhaled
sympathomimetic drugs.

5.12Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term
administration of products containing inhaled corticosteroids, including
mometasone furoate, one of the components of DULERA. The clinical significance
of small changes in BMD with regard to long-term outcomes, such as fracture, is
unknown. Patients with major risk factors for decreased bone mineral content,
such as prolonged immobilization, family history of osteoporosis, or chronic use
of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids)
should be monitored and treated with established standards of care.

In a 2-year double-blind study in 103 male and female asthma patients 18 to 50
years of age previously maintained on bronchodilator therapy (Baseline FEV1
85%-88% predicted), treatment with mometasone furoate dry powder inhaler 200 mcg
twice daily resulted in significant reductions in lumbar spine (LS) BMD at the
end of the treatment period compared to placebo. The mean change from Baseline
to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone
furoate group compared to 0.002 (0.25%) for the placebo group. In another 2-year
double-blind study in 87 male and female asthma patients 18 to 50 years of age
previously maintained on bronchodilator therapy (Baseline FEV1 82%-83%
predicted), treatment with mometasone furoate 400 mcg twice daily demonstrated
no statistically significant changes in lumbar spine BMD at the end of the
treatment period compared to placebo. The mean change from Baseline to Endpoint
in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group
compared to -0.006 (-0.43%) for the placebo group.

5.13Effect on Growth

Orally inhaled corticosteroids, including DULERA, may cause a reduction in
growth velocity when administered to pediatric patients. Monitor the growth of
pediatric patients receiving DULERA routinely (e.g., via stadiometry). To
minimize the systemic effects of orally inhaled corticosteroids, including
DULERA, titrate each patient`s dose to the lowest dosage that effectively
controls his/her symptoms [see Use in Specific Populations (8.4)].

5.14Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported
following the use of long-term administration of inhaled corticosteroids,
including mometasone furoate, a component of DULERA. Therefore, close monitoring
is warranted in patients with a change in vision or with a history of increased
intraocular pressure, glaucoma, and/or cataracts [see Adverse Reactions (6)].

5.15Coexisting Conditions

DULERA, like other medications containing sympathomimetic amines, should be used
with caution in patients with convulsive disorders or thyrotoxicosis; and in
patients who are unusually responsive to sympathomimetic amines. Doses of the
related beta2-agonist albuterol, when administered intravenously, have been
reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16Hypokalemia and Hyperglycemia

Beta2-agonist medications may produce significant hypokalemia in some patients,
possibly through intracellular shunting, which has the potential to produce
adverse cardiovascular effects. The decrease in serum potassium is usually
transient, not requiring supplementation. Clinically significant changes in
blood glucose and/or serum potassium were seen infrequently during clinical
studies with DULERA at recommended doses.

6ADVERSE REACTIONS

Long-acting beta2-adrenergic agonists, such as formoterol, one of the active
ingredients in DULERA, increase the risk of asthma-related death. Currently
available data are inadequate to determine whether concurrent use of inhaled
corticosteroids or other long-term asthma control drugs mitigates the increased
risk of asthma-related death from LABA. Available data from controlled clinical
trials suggest that LABA increase the risk of asthma-related hospitalization in
pediatric and adolescent patients. Data from a large placebo-controlled US trial
that compared the safety of another long-acting beta2-adrenergic agonist
(salmeterol) or placebo added to usual asthma therapy showed an increase in
asthma-related deaths in patients receiving salmeterol [seeWarnings and
Precautions (5.1)].

Systemic and local corticosteroid use may result in the following:

* Candida albicans infection [see Warnings and Precautions (5.4)]
* Immunosuppression [see Warnings and Precautions (5.5)]
* Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7)]
* Growth effects in pediatrics [see Warnings and Precautions (5.13)]
* Glaucoma and cataracts [see Warnings and Precautions (5.14)]

Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice.

6.1Clinical Trials Experience

The safety data described below is based on 3 clinical trials which randomized
1913 patients 12 years of age and older with asthma, including 679 patients
exposed to DULERA for 12 to 26 weeks and 271 patients exposed for 1 year. DULERA
was studied in two placebo- and active-controlled trials (n=781 and n=728,
respectively) and in a long term 52-week safety trial (n=404). In the 12 to
26-week clinical trials, the population was 12 to 84 years of age, 41% male and
59% female, 73% Caucasians, 27% non-Caucasians. Patients received two
inhalations twice daily of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone
furoate MDI (100 mcg or 200 mcg), formoterol MDI (5 mcg) or placebo. In the long
term 52-week active-comparator safety trial, the population was 12 years to 75
years of age with asthma, 37% male and 63% female, 47% Caucasians, 53%
non-Caucasians and received two inhalations twice daily of DULERA 100 mcg/5 mcg
or 200 mcg/5 mcg, or an active comparator.

The incidence of treatment emergent adverse reactions associated with DULERA in
Table 2 below is based upon pooled data from 2 clinical trials 12 to 26-week in
duration in patients 12 years and older treated with two inhalations twice daily
of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or
200 mcg), formoterol MDI (5mcg) or placebo.

Table 2: Treatment-emergent adverse reactions in DULERA groups occurring at an incidence of ≥3% and more commonly than placebo
Adverse Reactions DULERA* Mometasone Furoate* Formoterol* Placebo*
100 mcg/5 mcg 200 mcg/5 mcg 100 mcg 200 mcg 5 mcg n=196
n=424
n=255 n=192 n=240 n=202 n (%)
n (%) n (%) n (%) n (%) n (%)
Nasopharyngitis 20 (4.7) 12 (4.7) 15 (7.8) 13 (5.4) 13 (6.4) 7 (3.6)
Sinusitis 14 (3.3) 5 (2.0) 6 (3.1) 4 (1.7) 7 (3.5) 2 (1.0)
Headache 19 (4.5) 5 (2.0) 10 (5.2) 8 (3.3) 6 (3.0) 7 (3.6)
Average Duration of 116 81 165 79 131 138
Exposure (days)
*All treatments were administered as two inhalations twice daily.

Oral candidiasis has been reported in clinical trials at an incidence of 0.7% in
patients using DULERA 100 mcg/5 mcg, 0.8 % in patients using DULERA 200 mcg/5
mcg and 0.5 % in the placebo group.

Long Term Clinical Trial Experience

In a long term safety trial in patients 12 years and older treated for 52 weeks
with DULERA 100 mcg/5 mcg (n=141), DULERA 200 mcg/5 mcg (n=130) or an active
comparator (n=133), safety outcomes in general were similar to those observed in
the shorter 12 to 26 week controlled trials. No asthma-related deaths were
observed. Dysphonia was observed at a higher frequency in the longer term
treatment trial at a reported incidence of 7/141 (5%) patients receiving DULERA
100 mcg/5 mcg and 5/130 (3.8%) patients receiving DULERA 200 mcg/5 mcg. No
clinically significant changes in blood chemistry, hematology, or ECG were
observed.

7DRUG INTERACTIONS

In clinical trials, concurrent administration of DULERA and other drugs, such as
short-acting beta2-agonist and intranasal corticosteroids have not resulted in
an increased frequency of adverse drug reactions. No formal drug interaction
studies have been performed with DULERA. The drug interactions of the
combination are expected to reflect those of the individual components.

7.1Inhibitors of Cytochrome P450 3A4

The main route of metabolism of corticosteroids, including mometasone furoate, a
component of DULERA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After
oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean
plasma concentration of orally inhaled mometasone furoate increased. Concomitant
administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase
the systemic exposure to, mometasone furoate. Caution should be exercised when
considering the coadministration of DULERA with long-term ketoconazole and other
known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin,
indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see
Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

7.2Adrenergic agents

If additional adrenergic drugs are to be administered by any route, they should
be used with caution because the pharmacologically predictable sympathetic
effects of formoterol, a component of DULERA, may be potentiated.

7.3Xanthine derivatives

Concomitant treatment with xanthine derivatives may potentiate any hypokalemic
effect of formoterol, a component of DULERA.

7.4Diuretics

Concomitant treatment with diuretics may potentiate the possible hypokalemic
effect of adrenergic agonists. The ECG changes and/or hypokalemia that may
result from the administration of non-potassium sparing diuretics (such as loop
or thiazide diuretics) can be acutely worsened by beta-agonists, especially when
the recommended dose of the beta-agonist is exceeded. Although the clinical
significance of these effects is not known, caution is advised in the
coadministration of DULERA with non-potassium sparing diuretics.

7.5Monoamine oxidase inhibitors, tricyclic antidepressants, and drugs known to
prolong the QTc interval

DULERA should be administered with caution to patients being treated with
monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to
prolong the QTc interval or within 2 weeks of discontinuation of such agents,
because the action of formoterol, a component of DULERA, on the cardiovascular
system may be potentiated by these agents. Drugs that are known to prolong the
QTc interval have an increased risk of ventricular arrhythmias.

