Included as part of the PRECAUTIONS section.
Serious Asthma-Related Events – Hospitalizations,
Intubations, And Death
Use of LABA as monotherapy (without ICS) for asthma is
associated with an increased risk of asthma-related death [see Salmeterol
Multicenter Asthma Research Trial (SMART)]. Available data from controlled
clinical trials also suggest that use of LABA as monotherapy increases the risk
of asthma-related hospitalization in pediatric and adolescent patients. These
findings are considered a class effect of LABA monotherapy. When LABA are used
in fixed-dose combination with ICS, data from large clinical trials do not show
a significant increase in the risk of serious asthma-related events
(hospitalizations, intubations, death) compared to ICS alone [see Serious
Asthma-Related Events with ICS/LABA].
Serious Asthma-Related Events With ICS/LABA
Four large, 26-week, randomized, blinded,
active-controlled clinical safety trials were conducted to evaluate the risk of
serious asthma-related events when LABA were used in fixed-dose combination
with ICS compared to ICS alone in patients with asthma. Three trials included
adult and adolescent patients aged ≥12 years: one trial compared
mometasone furoate/formoterol (DULERA) to mometasone furoate [see Clinical
Studies]; one trial compared fluticasone propionate/salmeterol inhalation
powder to fluticasone propionate inhalation powder; and one trial compared
budesonide/formoterol to budesonide. The fourth trial included pediatric
patients 4 to 11 years of age and compared fluticasone propionate/salmeterol
inhalation powder to fluticasone propionate inhalation powder. The primary
safety endpoint for all four trials was serious asthma-related events
(hospitalizations, intubations and death). A blinded adjudication committee
determined whether events were asthma-related.
The three adult and adolescent trials were designed to
rule out a risk margin of 2.0, and the pediatric trial was designed to rule out
a risk of 2.7. Each individual trial met its pre-specified objective and
demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the
three adult and adolescent trials did not show a significant increase in risk
of a serious asthma-related event with ICS/LABA fixed-dose combination compared
with ICS alone (Table 1). These trials were not designed to rule out all risk
for serious asthma-related events with ICS/LABA compared with ICS.
Table 1: Meta-Analysis of Serious Asthma-Related
Events in Patients with Asthma Aged 12 Years and Older
|ICS/LABA vs. ICS Hazard ratio (95% CI)+
|Serious asthma-related event‡
|Asthma-related intubation (endotracheal)
|Asthma-related hospitalization (≥24 hour stay)
|ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic
* Randomized patients who had taken at least 1 dose of study drug. Planned
treatment used for analysis.
† Estimated using a Cox proportional hazards model for time to first event with
baseline hazards stratified by each of the 3 trials.
‡ Number of patients with events that occurred within 6 months after the first
use of study drug or 7 days after the last date of study drug, whichever date
was later. Patients can have one or more events, but only the first event was
counted for analysis. A single, blinded, independent adjudication committee
determined whether events were asthma-related.
The pediatric safety trial included 6208 pediatric
patients 4 to 11 years of age who received ICS/LABA (fluticasone
propionate/salmeterol inhalation powder) or ICS (fluticasone propionate
inhalation powder). In this trial, 27/3107 (0.9%) patients randomized to
ICS/LABA and 21/3101 (0.7%) patients randomized to ICS experienced a serious
asthma-related event. There were no asthma-related deaths or intubations.
ICS/LABA did not show a significantly increased risk of a serious
asthma-related event compared to ICS based on the pre-specified risk margin
(2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI:
Salmeterol Multicenter Asthma Research Trial (SMART)
A 28-week, placebo-controlled U.S. trial that compared
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; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS
was not required in SMART. The increased risk of asthma-related death is
considered a class effect of LABA monotherapy.
Formoterol Monotherapy Studies
Clinical studies with formoterol used as monotherapy
suggested a higher incidence of serious asthma exacerbation in patients who
received formoterol than in those who received placebo. The sizes of these
studies were not adequate to precisely quantify the difference in serious
asthma exacerbations between treatment groups.
Deterioration 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 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
Excessive Use Of DULERA And Use With Other Long-Acting
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.
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.
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.
