Included as part of the PRECAUTIONS section.
Serious Asthma-Related Events – Hospitalizations,
Use of LABA as monotherapy [without inhaled
corticosteroids (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 with ICS alone [see Serious Asthma-Related Events with Inhaled
Corticosteroid/Long-acting Beta2-adrenergic Agonists].
Serious Asthma-Related Events With Inhaled Corticosteroid/Long-acting
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 with ICS alone in subjects with asthma. Three (3) trials
included adult and adolescent subjects aged 12 years and older: 1 trial
compared budesonide/formoterol to budesonide, 1 trial compared fluticasone
propionate/salmeterol inhalation powder to fluticasone propionate inhalation
powder, and 1 trial compared mometasone furoate/formoterol to mometasone
furoate. The fourth trial included pediatric subjects aged 4 to 11 years and
compared fluticasone propionate/salmeterol inhalation powder to fluticasone
propionate inhalation powder. The primary safety endpoint for all 4 trials was
serious asthma-related events (hospitalizations, intubations, death). A blinded
adjudication committee determined whether events were asthma-related.
The 3 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 margin 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 3
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 Subjects with Asthma Aged 12 Years and Older
(n = 17,552)a
|ICS/LABA vs. ICS Hazard Ratio (95% CI)b
|Serious asthma-related event c
|Asthma-related intubation (endotracheal)
|Asthma-related hospitalization (≥24-hour stay)
|ICS = Inhaled Corticosteroid; LABA = Long-acting Beta2-adrenergic
a Randomized subjects who had taken at least 1 dose of study drug.
Planned treatment used for analysis.
b Estimated using a Cox proportional hazards model for time to first
event with baseline hazards stratified by each of the 3 trials.
c Number of subjects 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. Subjects 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 6,208 pediatric
patients aged 4 to 11 years who received ICS/LABA (fluticasone
propionate/salmeterol inhalation powder) or ICS (fluticasone propionate
inhalation powder). In this trial 27/3,107 (0.9%) of patients treated with
ICS/LABA and 21/3,101 (0.7%) of patients treated with 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 prespecified 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 subjects receiving salmeterol
(13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects
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.
Deterioration Of Disease And Acute Episodes
AirDuo Digihaler should not be initiated in patients
during rapidly deteriorating or potentially life-threatening episodes of
asthma. AirDuo Digihaler has not been studied in subjects with acutely
deteriorating asthma. The initiation of AirDuo Digihaler in this setting is not
Serious acute respiratory events, including fatalities,
have been reported when salmeterol, a component of AirDuo Digihaler, has been
initiated in patients with significantly worsening or acutely deteriorating
asthma. In most cases, these have occurred in patients with severe asthma
(e.g., patients with a history of corticosteroid dependence, low pulmonary
function, intubation, mechanical ventilation, frequent hospitalizations,
previous life-threatening acute asthma exacerbations) and in some patients with
acutely deteriorating asthma (e.g., patients with significantly increasing
symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing
response to usual medications; increasing need for systemic corticosteroids;
recent emergency room visits; deteriorating lung function). However, these
events have occurred in a few patients with less severe asthma as well. It was
not possible from these reports to determine whether salmeterol contributed to
Increasing use of inhaled, short-acting beta2-agonists is
a marker of deteriorating asthma. In this situation, the patient requires
immediate reevaluation with reassessment of the treatment regimen, giving
special consideration to the possible need for replacing the current strength
of AirDuo Digihaler with a higher strength, adding additional inhaled
corticosteroid, or initiating systemic corticosteroids. Patients should not use
more than 1 inhalation twice daily of AirDuo Digihaler.
AirDuo Digihaler should not be used 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 AirDuo Digihaler, should
be used to relieve acute symptoms such as shortness of breath. When prescribing
AirDuo Digihaler, the healthcare provider should also prescribe an inhaled,
short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms,
despite regular twice-daily use of AirDuo Digihaler.
When beginning treatment with AirDuo Digihaler, 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.
Excessive Use Of AirDuo Digihaler And Use With Other
AirDuo Digihaler should not be used more often than
recommended, at higher doses than recommended, or in conjunction with other
medicines containing LABA, 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 AirDuo Digihaler
should not use another medicine containing a LABA (e.g., salmeterol, formoterol
fumarate, arformoterol tartrate, indacaterol) for any reason.