7.6Beta-adrenergic receptor antagonists

Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit
the effect of each other when administered concurrently. Beta-blockers not only
block the therapeutic effects of beta2-agonists, such as formoterol, a component
of DULERA, but may produce severe bronchospasm in patients with asthma.
Therefore, patients with asthma should not normally be treated with
beta-blockers. However, under certain circumstances, e.g., as prophylaxis after
myocardial infarction, there may be no acceptable alternatives to the use of
beta-blockers in patients with asthma. In this setting, cardioselective
beta-blockers could be considered, although they should be administered with
caution.

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

DULERA: Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies of DULERA, mometasone furoate
only or formoterol fumarate only in pregnant women. Animal reproduction studies
of mometasone furoate and formoterol in mice, rats, and/or rabbits revealed
evidence of teratogenicity as well as other developmental toxic effects. Because
animal reproduction studies are not always predictive of human response, DULERA
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.

Mometasone Furoate: Teratogenic Effects

When administered to pregnant mice, rats, and rabbits, mometasone furoate
increased fetal malformations and decreased fetal growth (measured by lower
fetal weights and/or delayed ossification). Dystociaand related complications
were also observed when mometasone furoate was administered to rats late in
gestation. However, experience with oral corticosteroids suggests that rodents
are more prone to teratogenic effects from corticosteroid exposure than humans.

In a mouse reproduction study, subcutaneous mometasone furoate produced cleft
palate at approximately one-third of the maximum recommended daily human dose
(MRHD) on a mcg/m2 basis and decreased fetal survival at approximately 1 time
the MRHD. No toxicity was observed at approximately one-tenth of the MRHD on a
mcg/m2 basis.

In a rat reproduction study, mometasone furoate produced umbilical hernia at
topical dermal doses approximately 6 times the MRHD on a mcg/m2 basis and delays
in ossification at approximately 3 times the MRHD on a mcg/m2 basis.

In another study, rats received subcutaneous doses of mometasone furoate
throughout pregnancy or late in gestation. Treated animals had prolonged and
difficult labor, fewer live births, lower birth weight, and reduced early pup
survival at a dose that was approximately 8 times the MRHD on an area under the
curve (AUC) basis. Similar effects were not observed at approximately 4 times
MRHD on an AUC basis.

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front
paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal
doses approximately 3 times the MRHD on a mcg/m2 basis. In an oral study,
mometasone furoate increased resorptions and caused cleft palate and/or head
malformations (hydrocephaly and domed head) at a dose less than the MRHD based
on AUC. At a dose approximately 2 times the MRHD based on AUC, most litters were
aborted or resorbed [see Nonclinical Toxicology (13.2)].

Nonteratogenic Effects:

Hypoadrenalism may occur in infants born to women receiving corticosteroids
during pregnancy. Infants born to mothers taking substantial corticosteroid
doses during pregnancy should be monitored for signs of hypoadrenalism.

Formoterol Fumarate: Teratogenic Effects

Formoterol fumarate administered throughout organogenesis did not cause
malformations in rats or rabbits following oral administration. When given to
rats throughout organogenesis, oral doses of approximately 80 times the MRHD on
a mcg/m2 basis and above delayed ossification of the fetus, and doses of
approximately 2,400 times the MRHD on a mcg/m2 basis and above decreased fetal
weight. Formoterol fumarate has been shown to cause stillbirth and neonatal
mortality at oral doses of approximately 2,400 times the MRHD on a mcg/m2 basis
and above in rats receiving the drug during the late stage of pregnancy. These
effects, however, were not produced at a dose of approximately 80 times the MRHD
on a mcg/m2 basis.

In another testing laboratory, formoterol was shown to be teratogenic in rats
and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at
oral doses approximately 1,200 times and greater than the MRHD on a mcg/m2
basis. Brachygnathia, a skeletal malformation, was observed in rat fetuses at an
oral dose approximately 6,100 times the MRHD on a mcg/m2 basis. In another study
in rats, no teratogenic effects were seen at inhalation doses up to
approximately 500 times the MRHD on a mcg/m2 basis. Subcapsular cysts on the
liver were observed in rabbit fetuses at an oral dose approximately 49,000 times
the MRHD on a mcg/m2 basis. No teratogenic effects were observed at oral doses
up to approximately 3,000 times the MRHD on a mcg/m2 basis [see Nonclinical
Toxicology (13.2)].

8.2Labor and Delivery

There are no adequate and well-controlled human studies that have studied the
effects of DULERA during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility,
DULERA should be used during labor only if the potential benefit justifies the
potential risk [see Nonclinical Toxicology (13.2)].

8.3Nursing Mothers

DULERA: It is not known whether DULERA is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when DULERA is
administered to a nursing woman.

Since there are no data from well-controlled human studies on the use of DULERA
on nursing mothers, based on data for the individual components, a decision
should be made whether to discontinue nursing or to discontinue DULERA, taking
into account the importance of DULERA to the mother.

Mometasone Furoate: It is not known if mometasone furoate is excreted in human
milk. However, other corticosteroids are excreted in human milk.

Formoterol Fumarate: In reproductive studies in rats, formoterol was excreted in
the milk. It is not known whether formoterol is excreted in human milk.

8.4Pediatric Use

The safety and effectiveness of DULERA have been established in patients 12
years of age and older in 3 clinical trials up to 52 weeks in duration. In the 3
clinical trials, 101 patients 12 to 17 years of age were treated with DULERA.
Patients in this age-group demonstrated efficacy results similar to those
observed in patients 18 years of age and older. There were no obvious
differences in the type or frequency of adverse drug reactions reported in this
age group compared to patients 18 years of age and older. Similar efficacy and
safety results were observed in an additional 22 patients 12 to 17 years of age
who were treated with DULERA in another clinical trial. The safety and efficacy
of DULERA have not been established in children less than 12 years of age.

Controlled clinical studies have shown that inhaled corticosteroids may cause a
reduction in growth velocity in pediatric patients. In these studies, the mean
reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8
per year) and appears to depend upon dose and duration of exposure. This effect
was observed in the absence of laboratory evidence of
hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth
velocity is a more sensitive indicator of systemic corticosteroid exposure in
pediatric patients than some commonly used tests of HPA axis function. The
long-term effects of this reduction in growth velocity associated with orally
inhaled corticosteroids, including the impact on final adult height, are
unknown. The potential for "catch up" growth following discontinuation of
treatment with orally inhaled corticosteroids has not been adequately studied.

The growth of children and adolescents receiving orally inhaled corticosteroids,
including DULERA, should be monitored routinely (e.g., via stadiometry). If a
child or adolescent on any corticosteroid appears to have growth suppression,
the possibility that he/she is particularly sensitive to this effect should be
considered. The potential growth effects of prolonged treatment should be
weighed against clinical benefits obtained and the risks associated with
alternative therapies. To minimize the systemic effects of orally inhaled
corticosteroids, including DULERA, each patient should be titrated to his/her
lowest effective dose [see Dosage and Administration (2.2)].

8.5Geriatric Use

A total of 77 patients 65 years of age and older (of which 11 were 75 years and
older) have been treated with DULERA in 3 clinical trials up to 52 weeks in
duration. Similar efficacy and safety results were observed in an additional 28
patients 65 years of age and older who were treated with DULERA in another
clinical trial. No overall differences in safety or effectiveness were observed
between these patients and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. As with other products containing
beta2-agonists, special caution should be observed when using DULERA in
geriatric patients who have concomitant cardiovascular disease that could be
adversely affected by beta2-agonists. Based on available data for DULERA or its
active components, no adjustment of dosage of DULERA in geriatric patients is
warranted.

8.6Hepatic Impairment

Concentrations of mometasone furoate appear to increase with severity of hepatic
impairment [see Clinical Pharmacology (12.3)].

10OVERDOSAGE

10.1Signs and Symptoms

DULERA: DULERA contains both mometasone furoate and formoterol fumarate;
therefore, the risks associated with overdosage for the individual components
described below apply to DULERA.

Mometasone Furoate: Chronic overdosage may result in signs/symptoms of
hypercorticism [see Warnings and Precautions (5.7)]. Single oral doses up to
8000 mcg of mometasone furoate have been studied on human volunteers with no
adverse reactions reported.

Formoterol Fumarate: The expected signs and symptoms with overdosage of
formoterol are those of excessive beta-adrenergic stimulation and/or occurrence
or exaggeration of any of the following signs and symptoms: angina, hypertension
or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias,
nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation,
nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia.
Metabolic acidosis may also occur. Cardiac arrest and even death may be
associated with an overdose of formoterol.

The minimum acute lethal inhalation dose of formoterol fumarate in rats is 156
mg/kg (approximately 63,000 times the MRHD on a mcg/m2 basis). The median lethal
oral doses in Chinese hamsters, rats, and mice provide even higher multiples of
the MRHD.