Transferring Patients From Systemic Corticosteroid
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
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
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
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.
Hypercorticism 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.
Drug Interactions With Strong Cytochrome P450 3A4
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 and CLINICAL PHARMACOLOGY].
Paradoxical 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 bronchodilator. DULERA should be discontinued
immediately and alternative therapy instituted.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after
administration of DULERA, as demonstrated by cases of urticaria, flushing,
allergic dermatitis, and bronchospasm.
Cardiovascular 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.
Reduction 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
Effect 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
Glaucoma 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
DULERA, like other medications containing sympathomimetic
amines, should be used with caution in patients with aneurysm,
pheochromocytoma, 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.
Hypokalemia 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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Serious Asthma-Related Events
Inform patients with asthma that LABA when used alone
increases the risk of asthma-related hospitalization, or asthma-related death.
Available data show that when ICS and LABA are used together, such as with
DULERA, there is not a significant increase in risk of these events.
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
- If they need more inhalations of a short-acting beta2-agonist
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].
Do Not Use Additional Long-Acting Beta2-Agonists
When patients are prescribed DULERA, other long-acting
beta2-agonists should not be used [see WARNINGS AND PRECAUTIONS].
Risks Associated With Corticosteroid Therapy
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].
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
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].
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].
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].
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].
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].
Instructions For Use
Patients should be instructed regarding the following:
- Read the Patient Information before use and follow the
Instructions for Use carefully.
- Patients should be reminded to:
- Remove the cap from the mouthpiece of the actuator before
- Rinse their mouth with water after breathing in the
medicine. To spit out the water and not to swallow it.
- Not remove the canister from the actuator.
- Not wash inhaler in water. The mouthpiece should be
cleaned using a dry wipe after every 7 days of use.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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
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).
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
Use In Specific Populations
There are no randomized clinical studies of DULERA, mometasone
furoate, or formoterol fumarate in pregnant women. There are clinical
considerations with the use of DULERA in pregnant women [see Clinical
Considerations]. Animal reproduction studies with DULERA are not available;
however, studies are available with its individual components, mometasone
furoate and formoterol fumarate. In animal reproduction studies, subcutaneous
administration of mometasone furoate to pregnant mice, rats, or rabbits caused
increased fetal malformations and decreased fetal survival and growth following
administration of doses that produced exposures approximately 1/3 to 8 times
the maximum recommended human dose (MRHD) on a mcg/m² or AUC basis [see Data].
However, experience with oral corticosteroids suggests that rodents are more
prone to teratogenic effects from corticosteroid exposure than humans. In
animal reproduction studies, oral administration of formoterol fumarate to
pregnant rats and rabbits caused increased fetal malformations (rats and
rabbits), decreased fetal weight (rats), and increased neonatal mortality
(rats) following administration of doses that produced exposures approximately
1200 to 49,000 times the MRHD on a mg/m² or AUC basis [see Data]. These
adverse effects generally occurred at large multiples of the MRHD when
formoterol fumarate was administered by the oral route to achieve high systemic
exposures. No effects were observed in a study with rats that received
formoterol fumarate by the inhalation route at an exposure approximately 500
times the MRHD.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
In women with poorly or moderately controlled asthma,
there is an increased risk of several perinatal adverse outcomes such as
preeclampsia in the mother and prematurity, low birth weight, and small for
gestational age in the neonate. Pregnant women with asthma should be closely
monitored and medication adjusted as necessary to maintain optimal asthma control.
Labor Or delivery
There are no adequate and well-controlled human studies
that have studied the effects of DULERA during labor and delivery. Because of
the potential for beta-agonist interference with uterine contractility, use of
DULERA during labor should be restricted to those patients in whom the benefits
clearly outweigh the risk.
In an embryofetal development study with pregnant mice
dosed throughout the period of organogenesis, mometasone furoate produced cleft
palate at an exposure approximately one-third of the MRHD (on a mcg/m² basis
with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal
survival at an exposure approximately equivalent to the MRHD (on a mcg/m² basis
with a maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with
a dose that produced an exposure approximately one-tenth of the MRHD (on a
mcg/m² basis with maternal topical dermal doses of 20 mcg/kg and above).