Local Effects Of Inhaled Corticosteroids
In clinical trials, the development of localized
infections of the mouth and pharynx with Candida albicans has occurred in
subjects treated with fluticasone propionate and salmeterol MDPI. When such an
infection develops, it should be treated with appropriate local or systemic
(i.e., oral) antifungal therapy while treatment with AirDuo Digihaler
continues, but at times therapy with AirDuo Digihaler may need to be
interrupted. Advise the patient to rinse his/her mouth with water without
swallowing following inhalation to help reduce the risk of oropharyngeal
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 adolescents or adults using corticosteroids. In such patients who
have not had these diseases or who have not been 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 a patient is exposed
to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) or
pooled intravenous immunoglobulin (IVIG) may be indicated. If a patient is
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.
Inhaled corticosteroids should be used with caution, if
at all, in patients with active or quiescent tuberculosis infections of the
respiratory tract; 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 inhaled corticosteroids
because deaths due to adrenal insufficiency have occurred in patients with
asthma 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 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 AirDuo Digihaler 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 that is necessary for coping with these
During periods of stress or a severe asthmatic attack,
patients who have been withdrawn from systemic corticosteroids should be
instructed to resume oral corticosteroids (in large doses) immediately and to
contact their physician for further instruction. These patients should also be
instructed to carry a medical identification warning card indicating that they
may need supplementary systemic corticosteroids during periods of stress or a
severe asthma attack.
Patients requiring systemic corticosteroids should be
weaned slowly from systemic corticosteroid use after transferring to AirDuo
Digihaler. Lung function (mean forced expiratory volume in 1 second [FEV1] or
morning peak expiratory flow [AM 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 AirDuo Digihaler may unmask allergic conditions previously suppressed by the
systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema,
arthritis, 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, depression) despite
maintenance or even improvement of respiratory function.
Hypercorticism And Adrenal Suppression
Fluticasone propionate, a component of AirDuo Digihaler,
will often help control asthma symptoms with less suppression of HPA function
than therapeutically equivalent oral doses of prednisone. Since fluticasone
propionate is absorbed into the circulation and can be systemically active at
higher doses, the beneficial effects of AirDuo Digihaler in minimizing HPA
dysfunction may be expected only when recommended dosages are not exceeded and
individual patients are titrated to the lowest effective dose. A relationship
between plasma levels of fluticasone propionate and inhibitory effects on
stimulated cortisol production has been shown after 4 weeks of treatment with
fluticasone propionate inhalation aerosol. Since individual sensitivity to
effects on cortisol production exists, physicians should consider this
information when prescribing AirDuo Digihaler.
Because of the possibility of significant systemic
absorption of inhaled corticosteroids, patients treated with AirDuo Digihaler
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 who are sensitive to these effects. If such
effects occur, AirDuo Digihaler 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
The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors
(e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole,
nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with AirDuo
Digihaler is not recommended because increased systemic corticosteroid and
increased cardiovascular adverse effects may occur [see DRUG INTERACTIONS
and, CLINICAL PHARMACOLOGY].
Paradoxical Bronchospasm And Upper Airway Symptoms
As with other inhaled medicines, AirDuo Digihaler can
produce paradoxical bronchospasm, which may be life-threatening. If paradoxical
bronchospasm occurs following dosing with inhaled fluticasone
propionate/salmeterol medicines, it should be treated immediately with an
inhaled, short-acting bronchodilator; inhaled fluticasone propionate/salmeterol
medicines should be discontinued immediately; and alternative therapy should be
instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling,
such as stridor and choking, have been reported in patients receiving inhaled
fluticasone propionate/salmeterol medicines.
Hypersensitivity Reactions, Including Anaphylaxis
Immediate hypersensitivity reactions (e.g., urticaria,
angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur
after administration of AirDuo Digihaler. There have been reports of
anaphylactic reactions in patients with severe milk protein allergy after
inhalation of other powder products containing lactose; therefore, patients
with severe milk protein allergy should not use AirDuo Digihaler [see CONTRAINDICATIONS].
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 [see OVERDOSAGE]. Therefore,
AirDuo Digihaler, like all products containing sympathomimetic amines, should
be used with caution in patients with cardiovascular disorders, especially
coronary insufficiency, cardiac arrhythmias, and hypertension.