10.2Treatment

DULERA: Treatment of overdosage consists of discontinuation of DULERA together
with institution of appropriate symptomatic and/or supportive therapy. The
judicious use of a cardioselective beta-receptor blocker may be considered,
bearing in mind that such medication can produce bronchospasm. There is
insufficient evidence to determine if dialysis is beneficial for overdosage of
DULERA. Cardiac monitoring is recommended in cases of overdosage.

11DESCRIPTION

DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg, are combinations of mometasone
furoate and formoterol fumarate dihydrate for oral inhalation only.

One active component of DULERA is mometasone furoate, a corticosteroid having
the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16
(alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) with the following
chemical structure:

(Graphic Omitted)

Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6,
and molecular weight 521.44. It is practically insoluble in water; slightly
soluble in methanol, ethanol, and isopropanol; soluble in acetone.

One active component of DULERA is formoterol fumarate dihydrate, a racemate.
Formoterol fumarate dihydrate is a selective beta2-adrenergic bronchodilator
having the chemical name of
(±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide
fumarate dihydrate with the following chemical structure:

(Graphic Omitted)

Formoterol fumarate dihydrate has a molecular weight of 840.9, and its empirical
formula is (C19H24N2O4)2•C4H4O4•2H2O. Formoterol fumarate dihydrate is a white
to yellowish powder, which is freely soluble in glacial acetic acid, soluble in
methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in
water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.

Each DULERA 100 mcg/5 mcg and 200 mcg/5 mcg is a hydrofluoroalkane (HFA-227)
propelled pressurized metered dose inhaler containing sufficient amount of drug
for 120 inhalations [see How Supplied/Storage and Handling (16)]. After priming,
each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate and
5.5 mcg of formoterol fumarate dihydrate in 69.6 mg of suspension from the valve
and delivers 100 or 200 mcg of mometasone furoate and 5 mcg of formoterol
fumarate dihydrate from the actuator. The actual amount of drug delivered to the
lung may depend on patient factors, such as the coordination between actuation
of the device and inspiration through the delivery system. DULERA also contains
anhydrous alcohol as a cosolvent and oleic acid as a surfactant.

DULERA should be primed before using for the first time by releasing 4 test
sprays into the air, away from the face, shaking well before each spray. In
cases where the inhaler has not been used for more than 5 days, prime the
inhaler again by releasing 4 test sprays into the air, away from the face,
shaking well before each spray.

12CLINICAL PHARMACOLOGY

12.1Mechanism of Action

DULERA: DULERA contains both mometasone furoate and formoterol fumarate;
therefore, the mechanisms of actions described below for the individual
components apply to DULERA. These drugs represent two different classes of
medications (a synthetic corticosteroid and a selective long-acting
beta2-adrenergic receptor agonist) that have different effects on clinical,
physiological, and inflammatory indices of asthma.

Mometasone furoate: Mometasone furoate is a corticosteroid demonstrating potent
anti-inflammatory activity. The precise mechanism of corticosteroid action on
asthma is not known. Inflammation is an important component in the pathogenesis
of asthma. Corticosteroids have been shown to have a wide range of inhibitory
effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils,
macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids,
leukotrienes, and cytokines) involved in inflammation and in the asthmatic
response. These anti-inflammatory actions of corticosteroids may contribute to
their efficacy in asthma.

Mometasone furoate has been shown in vitro to exhibit a binding affinity for the
human glucocorticoid receptor, which is approximately 12 times that of
dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of
budesonide, and 1.5 times that of fluticasone. The clinical significance of
these findings is unknown.

Formoterol fumarate: Formoterol fumarate is a long-acting selective
beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate
acts locally in the lung as a bronchodilator. In vitro studies have shown that
formoterol has more than 200-fold greater agonist activity at beta2-receptors
than at beta1-receptors. Although beta2-receptors are the predominant adrenergic
receptors in bronchial smooth muscle and beta1-receptors are the predominant
receptors in the heart, there are also beta2-receptors in the human heart
comprising 10% to 50% of the total beta-adrenergic receptors. The precise
function of these receptors has not been established, but they raise the
possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including
formoterol, are at least in part attributable to stimulation of intracellular
adenyl cyclase, the enzyme that catalyzes the conversion of adenosine
triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP).
Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and
inhibition of release of mediators of immediate hypersensitivity from cells,
especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell
mediators, such as histamine and leukotrienes, from the human lung. Formoterol
also inhibits histamine-induced plasma albumin extravasation in anesthetized
guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway
hyper-responsiveness. The relevance of these in vitro and animal findings to
humans is unknown.

12.2Pharmacodynamics

Cardiovascular Effects:

DULERA:

In a single dose, double blind placebo controlled crossover trial in 25 patients
with asthma, single dose treatment of 10 mcg formoterol fumarate in combination
with 400 mcg of mometasone furoate delivered via DULERA 200 mcg/5 mcg were
compared to formoterol fumarate 10 mcg MDI, formoterol fumarate 12 mcg dry
powder inhaler (DPI; nominal dose of formoterol fumarate delivered 10 mcg), or
placebo. The degree of bronchodilation at 12 hours after dosing with DULERA was
similar to formoterol fumarate delivered alone via MDI or DPI.

ECGs and blood samples for glucose and potassium were obtained prior to dosing
and post dose. No downward trend in serum potassium was observed and values were
within the normal range and appeared to be similar across all treatments over
the 12 hour period. Mean blood glucose appeared similar across all groups for
each time point. There was no evidence of significant hypokalemia or
hyperglycemia in response to formoterol treatment.

No relevant changes in heart rate or changes in ECG data were observed with
DULERA in the trial. No patients had a QTcB (QTc corrected by Bazett`s formula)
≥500 msec during treatment.

In a single dose crossover trial involving 24 healthy subjects, single dose of
formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone
furoate delivered via DULERA were evaluated for safety (ECG, blood potassium and
glucose changes). ECGs and blood samples for glucose and potassium were obtained
at baseline and post dose. Decrease in mean serum potassium was similar across
all three treatment groups (approximately 0.3 mmol/L) and values were within the
normal range. No clinically significant increases in mean blood glucose values
or heart rate were observed. No subjects had a QTcB >500 msec during treatment.

Three active- and placebo-controlled trials (study duration ranging from 12, 26,
and 52 weeks) evaluated 1913 patients 12 years of age and older with asthma. No
clinically meaningful changes were observed in potassium and glucose values,
vital signs, or ECG parameters in patients receiving DULERA.

HPA Axis Effects:

The effects of inhaled mometasone furoate administered via DULERA on adrenal
function were evaluated in two clinical trials in patients with asthma. HPA-axis
function was assessed by 24-hour plasma cortisol AUC. Although both these trials
have open-label design and contain small number of subjects per treatment arm,
results from these trials taken together demonstrated suppression of 24-hour
plasma cortisol AUC for DULERA 200 mcg/5 mcg compared to placebo consistent with
the known systemic effects of inhaled corticosteroid.

In a 42-day, open-label, placebo and active-controlled study 60 patients with
asthma 18 years of age and older were randomized to receive two inhalations
twice daily of 1 of the following treatments: DULERA 100 mcg/5 mcg, DULERA 200
mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg, or
placebo. At Day 42, the mean change from baseline plasma cortisol AUC (0-24 hr)
was 8%, 22% and 34% lower compared to placebo for the DULERA 100 mcg/5 mcg
(n=13), DULERA 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol
xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively.

In a 52-week, open-label safety study, primary analysis of the plasma cortisol
24-hour AUC was performed on 57 patients with asthma who received 2 inhalations
twice daily of DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone
propionate/salmeterol xinafoate 250/50, or fluticasone propionate/salmeterol
xinafoate 500/50. At Week 52, the mean plasma cortisol AUC (0-24 hr) was 2.2%,
29.6%, 16.7%, and 32.2% lower from baseline for the DULERA 100 mcg/5 mcg (n=18),
DULERA 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 250/50
mcg (n=8), and fluticasone propionate/salmeterol xinafoate 500/50 mcg (n=11)
treatment groups, respectively.

Other Mometasone Products

HPA Axis Effects:

The potential effect of mometasone furoate via a dry powder inhaler (DPI) on the
HPA axis was assessed in a 29-day study. A total of 64 adult patients with mild
to moderate asthma were randomized to one of 4 treatment groups: mometasone
furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily,
oral prednisone 10 mg once daily, or placebo. The 30-minute post-Cosyntropin
stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dl for the
mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dl for the
mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dl for
the oral prednisone 10 mg group and 25 mcg/dl for the placebo group. The
difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum
recommended dose) and placebo was statistically significant.