In an embryofetal development study with pregnant rats
dosed throughout the period of organogenesis, mometasone furoate produced fetal
umbilical hernia at exposures approximately 6 times the MRHD (on a mcg/m² basis
with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal
ossification at exposures approximately 3 times the MRHD (on a mcg/m² basis
with maternal topical dermal doses of 300 mcg/kg and above).
In another reproductive toxicity study, pregnant rats
were dosed with 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 an exposure that was
approximately 8 times the MRHD (on an area under the curve (AUC) basis with a
maternal subcutaneous dose of 15 mcg/kg). There were no findings with an
exposure approximately 4 times the MRHD (on an AUC basis with a maternal
subcutaneous dose of 7.5 mcg/kg).
Embryofetal development studies were conducted with
pregnant rabbits dosed with mometasone furoate by either the topical dermal
route or oral route throughout the period of organogenesis. In the study using
the topical dermal route, mometasone furoate caused multiple malformations in
fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia,
hydrocephaly) at an exposure approximately 3 times the MRHD (on a mcg/m² basis
with maternal topical dermal doses of 150 mcg/kg and above). In the study using
the oral route, mometasone furoate caused increased fetal resorptions and cleft
palate and/or head malformations (hydrocephaly and domed head) at an exposure
approximately ½ of the MRHD (on AUC basis with a maternal oral dose of 700
mcg/kg). At an exposure approximately 2 times the MRHD (on an AUC basis with a
maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No
effects were observed at an exposure approximately 1/10 of the MRHD (on an AUC
basis with a maternal oral dose of 140 mcg/kg).
In embryofetal development studies with pregnant rats and
rabbits dosed throughout the period of organogenesis, formoterol fumarate did
not cause malformations in either species. However, for pregnant rats dosed
throughout organogenesis, formoterol fumarate caused delayed fetal ossification
at an exposure approximately 80 times the MRHD (on a mcg/m² basis with maternal
oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure
approximately 2400 times the MRHD (on a mcg/m² basis with maternal oral doses
of 6000 mcg/kg and above). In a pre-and post-natal development study with rats
dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth
and neonatal mortality at an exposure approximately 2400 times the MRHD (on a
mcg/m² basis with maternal oral doses of 6000 mcg/kg and above). However, no
effects were observed in this study at an exposure approximately 80 times the
MRHD (on a mcg/m² basis with a maternal oral dose of 200 mcg/kg).
In embryofetal development studies, conducted by another
testing laboratory, with pregnant rats and rabbits dosed throughout the period
of organogenesis, formoterol fumarate was teratogenic in both species.
Umbilical hernia, a malformation, was observed in rat fetuses at exposures
approximately 1200 times the MRHD (on a mcg/m² basis with maternal oral doses
of 3000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was
observed in rat fetuses at an exposure approximately 6100 times the MRHD (on a
mcg/m² basis with a maternal oral dose of 15,000 mcg/kg/day). In another study
with rats, no teratogenic effects were observed with exposures up to
approximately 500 times the MRHD (on a mcg/m² basis with a maternal inhalation
dose of 1200 mcg/kg/day). Subcapsular cysts on the liver were observed in
rabbit fetuses at an exposure approximately 49,000 times the MRHD (on a mcg/m² basis
with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were
observed with exposures up to approximately 3000 times the MRHD (on a mcg/m² basis
with a maternal oral dose of 3500 mcg/kg).
There are no available data on the presence of DULERA,
mometasone furoate, or formoterol fumarate in human milk, the effects on the
breastfed child, or the effects on milk production. Other inhaled
corticosteroids, similar to mometasone furoate, are present in human milk.
Formoterol fumarate is present in rat milk; however, due to species specific
differences in lactation physiology, animal lactation data may not reliably
predict levels in human milk. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for
DULERA and any potential adverse effects on the breastfed infant from DULERA or
from the underlying maternal condition.
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-pituitaryadrenal (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
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].
A total of 77 patients 65 years of age and older (11 of
whom 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.
Concentrations of mometasone furoate appear to increase
with severity of hepatic impairment [see CLINICAL PHARMACOLOGY].