Salmeterol, a component of AirDuo Digihaler, 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 salmeterol at recommended doses, if they occur, the
drug may need to be discontinued. In addition, beta-agonists have been reported
to produce electrocardiogram (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. Large doses of inhaled or oral
salmeterol (12 to 20 times the recommended dose) have been associated with
clinically significant prolongation of the QTc interval, which has the
potential for producing ventricular arrhythmias. 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. The clinical significance of small changes in BMD with regard
to long-term consequences 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, oral corticosteroids) should be monitored and
treated with established standards of care.
Effect On Growth
Orally inhaled corticosteroids, including AirDuo
Digihaler, may cause a reduction in growth velocity when administered to
pediatric patients. Monitor the growth of pediatric patients receiving AirDuo
Digihaler routinely (e.g., via stadiometry). To minimize the systemic effects
of orally inhaled corticosteroids, including AirDuo Digihaler, titrate each
patient’s dosage to the lowest dosage that effectively controls his/her
symptoms [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Glaucoma And Cataracts
Glaucoma, increased intraocular pressure, and cataracts
have been reported in patients following the long-term administration of
inhaled corticosteroids, including fluticasone propionate, a component of
AirDuo Digihaler. Therefore, close monitoring is warranted in patients with a
change in vision or with a history of increased intraocular pressure, glaucoma,
Effects of treatment with other Fluticasone Propionate
and Salmeterol Inhalation Powder 500/50, fluticasone propionate 500 mcg,
salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was
evaluated in a subset of 658 subjects with COPD in the 3-year survival trial.
Ophthalmic examinations were conducted at baseline and at 48, 108, and 158
weeks. Conclusions about cataracts cannot be drawn from this trial because the
high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate
number of subjects treated with other Fluticasone Propionate and Salmeterol
Inhalation Powder 500/50 who were eligible and available for evaluation of
cataracts at the end of the trial (n = 53). The incidence of newly diagnosed
glaucoma was 2% with other Fluticasone Propionate and Salmeterol Inhalation
Powder 500/50, 5% with fluticasone propionate, 0% with salmeterol, and 2% with
Eosinophilic Conditions And Churg-Strauss Syndrome
In rare cases, patients on inhaled fluticasone
propionate, a component of AirDuo Digihaler, may present with systemic
eosinophilic conditions. Some of these patients have clinical features of
vasculitis consistent with Churg-Strauss syndrome, a condition that is often
treated with systemic corticosteroid therapy. These events usually, but not
always, have been associated with the reduction and/or withdrawal of oral
corticosteroid therapy following the introduction of fluticasone propionate.
Cases of serious eosinophilic conditions have also been reported with other
inhaled corticosteroids in this clinical setting. Physicians should be alert to
eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal
relationship between fluticasone propionate and these underlying conditions has
not been established.
AirDuo Digihaler, like all medicines containing
sympathomimetic amines, should be used with caution in patients with convulsive
disorders or thyrotoxicosis and in those who are unusually responsive to
sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist
albuterol, when administered intravenously, have been reported to aggravate
preexisting diabetes mellitus and ketoacidosis.
Hypokalemia And Hyperglycemia
Beta-adrenergic agonist medicines may produce significant
hypokalemia in some patients, possibly through intracellular shunting, which
has the potential to produce adverse cardiovascular effects [see CLINICAL
PHARMACOLOGY]. 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 trials with
fluticasone propionate/salmeterol multidose dry powder inhaler (AIRDUO
RESPICLICK hereafter referred to as fluticasone propionate/salmeterol MDPI) at
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Patients should be given the following information:
Serious Asthma Events
Inform patients with asthma that LABA when used alone
increases the risk of asthma-related hospitalization and asthma-related death.
Available data show that when ICS and LABA are used together, such as with
AirDuo Digihaler, there is not a significant increase in the risk of these
Not for Acute Symptoms
Inform patients that AirDuo Digihaler is not meant to
relieve acute asthma symptoms and extra doses should not be used for that
purpose. Advise patients to treat acute asthma symptoms with an inhaled,
short-acting beta2-agonist such as albuterol. Provide patients with such
medication and instruct them in how it should be used.
Instruct patients to seek medical attention if they
experience any of the following:
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
- Need for more inhalations than usual of inhaled,
- Significant decrease in lung function as outlined by the
Tell patients they should not stop therapy with AirDuo
Digihaler without physician/provider guidance since symptoms may recur after
Do Not Use Additional Long-Acting Beta2-Agonists
Instruct patients not to use other LABA for asthma.