12.3Pharmacokinetics

Absorption

Mometasone furoate:

Healthy Subjects: The systemic exposures to mometasone furoate from DULERA
versus mometasone furoate delivered via DPI were compared. Following oral
inhalation of single and multiple doses of the DULERA, mometasone furoate was
absorbed in healthy subjects with median Tmax values ranging from 0.50 to 4
hours. Following single-dose administration of higher than recommended dose of
DULERA (4 inhalations of DULERA 200 mcg/5 mcg) in healthy subjects, the
arithmetic mean (CV%) Cmax and AUC (0-12h) values for MF were 67.8 (49) pg/mL
and 650 (51) pg.hr/mL, respectively while the corresponding estimates following
5 days of BID dosing of DULERA 800 mcg/20 mcg were 241 (36) pg/mL and 2200 (35)
pg.hr/mL. Exposure to mometasone furoate increased with increasing inhaled dose
of DULERA 100 mcg/5 mcg to 200 mcg/5 mcg. Studies using oral dosing of labeled
and unlabeled drug have demonstrated that the oral systemic bioavailability of
mometasone furoate is negligible (<1%).

The above study demonstrated that the systemic exposure to mometasone furoate
(based on AUC) was approximately 52% and 25% lower on Day 1 and Day 5,
respectively, following DULERA administration compared to mometasone furoate via
a DPI.

Asthma Patients: Following oral inhalation of single and multiple doses of the
DULERA, mometasone furoate was absorbed in asthma patients with median Tmax
values ranging from 1 to 2 hours. Following single-dose administration of DULERA
400 mcg/10 mcg, the arithmetic mean (CV%) Cmax and AUC (0-12h) values for MF
were 20 (88) pg/mL and 170 (94) pg.hr/mL, respectively while the corresponding
estimates following BID dosing of DULERA 400 mcg/10 mcg at steady-state were 60
(36) pg/mL and 577 (40) pg.hr/mL.

Formoterol fumarate:

Healthy Subjects: When DULERA was administered to healthy subjects, formoterol
was absorbed with median Tmax values ranging from 0.167 to 0.5 hour. In a
single-dose study with DULERA 400 mcg/10 mcg in healthy subjects, arithmetic
mean (CV%) Cmax and AUC for formoterol were 15 (50) pmol/L and 81 (51) pmol*h/L,
respectively. Over the dose range of 10 to 40 mcg for formoterol from DULERA,
the exposure to formoterol was dose proportional.

Asthma Patients: When DULERA was administered to patients with asthma,
formoterol was absorbed with median Tmax values ranging from 0.58 to 1.97 hours.
In a single-dose study with DULERA 400 mcg/10 mcg in patients with asthma,
arithmetic mean (CV%) Cmax and AUC (0-12h) for formoterol were 22 (29) pmol/L
and 125 (42) pmol*h/L, respectively. Following multiple-dose administration of
DULERA 400 mcg/10 mcg, the steady-state arithmetic mean (CV%) Cmax and AUC
(0-12h) for formoterol were 41 (59) pmol/L and 226 (54) pmol*hr/L.

Distribution

Mometasone furoate: Based on the study employing a 1000 mcg inhaled dose of
tritiated mometasone furoate inhalation powder in humans, no appreciable
accumulation of mometasone furoate in the red blood cells was found. Following
an intravenous 400 mcg dose of mometasone furoate, the plasma concentrations
showed a biphasic decline, with a mean steady-state volume of distribution of
152 liters. The in vitro protein binding for mometasone furoate was reported to
be 98 to 99% (in a concentration range of 5 to 500 ng/mL).

Formoterol fumarate: The binding of formoterol to human plasma proteins in vitro
was 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum
albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL. The
concentrations of formoterol used to assess the plasma protein binding were
higher than those achieved in plasma following inhalation of a single 120 mcg
dose.

Metabolism

Mometasone furoate: Studies have shown that mometasone furoate is primarily and
extensively metabolized in the liver of all species investigated and undergoes
extensive metabolism to multiple metabolites. In-vitro studies have confirmed
the primary role of human liver cytochrome P-450 3A4 (CYP3A4) in the metabolism
of this compound, however, no major metabolites were identified. Human liver
CYP3A4 metabolizes mometasone furoate to 6-beta hydroxy mometasone furoate.

Formoterol fumarate: Formoterol is metabolized primarily by direct
glucuronidation at either the phenolic or aliphatic hydroxyl group and
O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl
groups. Minor pathways involve sulfate conjugation of formoterol and
deformylation followed by sulfate conjugation. The most prominent pathway
involves direct conjugation at the phenolic hydroxyl group. The second major
pathway involves O-demethylation followed by conjugation at the phenolic
2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and
CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not
inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients
may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both
of these isozymes results in elevated systemic exposure to formoterol or
systemic adverse effects has not been adequately explored.

Excretion

Mometasone furoate: Following an intravenous dosing, the terminal half-life was
reported to be about 5 hours. Following the inhaled dose of tritiated 1000 mcg
mometasone furoate, the radioactivity is excreted mainly in the feces (a mean of
74%), and to a small extent in the urine (a mean of 8%) up to 7 days. No
radioactivity was associated with unchanged mometasone furoate in the urine.
Absorbed mometasone furoate is cleared from plasma at a rate of approximately
12.5 mL/min/kg, independent of dose. The effective t½ for mometasone furoate
following inhalation with DULERA was 25 hours in healthy subjects and in
patients with asthma.

Formoterol fumarate: Following oral administration of 80 mcg of radiolabeled
formoterol fumarate to 2 healthy subjects, 59% to 62% of the radioactivity was
eliminated in the urine and 32% to 34% in the feces over a period of 104 hours.
In an oral inhalation study with DULERA, renal clearance of formoterol from the
blood was 217 mL/min. In single-dose studies, the mean t½ values for formoterol
in plasma were 9.1 hours and 10.8 hours from the urinary excretion data. The
accumulation of formoterol in plasma after multiple dose administration was
consistent with the increase expected with a drug having a terminal t½ of 9 to
11 hour.

Following single inhaled doses ranging from 10 to 40 mcg to healthy subjects
from the MFF MDI, 6.2% to 6.8% of the formoterol dose was excreted in urine
unchanged. The (R,R) and (S,S)-enantiomers accounted, respectively, for 37% and
63% of the formoterol recovered in urine. From urinary excretion rates measured
in healthy subjects, the mean terminal elimination half-lives for the (R,R)- and
(S,S)-enantiomers were determined to be 13 and 9.5 hours, respectively. The
relative proportion of the two enantiomers remained constant over the dose range
studied.

SpecialPopulations

Hepatic/Renal Impairment: There are no data regarding the specific use of DULERA
in patients with hepatic or renal impairment.

A study evaluating the administration of a single inhaled dose of 400 mcg
mometasone furoate by a dry powder inhaler to subjects with mild (n=4), moderate
(n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in
each group having detectable peak plasma concentrations of mometasone furoate
(ranging from 50-105 pcg/mL). The observed peak plasma concentrations appear to
increase with severity of hepatic impairment; however, the numbers of detectable
levels were few.

Gender and Race: Specific studies to examine the effects of gender and race on
the pharmacokinetics of DULERA have not been specifically studied.

Geriatrics: The pharmacokinetics of DULERA have not been specifically studied in
the elderly population.

Drug-Drug Interactions

A single-dose crossover study was conducted to compare the pharmacokinetics of 4
inhalations of the following: mometasone furoate MDI, formoterol MDI, DULERA
(mometasone furoate/formoterol fumarate MDI), and mometasone furoate MDI plus
formoterol fumarate MDI administered concurrently. The results of the study
indicated that there was no evidence of a pharmacokinetic interaction between
the two components of DULERA.

Inhibitors of Cytochrome P450 Enzymes: Ketoconazole: In a drug interaction
study, an inhaled dose of mometasone furoate 400 mcg delivered by a dry powder
inhaler was given to 24 healthy subjects twice daily for 9 days and ketoconazole
200 mg (as well as placebo) were given twice daily concomitantly on Days 4 to 9.
Mometasone furoate plasma concentrations were <150 pcg/mL on Day 3 prior to
coadministration of ketoconazole or placebo. Following concomitant
administration of ketoconazole, 4 out of 12 subjects in the ketoconazole
treatment group (n=12) had peak plasma concentrations of mometasone furoate >200
pcg/mL on Day 9 (211-324 pcg/mL. Mometasone furoate plasma levels appeared to
increase and plasma cortisol levels appeared to decrease upon concomitant
administration of ketoconazole.

Specific drug-drug interaction studies with formoterol have not been performed.

13NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

Mometasone furoate: In a 2-year carcinogenicity study in Sprague Dawley® rats,
mometasone furoate demonstrated no statistically significant increase in the
incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times
the MRHD on an AUC basis). In a 19-month carcinogenicity study in Swiss CD-1
mice, mometasone furoate demonstrated no statistically significant increase in
the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 9
times the MRHD on an AUC basis).

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese
hamster ovary cell assay, but did not have this effect in an in vitro Chinese
hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test
or mouse lymphoma assay, and was not clastogenic in an in vivo mouse
micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse
male germ-cell chromosomal aberration assay. Mometasone furoate also did not
induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced by
subcutaneous doses up to 15 mcg/kg (approximately 8 times the MRHD on an AUC
basis).

Formoterol fumarate: The carcinogenic potential of formoterol fumarate has been
evaluated in 2-year drinking water and dietary studies in both rats and mice. In
rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and
above in the drinking water study and at 20 mg/kg in the dietary study, but not
at dietary doses up to 5 mg/kg (AUC exposure approximately 265 times human
exposure at the MRHD). In the dietary study, the incidence of benign ovarian
theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at
the low dose of 0.5 mg/kg was approximately 27 times human exposure at the
MRHD). This finding was not observed in the drinking water study, nor was it
seen in mice (see below).

In mice, the incidence of adrenal subcapsular adenomas and carcinomas was
increased in males at doses of 69 mg/kg and above in the drinking water study,
but not at doses up to 50 mg/kg (AUC exposure approximately 350 times human
exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas
was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50
mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC
exposure approximately 35 times human exposure at the MRHD). Also in the dietary
study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at
doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was
approximately 14 times human exposure at the MRHD). Increases in leiomyomas of
the rodent female genital tract have been similarly demonstrated with other
beta-agonist drugs.

Formoterol fumarate was not mutagenic or clastogenic in the following tests:
mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in
mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and
human fibroblasts, transformation assay in mammalian fibroblasts and
micronucleus tests in mice and rats.

Reproduction studies in rats revealed no impairment of fertility at oral doses
up to 3 mg/kg (approximately 1200 times the MRHD on a mcg/m2 basis).

13.2Animal Toxicology and/or Pharmacology

Animal Pharmacology

Formoterol fumarate: Studies in laboratory animals (minipigs, rodents, and dogs)
have demonstrated the occurrence of cardiac arrhythmias and sudden death (with
histologic evidence of myocardial necrosis) when beta-agonists and
methylxanthines are administered concurrently. The clinical significance of
these findings is unknown.

Reproductive Toxicology Studies

Mometasone furoate: In mice, mometasone furoate caused cleft palate at
subcutaneous doses of 60 mcg/kg and above (approximately 1/3 of the maximum
recommended human dose MRHD on a mcg/m2 basis). Fetal survival was reduced at
180 mcg/kg (approximately equal to the MRHD on a mcg/m2 basis). No toxicity was
observed at 20 mcg/kg (approximately one-tenth of the MRHD on a mcg/m2 basis).

In rats, mometasone furoate produced umbilical hernia at topical dermal doses of
600 mcg/kg and above (approximately 6 times the MRHD on a mcg/m2 basis). A dose
of 300 mcg/kg (approximately 3 times the MRHD on a mcg/m2 basis) produced delays
in ossification, but no malformations.

When rats received subcutaneous doses of mometasone furoate throughout pregnancy
or during the later stages of pregnancy, 15 mcg/kg (approximately 8 times the
MRHD on an AUC basis) caused prolonged and difficult labor and reduced the
number of live births, birth weight, and early pup survival. Similar effects
were not observed at 7.5 mcg/kg (approximately 4 times the MRHD on an AUC
basis).

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front
paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal
doses of 150 mcg/kg and above (approximately 3 times the MRHD on a mcg/m2
basis). In an oral study, mometasone furoate increased resorptions and caused
cleft palate and/or head malformations (hydrocephaly and domed head) at 700
mcg/kg (less than the MRHD on an area under the curve [AUC] basis). At 2800
mcg/kg (approximately 2 times the MRHD on an AUC basis) most litters were
aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the MRHD
on an AUC basis).

Formoterol fumarate: Formoterol fumarate administered throughout organogenesis
did not cause malformations in rats or rabbits following oral administration.
When given to rats throughout organogenesis, oral doses of 0.2 mg/kg
(approximately 80 times the MRHD on a mcg/m2 basis) and above delayed
ossification of the fetus, and doses of 6 mg/kg (approximately 2400 times the
MRHD on a mcg/m2 basis) and above decreased fetal weight. Formoterol fumarate
has been shown to cause stillbirth and neonatal mortality at oral doses of 6
mg/kg (approximately 2400 times the MRHD on a mcg/m2 basis) and above in rats
receiving the drug during the late stage of pregnancy. These effects, however,
were not produced at a dose of 0.2 mg/kg (approximately 80 times the MRHD on a
mcg/m2 basis).

In another testing laboratory, formoterol fumarate was shown to be teratogenic
in rats and rabbits. Umbilical hernia, a malformation, was observed in rat
fetuses at oral doses of 3 mg/kg/day and above (approximately 1,200 times
greater than the MRHD on a mcg/m2 basis). Brachygnathia, a skeletal
malformation, was observed for rat fetuses at an oral dose of 15 mg/kg/day
(approximately 6,100 times the MRHD on a mcg/m2 basis). In another study in
rats, no teratogenic effects were seen at inhalation doses up to 1.2 mg/kg/day
(approximately 500 times the MRHD on a mcg/m2 basis). Subcapsular cysts on the
liver were observed for rabbit fetuses at an oral dose of 60 mg/kg
(approximately 49,000 times the MRHD on a mcg/m2 basis). No teratogenic effects
were observed at oral doses up to 3.5 mg/kg (approximately 3,000 times the MRHD
on a mcg/m2 basis).

14CLINICAL STUDIES

14.1 Asthma

The safety and efficacy of DULERA were demonstrated in two randomized,
double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in
duration involving 1509 patients 12 years of age and older with persistent
asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline
FEV1 means of 66% to 73% of predicted normal). These studies included a 2 to
3-week run-in period with mometasone furoate to establish a certain level of
asthma control. One clinical trial compared DULERA to placebo and the individual
components, mometasone furoate and formoterol (Trial 1) and one clinical trial
compared two different strengths of DULERA to mometasone furoate alone (Trial
2).

Trial 1: Clinical Trial with DULERA 100 mcg/5 mcg

This 26-week, placebo controlled trial evaluated 781 patients 12 years of age
and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate
100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo
(n=196 patients); each administered as 2 inhalations twice daily by metered dose
inhalation aerosols. All other maintenance therapies were discontinued. This
study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2
inhalations twice daily. This trial included patients ranging from 12 to 76
years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian.
Patients had persistent asthma and were not well controlled on medium dose of
inhaled corticosteroids prior to randomization. All treatment groups were
balanced with regard to baseline characteristics. Mean FEV1 and mean percent
predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Eight (4%)
patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone
furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46
(23%) patients receiving placebo discontinued the study early due to treatment
failure.

FEV1 AUC (0-12hr) was assessed as a co-primary efficacy endpoint to evaluate the
contribution of the formoterol component to DULERA. Patients receiving DULERA
100 mcg/5 mcg had significantly higher increases from baseline at Week 12 in
mean FEV1 AUC (0-12 hr) compared to mometasone furoate 100 mcg (the primary
treatment comparison) and vs. placebo (both p<0.001) (Figure 1). These
differences were maintained through Week 26. Figure 1 shows the change from
baseline post-dose serial FEV1 evaluations in Trial 1.

(Graphic Omitted)

Clinically judged deteriorations in asthma or reductions in lung function were
assessed as another primary endpoint to evaluate the contribution of mometasone
furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison DULERA vs.
formoterol). Deteriorations in asthma were defined as any of the following: a
20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days;
emergency treatment, hospitalization, or treatment with systemic corticosteroids
or other asthma medications not allowed per protocol. Fewer patients who
received DULERA 100 mcg/5 mcg reported an event compared to patients who
received formoterol 5 mcg (p<0.001).

Table 3: Trial 1 - Clinically judged deterioration in asthma or reduction in lung function*
DULERA Mometasone Formoterol Placebo§
100 mcg/ furoate 5 mcg§ (n=196)
5 mcg§ 100 mcg§ (n=202)
(n=191) (n=192)
Clinically judged 58 65 109 109
deterioration in asthma or (30%) (34%) (54%) (56%)
reduction in lung function*
Decrease in FEV1** 18 19 31 41
(9%) (10%) (15%) (21%)
Decrease in PEF† 37 41 62 61
(19%) (21%) (31%) (31%)
Emergency treatment 0 1 4 1
(<1%) (2%) (<1%)
Hospitalization 1 0 0 0
(<1%)
Treatment with excluded 2 4 17 8
asthma medication‡ (1%) (2%) (8%) (4%)
*Includes only the first event day for each patient. Patients could have experienced more than one event criterion.
**Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication)
†Decrease in AM or PM peak expiratory flow (PEF) on 2 or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period)
‡Thirty patients received glucocorticosteroids; 1 patient received formoterol via dry powder inhaler in the Formoterol 5 mcg group.
§Two inhalations, twice daily.

The change in mean trough FEV1 from baseline to Week 12 was assessed as another
endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA
100 mcg/5 mcg. A significantly greater increase in mean trough FEV1 was observed
for DULERA 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment
comparison) as well as to placebo (Table 4).

Table 4: Trial 1 - Change in trough FEV1 from baseline to Week 12
Treatment arm N Baseline Change from Treatment P-value P-value
(L) baseline at Week difference from vs. placebo vs. formoterol
12 (L) placebo (L)
DULERA 100 mcg/5 mcg 167 2.33 0.13 0.18 <0.001 <0.001
Mometasone furoate 100 mcg 175 2.36 0.07 0.12 <0.001 0.058
Formoterol fumarate 5 mcg 141 2.29 0.00 0.05 0.170
Placebo 145 2.30 -0.05
LS means and p-values are from Week 12 estimates of a longitudinal analysis model.

The effect of DULERA 100 mcg/5 mcg, two inhalations twice daily on selected
secondary efficacy endpoints, including proportion of nights with nocturnal
awakenings (-60% vs. -15%), change in total rescue medication use (-0.6 vs. +1.1
puffs/day), change in morning peak flow (+18.1 vs. -28.4 L/min) and evening peak
flow (+10.8 vs. -32.1 L/min) further supports the efficacy of DULERA 100 mcg/5
mcg compared to placebo.

The subjective impact of asthma on patients` health-related quality of life was
evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a
7-point scale where 1 = maximum impairment and 7 = no impairment). A change from
baseline >0.5 points is considered a clinically meaningful improvement. The mean
difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo
was 0.5 [95% CI 0.32, 0.68].

Trial 2: Clinical Trial With DULERA 200 mcg/5 mcg

This 12-week double-blind trial evaluated 728 patients 12 years of age and older
comparing DULERA 200 mcg/5 mcg (n=255 patients) with DULERA 100 mcg/5 mcg (n=233
patients) and mometasone furoate 200 mcg (n=240 patients), each administered as
2 inhalations twice daily by metered dose inhalation aerosols. All other
maintenance therapies were discontinued. This trial included a 2 to 3-week
run-in period with mometasone furoate 200 mcg, 2 inhalations twice daily.
Patients had persistent asthma and were uncontrolled on high dose inhaled
corticosteroids prior to study entry. All treatment groups were balanced with
regard to baseline characteristics. This trial included patients ranging from 12
to 84 years of age, 44% male and 56% female, and 89% Caucasian and 11%
non-Caucasian. Mean FEV1 and mean percent predicted FEV1 values were similar
among all treatment groups (2.05 L, 66%). Eleven (5%) patients receiving DULERA
100 mcg/5 mcg, 8 (3%) patients receiving DULERA 200 mcg/5 mcg and 13 (5%)
patients receiving mometasone furoate 200 mcg discontinued the trial early due
to treatment failure.

The primary efficacy endpoint was the mean change in FEV1 AUC (0-12 hr) from
baseline to Week 12. Patients receiving DULERA 100 mcg/5 mcg and DULERA 200
mcg/5 mcg had significantly greater increases from baseline at Day 1 in mean
FEV1 AUC (0-12 hr) compared to mometasone furoate 200 mcg. The difference was
maintained over 12 weeks of therapy.

Mean change in trough FEV1 from baseline to Week 12 was also assessed to
evaluate the relative contribution of mometasone furoate to DULERA 100 mcg/5 mcg
and DULERA 200 mcg/5 mcg (Table 5). A greater numerical increase in the mean
trough FEV1 was observed for DULERA 200 mcg/5 mcg compared to DULERA 100 mcg/5
mcg and mometasone furoate 200 mcg.

Table 5: Trial 2 - Change in trough FEV1 from baseline to Week 12
Treatment arm N Baseline Change from baseline at Week 12
(L) (L)
DULERA 100 mcg/5 mcg 232 2.10 0.14
DULERA 200 mcg/5 mcg 255 2.05 0.19
Mometasone furoate 200 mcg 239 2.07 0.10

Clinically judged deterioration in asthma or reduction in lung function was
assessed as an additional endpoint. Fewer patients who received DULERA 200 mcg/5
mcg or DULERA 100/5 mcg compared to mometasone furoate 200 mcg alone reported an
event, defined as in Trial 1 by any of the following: a 20% decrease in FEV1; a
30% decrease in PEF on two or more consecutive days; emergency treatment,
hospitalization, or treatment with systemic corticosteroids or other asthma
medications not allowed per protocol.

Table 6: Trial 2 - Clinically judged deterioration in asthma or reduction in lung function*
DULERA DULERA Mometasone
100 mcg/ 200 mcg/ furoate
5 mcg§ 5 mcg§ 200 mcg§
(n=233) (n=255) (n=240)
Clinically judged 29 31 44
deterioration in asthma or (12%) (12%) (18%)
reduction in lung function*
Decrease in FEV1** 23 17 33
(10%) (7%) (14%)
Decrease in PEF on two 2 4 3
consecutive days† (1%) (2%) (1%)
Emergency treatment 2 1 1
(1%) (<1%) (<1%)
Hospitalization 0 1 0
(<1%)
Treatment with excluded 5 8 12
asthma medication‡ (2%) (3%) (5%)
*Includes only the first event day for each patient. Patients could have experienced more than one event criterion.
**Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication)
†Decrease in AM or PM peak expiratory flow (PEF) below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period)
‡Twenty four patients received glucocorticosteroids; 1 patient received albuterol in the DULERA 200 mcg / 5 mcg group.
§Two inhalations, twice daily.

Other Studies

In addition to Trial 1 and Trial 2, the safety and efficacy of the individual
components, mometasone furoate MDI 100 mcg and 200 mcg, in comparison to placebo
were demonstrated in three other, 12-week, placebo controlled trials which
evaluated the mean change in FEV1 from baseline as a primary endpoint. The
safety and efficacy of formoterol MDI 5 mcg alone in comparison to placebo was
replicated in another 26-week trial that evaluated a lower dose of mometasone
furoate MDI in combination with formoterol.

16HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

DULERA is available in two strengths (Table 7):

Table 7
Package NDC
DULERA 100 mcg/5 mcg 0085-7206-01
DULERA 200 mcg/5 mcg 0085-4610-01

Each strength is supplied as a pressurized aluminum canister that has a blue
plastic actuator integrated with a dose counter and a blue dust cap. Each
120-inhalation canister has a net fill weight of 13 grams. Each canister is
placed into a carton. Each carton contains 1 canister and a Medication Guide.

Initially the dose counter will display "124" actuations. After the initial
priming with 4 actuations, the dose counter will read "120" and the inhaler is
now ready for use.

16.2Storage and Handling

The DULERA canister should only be used with the DULERA actuator. The DULERA
actuator should not be used with any other inhalation drug product. Actuators
from other products should not be used with the DULERA canister.

The correct amount of medication in each inhalation cannot be ensured after the
labeled number of actuations from the canister has been used, even though the
inhaler may not feel completely empty and may continue to operate. The inhaler
should be discarded when the labeled number of actuations has been used (the
dose counter will read "0").

Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted
to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

For best results, the canister should be at room temperature before use. Shake
well before using. Keep out of reach of children. Avoid spraying in eyes.

Contents Under Pressure: Do not puncture. Do not use or store near heat or open
flame. Exposure to temperatures above 120°F may cause bursting. Never throw
container into fire or incinerator.

17PATIENT COUNSELING INFORMATION

[See Medication Guide.]

17.1 Asthma-Related Death

[See Medication Guide.]

Patients should be informed that formoterol, one of the active ingredients in
DULERA, increases the risk of asthma-related death. In pediatric and adolescent
patients, formoterol may increase the risk of asthma-related hospitalization.
They should also be informed that data are not adequate to determine whether the
concurrent use of inhaled corticosteroids, the other component of DULERA, or
other long-term asthma-control therapy mitigates or eliminates this risk [see
Warnings and Precautions (5.1)].

17.2 Not for Acute Symptoms

DULERA is not indicated to relieve acute asthma symptoms and extra doses should
not be used for that purpose. Acute symptoms should be treated with an inhaled,
short-acting, beta2-agonist (the health care provider should prescribe the
patient with such medication and instruct the patient in how it should be used).

Patients should be instructed to seek medical attention immediately if they
experience any of the following:

* If their symptoms worsen
* Significant decrease in lung function as outlined by the physician
* If they need more inhalations of a short-acting beta2-agonist than usual

Patients should be advised not to increase the dose or frequency of DULERA. The
daily dosage of DULERA should not exceed two inhalations twice daily. If they
miss a dose, they should be instructed to take their next dose at the same time
they normally do. DULERA provides bronchodilation for up to 12 hours.

Patients should not stop or reduce DULERA therapy without physician/provider
guidance since symptoms may recur after discontinuation [see Warnings and
Precautions(5.2)].

17.3 Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed DULERA, other long-acting beta2-agonists should not
be used [seeWarnings and Precautions(5.3)].

17.4 Risks Associated With Corticosteroid Therapy

Local Effects: Patients should be advised that localized infections with Candida
albicans occurred in the mouth and pharynx in some patients. If oropharyngeal
candidiasis develops, it should be treated with appropriate local or systemic
(i.e., oral) antifungal therapy while still continuing with DULERA therapy, but
at times therapy with DULERA may need to be temporarily interrupted under close
medical supervision. Rinsing the mouth after inhalation is advised [see Warnings
and Precautions (5.4)].

Immunosuppression: Patients who are on immunosuppressant doses of
corticosteroids should be warned to avoid exposure to chickenpox or measles and,
if exposed, to consult their physician without delay. Patients should be
informed of potential worsening of existing tuberculosis, fungal, bacterial,
viral, or parasitic infections, or ocular herpes simplex [see Warnings and
Precautions (5.5)].

Hypercorticism and Adrenal Suppression: Patients should be advised that DULERA
may cause systemic corticosteroid effects of hypercorticism and adrenal
suppression. Additionally, patients should be instructed that deaths due to
adrenal insufficiency have occurred during and after transfer from systemic
corticosteroids. Patients should taper slowly from systemic corticosteroids if
transferring to DULERA [see Warnings and Precautions (5.7)].

Reduction in Bone Mineral Density: Patients who are at an increased risk for
decreased BMD should be advised that the use of corticosteroids may pose an
additional risk and should be monitored and, where appropriate, be treated for
this condition [see Warnings and Precautions (5.12)].

Reduced Growth Velocity: Patients should be informed that orally inhaled
corticosteroids, a component of DULERA, may cause a reduction in growth velocity
when administered to pediatric patients. Physicians should closely follow the
growth of pediatric patients taking corticosteroids by any route [see Warnings
and Precautions (5.13)].

Glaucoma and Cataracts: Long-term use of inhaled corticosteroids may increase
the risk of some eye problems (glaucoma or cataracts); regular eye examinations
should be considered [see Warnings and Precautions (5.14)].

17.5 Risks Associated With Beta-Agonist Therapy

Patients should be informed that treatment with beta2-agonists may lead to
adverse events which include palpitations, chest pain, rapid heart rate, tremor
or nervousness [see Warnings and Precautions (5.11)].

Manufactured by 3M Health Care Ltd., Loughborough, United Kingdom.
Manufactured for Schering Corporation, a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889 USA.

Copyright © 2010 Schering Corporation, a subsidiary of Merck & Co., Inc.
All rights reserved.
U.S. Patent Nos. 5889015; 6057307; 6677323; 6068832; 7067502; and 7566705.
The trademarks depicted in this piece are owned by their respective companies.

Medication Guide

DULERA [dew-LAIR-ah] 100 mcg/5 mcg

(mometasone furoate 100 mcg and formoterol fumarate dihydrate 5 mcg inhalation
aerosol)

DULERA 200 mcg/5 mcg

(mometasone furoate 200 mcg and formoterol fumarate dihydrate 5 mcg inhalation
aerosol)

Read the Medication Guide that comes with DULERA before you start using it and
each time you get a refill. There may be new information. This Medication Guide
does not take the place of talking to your healthcare provider about your
medical condition or treatment.

What is the most important information I should know about DULERA?

DULERA can cause serious side effects, including:

1.People with asthma who take long-acting beta2-adrenergic agonist (LABA)
medicines such as formoterol (one of the medicines in DULERA), have an increased
risk of death from asthma problems. It is not known whether mometasone furoate,
the other medicine in DULERA, reduces the risk of death from asthma problems
seen with formoterol.

* Call your healthcare provider if breathing problems worsen overtime while
using DULERA. You may need different treatment.
* Get emergency medical care if:

* breathing problems worsen quickly, and
* you use your rescue inhaler medicine, but it does not relieve your breathing
problems.

2.DULERA should be used only if your healthcare provider decides that your
asthma is not well controlled with a long-term asthma control medicine, such as
an inhaled corticosteroid.

3. When your asthma is well controlled, your healthcare provider may tell you to
stop taking DULERA. Your healthcare provider will decide if you can stop DULERA
without loss of asthma control. Your healthcare provider may prescribe a
different long-term asthma-control medicine for you, such as an inhaled
corticosteroid.

4. Children and adolescents who take LABA medicines may have an increased risk
of being hospitalized for asthma problems.

What is DULERA?

DULERA combines an inhaled corticosteroid medicine, mometasone furoate (the same
medicine found in ASMANEX TWISTHALER), and a long-acting beta2-agonist medicine
(LABA), formoterol (the same medicine found in FORADIL AEROLIZER).

* Inhaled corticosteroids help to decrease inflammation in the lungs.
Inflammation in the lungs can lead to asthma symptoms.
* LABA medicines are used in people with asthma. LABA medicines help the muscles
around the airways in your lungs stay relaxed to prevent asthma symptoms, such
as wheezing and shortness of breath. These symptoms can happen when the muscles
around the airways tighten. This makes it hard to breathe. In severe cases,
wheezing can stop your breathing and may lead to death if not treated right
away.

DULERA is used to control symptoms of asthma and prevent symptoms such as
wheezing in people 12 years of age and older.

DULERA should not be used as a rescue inhaler.

DULERA contains formoterol (the same medicine found in FORADIL AEROLIZER). LABA
medicines such as formoterol increase the risk of death from asthma problems.

DULERA is not for children and adults with asthma who:

* are well controlled with an asthma-control medicine, such as a low to medium
dose of an inhaled corticosteroid medicine
* only need a rescue inhaler once in awhile

It is not known if DULERA is safe and effective in children less than 12 years
of age.

Who should not use DULERA?

Do not use DULERA:

* to treat sudden severe symptoms of asthma
* if you are allergic to any of the ingredients in DULERA. See the end of the
Medication Guide for a list of ingredients in DULERA.

What should I tell my healthcare provider before using DULERA?

Tell your healthcare provider about all of your health conditions, including if
you:

* have heart problems
* have high blood pressure
* have seizures
* have thyroid problems
* have diabetes
* have liver problems
* have osteoporosis
* have an immune system problem
* have eye problems such as increased pressure in the eye, glaucoma, or
cataracts
* are allergic to any medicines
* are exposed to chickenpox or measles
* have any other medical problems
* are pregnant or planning to become pregnant. It is not known if DULERA may
harm your unborn baby.
* are breastfeeding. It is not known if DULERA passes into your milk and if it
can harm your baby. You and your healthcare provider should decide if you will
take DULERA while breastfeeding.

Tell your healthcare provider about all the medicines you take including
prescription and non-prescription medicines, vitamins, and herbal supplements.
DULERA and certain other medicines may interact with each other. This may cause
serious side effects.

Especially, tell your healthcare provider if you take antifungal medicines, such
as ketoconazole, or anti-HIV medicines, such as ritonavir. The anti-HIV
medicines NORVIR (ritonavir capsules) Soft Gelatin, NORVIR (ritonavir oral
solution), and KALETRA (lopinavir/ritonavir) Tablets contain ritonavir.

Know the medicines you take. Keep a list and show it to your healthcare provider
and pharmacist each time you get a new medicine.

How should I use DULERA?

See the step-by-step instructions for using DULERA at the end of this Medication
Guide. Do not use DULERA unless your healthcare provider has taught you and you
understand everything. Ask your healthcare provider or pharmacist if you have
any questions.

* Use DULERA exactly as prescribed. Do not use DULERA more often than
prescribed. DULERA comes in 2 strengths. Your healthcare provider has prescribed
the strength that is best for you. Note the differences between DULERA and your
other inhaled medications, including the differences in prescribed use and
physical appearance.
* DULERA should be taken every day as 2 puffs in the morning and 2 puffs in the
evening.
* If you miss a dose of DULERA, skip your missed dose and take your next dose at
your regular time. Do not take DULERA more often or use more puffs than you have
been prescribed.
* While you are using DULERA 2 times each day, do not use other medicines that
contain a long-acting beta2-agonist (LABA) for any reason. Ask your healthcare
provider or pharmacist if any of your other medicines are LABA medicines.
* If you take more DULERA than your healthcare provider has prescribed, get
medical help right away if you have any unusual symptoms, such as problems
breathing, palpitations, chest pain, increased heart rate, nervousness or
shakiness.
* Do not change or stop using DULERA or other asthma medicines used to control
or treat your breathing problems unless told to do so by your healthcare
provider. Your healthcare provider will change your medicines as needed.
* DULERA does not relieve sudden asthma symptoms. Always have a rescue inhaler
with you to treat sudden symptoms. Use your rescue inhaler if you have breathing
problems between doses of DULERA. If you do not have a rescue inhaler, call your
healthcare provider to have one prescribed for you.
* Rinse your mouth with water after each dose (2 puffs) of DULERA. This will
help to lessen the chance of getting a yeast infection (thrush) in the mouth and
throat.
* Do not spray DULERA in your eyes. If you accidentally get DULERA in your eyes,
rinse your eyes with water and if redness or irritation continues, call your
healthcare provider.
* Call your healthcare provider or get medical care right away if:

* your breathing problems worsen with DULERA
* you need to use your rescue inhaler more often than usual
* your rescue inhaler does not work as well for you at relieving symptoms
* you need to use 4 or more inhalations of your rescue inhaler for 2 or more
days in a row
* you use 1 whole canister of your rescue inhaler in 8 weeks` time
* your peak flow meter results decrease. Your healthcare provider will tell you
the numbers that are right for you.
* you have asthma and your symptoms do not improve after using DULERA regularly
for 1 to 2 weeks

What are the possible side effects of DULERA?

DULERA can cause serious side effects, including:

* See "What is the most important information I should know about DULERA?"
* Thrush in the mouth and throat. You may develop a yeast infection (Candida
albicans) in your mouth or throat. Rinse your mouth with water after using
DULERA to help prevent an infection in your mouth or throat.
* Immune system effects and a higher chance for infections.
* Tell your healthcare provider about any signs of infection such as:

* fever
* feeling tired
* pain
* nausea
* body aches
* vomiting
* chills

* Adrenal insufficiency. Adrenal insufficiency is a condition in which the
adrenal glands do not make enough steroid hormones. This can happen when you
stop taking oral corticosteroid medicines and start inhaled corticosteroid
medicines.
* Increased wheezing right after taking DULERA. Always have a rescue inhaler
with you to treat sudden wheezing.
* Serious allergic reactions. Call your healthcare provider or get emergency
medical care if you get any of the following symptoms of a serious allergic
reaction:

* rash
* hives
* swelling of the face, mouth, and tongue
* breathing problems

* Using too much of a LABA medicine may cause:

* chest pain
* increased or decreased blood pressure
* a fast and irregular heartbeat
* headache
* tremor
* nervousness
* dizziness
* weakness
* seizures

* Lower bone mineral density. This may be a problem for people who already have
a higher chance for low bone density (osteoporosis).
* Slowed growth in children. A child`s growth should be checked often.
* Eye problems including glaucoma and cataracts. You should haveregulareye exams
while using DULERA.
* Decreases in blood potassium levels (hypokalemia)
* Increases in blood sugar levels (hyperglycemia)

The most common side effects of DULERA include:

* inflammation of the nose and throat (nasopharyngitis)
* inflammation of the sinuses (sinusitis)
* headache

Tell your healthcare provider about any side effect that bothers you or that
does not go away.

These are not all the side effects with DULERA. Ask your healthcare provider or
pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.

You may also report side effects to Schering Corporation, a subsidiary of Merck
& Co., Inc., at 1-800-526-4099.

How do I store DULERA?

* Store DULERA at room temperature between 59°F to 86°F (15°C to 30°C).
* The contents of your DULERA are under pressure. Do not puncture. Do not use or
store near heat or open flame. Storage above 120°F may cause the canister to
burst.
* Do not throw container into fire or incinerator.
* Keep DULERA and all medicines out of the reach of children.

General Information about DULERA

Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use DULERA for a condition for which it was not
prescribed. Do not give your DULERA to other people, even if they have the same
condition. It may harm them.

This Medication Guide summarizes the most important information about DULERA. If
you would like more information, talk with your healthcare provider. You can ask
your healthcare provider or pharmacist for information about DULERA that was
written for healthcare professionals. For more information about DULERA, go to
www.DULERA.com or call 1-800-526-4099.

What are the ingredients in DULERA?

Active ingredients: mometasone furoate and formoterol fumarate dihydrate

Inactive ingredient: hydrofluoroalkane (HFA-227), anhydrous alcohol and oleic
acid

Patient Instructions for Use

DULERA

DULERA 100 mcg/5 mcg

(mometasone furoate 100 mcg and formoterol fumarate dihydrate 5 mcg inhalation
aerosol)

DULERA 200 mcg/5 mcg

(mometasone furoate 200 mcg and formoterol fumarate dihydrate 5 mcg inhalation
aerosol)

How to use your DULERA

Before using your DULERA, read the complete instructions and use only as
directed.

The parts of your DULERA:

There are 2 main parts to your DULERA inhaler - the metal canister that holds
the medicine and the blue plastic actuator that sprays the medicine from the
canister. The inhaler also has a cap that covers the mouthpiece of the actuator
(see Figure 1). The inhaler contains 120 actuations (puffs).

(Graphic Omitted)

Figure 1

The inhaler comes with dose counter located on the plastic actuator. See Figure
1. The counter display will show the number of actuations (puffs) of medicine
remaining. The dose counter will initially display "124" actuations remaining.
Each time you press the canister, a puff of medicine is released and the counter
will count down by 1. The counter will stop counting at 0.

* You should not remove the canister from the actuator because reinsertion may
cause the counter to count down by 1 and discharge a puff.
* Use the DULERA canister only with the actuator supplied with the product. Do
not use parts of the DULERA inhaler with parts from any other inhalation
medicine.

Before using your DULERA:

Remove the cap from the mouthpiece of the actuator (see Figure 2). Check the
mouthpiece for objects before use. Make sure the canister is fully inserted into
the actuator.

(Graphic Omitted)

Figure 2

Priming your DULERA Inhaler:

Before you use DULERA for the first time, you must prime the inhaler.

1. To prime the inhaler, hold it in the upright position and release 4
actuations (puffs) into the air, away from your face.

2. Shake the inhaler well before each of the priming actuations. After priming 4
times, the dose counter should read "120".

3. If you do not use your DULERA for more than 5 days, you will need to prime it
again before use.

Using your DULERA

4. Remove the cap from the mouthpiece of the actuator (see Figure 2). Check the
mouthpiece for objects before use. Make sure the canister is fully inserted into
the actuator.

5. Shake the inhaler well before each use.

6. Breathe out as fully as you comfortably can through your mouth. Push out as
much air from your lungs as possible. Hold the inhaler in the upright position
and place the mouthpiece into your mouth (see Figure 3). Close your lips around
the mouthpiece.

(Graphic Omitted)

Figure 3

7. Take a deep breath (inhale) in slowly through your mouth. While doing this,
press down firmly and fully on the top of the canister until it stops moving in
the actuator. Take your finger off the canister.

8. When you have finished breathing in, hold your breath as long as you
comfortably can, up to 10 seconds. Then remove the inhaler from your mouth and
breathe out through your nose, while keeping your lips closed.

9. Wait at least 30 seconds, to take your second puff of DULERA.

10. Shake the inhaler well again and repeat steps 3 through 5 before you take
your second puff of DULERA.

After using your DULERA inhaler:

11. Replace the cap over the mouthpiece right away after use.

12. After you finish taking DULERA (2 puffs), rinse your mouth with water.

Reading the counter

* The dose counter identifies the number of inhalations (puffs) left in your
inhaler.
* The counter will count down each time you release a puff of medicine (either
when preparing your DULERA inhaler for use or when taking the medicine).

(Graphic Omitted)

When to replace your DULERA:

* It is important that you pay attention to the number of inhalations (puffs)
left in your DULERA inhaler by reading the counter.
* When the counter reads 20, you should refill your prescription or ask your
healthcare provider if you need a new prescription for DULERA.
* Throw away DULERA after the counter reaches 0, indicating that you have used
the number of actuations on the product label and box. Your inhaler may not feel
empty and it may continue to operate, but you will not get the right amount of
medicine if you keep using it.
* Never try to change the numbers on the counter or remove the counter from the
actuator.
* Do not use the inhaler after the expiration date.

How do I store DULERA?

* Store DULERA at room temperature between 59°F to 86°F (15°C to 30°C).
* The contents of your DULERA canister are under pressure. Do not puncture or
throw the canister into a fire or incinerator. Do not use or store it near heat
or open flame. Storage above 120ºF (50°C) may cause the canister to burst.
* Keep DULERA and all medicines out of the reach of children.

How to clean your DULERA:

The mouthpiece should be cleaned using a dry wipe after every 7 days of use.

Routine cleaning instructions:

* Remove the cap off the mouthpiece. Wipe the inside and outside surfaces of the
actuator mouthpiece with a clean, dry, lint-free tissue or cloth. Put the cap
back on the mouthpiece after cleaning.
* Do not attempt to unblock the actuator with a sharp object, such as a pin.
* Do not wash or put any parts of your inhaler in water.

Manufactured by 3M Health Care Ltd., Loughborough, United Kingdom.

Manufactured for Schering Corporation, a subsidiary of Merck & Co., Inc.,
Whitehouse Station, NJ 08889 USA.

Month Year

This Medication Guide has been approved by the U.S. Food and Drug
Administration.

Copyright © 2010 Schering Corporation, a subsidiary of Merck & Co., Inc. All
rights reserved.

The trademarks depicted in this piece are owned by their respective companies.

FORADIL is a registered trademark of Astellas Pharma Inc.

AEROLIZER is a registered trademark of Novartis AG.

NORVIR and KALETRA are registered trademarks of Abbott Laboratories.

Merck
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