Inform patients that localized infections with Candida
albicans occurred in the mouth and pharynx in some patients. If oropharyngeal
candidiasis develops, treat it with appropriate local or systemic (i.e., oral)
antifungal therapy while still continuing therapy with AirDuo Digihaler, but at
times therapy with AirDuo Digihaler may need to be temporarily interrupted
under close medical supervision. Rinsing the mouth with water without
swallowing after inhalation is advised to help reduce the risk of thrush.
Warn patients who are on immunosuppressant doses of
corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to
consult their physicians without delay. Inform patients of potential worsening
of existing tuberculosis, fungal, bacterial, viral, or parasitic infections; or
ocular herpes simplex.
Hypercorticism And Adrenal Suppression
Advise patients that AirDuo Digihaler may cause systemic
corticosteroid effects of hypercorticism and adrenal suppression. Additionally,
inform patients 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 AirDuo Digihaler.
Immediate Hypersensitivity Reactions
Advise patients that immediate hypersensitivity reactions
(e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including
anaphylaxis, may occur after administration of AirDuo Digihaler. Patients
should discontinue AirDuo Digihaler if such reactions occur and contact their healthcare
provider or get emergency medical help. There have been reports of anaphylactic
reactions in patients with severe milk protein allergy after inhalation of
powder products containing lactose; therefore, patients with severe milk
protein allergy should not take AirDuo Digihaler.
Reduction In Bone Mineral Density
Advise patients who are at an increased risk for
decreased BMD that the use of corticosteroids may pose an additional risk.
Reduced Growth Velocity
Inform patients that orally inhaled corticosteroids,
including fluticasone propionate, may cause a reduction in growth velocity when
administered to adolescent patients. Physicians should closely follow the
growth of adolescents taking corticosteroids by any route.
Long-term use of inhaled corticosteroids may increase the
risk of some eye problems (cataracts or glaucoma); consider regular eye
Risks Associated With Beta-Agonist Therapy
Inform patients of adverse effects associated with beta2-agonists,
such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
Inform patients who are pregnant or nursing that they
should contact their physician about the use of AirDuo Digihaler.
Use Daily For Best Effect
Patients should use AirDuo Digihaler at regular intervals
as directed. The daily dosage of AirDuo Digihaler should not exceed 1
inhalation twice a day. Advise patients, if they miss a dose, to take their
next dose at the same time they normally do and to not take 2 doses at one
time. Individual patients will experience a variable time to onset and degree
of symptom relief and full benefit may not be achieved until treatment has been
administered for 1 to 2 weeks or longer. Patients should not increase the
prescribed dosage but should contact their physicians if symptoms do not
improve or if the condition worsens. Instruct patients not to stop use of
AirDuo Digihaler abruptly. Patients should contact their physicians immediately
if they discontinue use of AirDuo Digihaler.
Use Of AirDuo Digihaler And Mobile App
Direct the patient to the Instructions for Use (IFU) for
information on how to set up the App and use the inhaler. Advise the patient
that pairing of the inhaler to the App, having Bluetooth turned on, or being
near their smartphone is not required for delivery of the medication from the
inhaler or for normal use of the product.
Instruct patients that the AirDuo Digihaler has a dose
counter that displays the number of actuations (inhalations) left in the inhaler.
When the patient receives a new inhaler, the number 60 will be displayed. The
dose counter will count down each time the mouthpiece is opened and closed.
When the dose counter reaches 20, the color of the numbers will change to red
to remind the patient to contact their pharmacist or healthcare provider for a
refill of their medication. When the dose counter reaches 0, the patient should
stop using the inhaler, and it should be disposed of in accordance with state
and local regulations.
Caring For And Storing The Inhaler
Instruct patients to not open their inhaler unless
they are taking a dose. Repeated opening and closing the cover without
taking medication will waste medication and may damage the inhaler.
Advise patients to keep their inhaler dry and clean at
all times. Never wash or put any part of the inhaler in water. Patient
should replace inhaler if washed or placed in water. Advise patients to
immediately replace inhaler if mouthpiece cover is damaged or broken.
Gently wipe the mouthpiece with a dry cloth or tissue as
Instruct patients to store the inhaler at room
temperature and to avoid exposure to extreme heat, cold, or humidity.
Instruct patients to never take the inhaler apart.
Inform patients that AirDuo Digihaler has a dose counter.
When the patient receives the inhaler, the number 60 will be displayed. The
dose counter will count down each time the mouthpiece cap is opened and closed.
The dose-counter window displays the number of actuations left in the inhaler
in units of two (e.g., 60, 58, 56, etc.). When the counter displays 20, the
color of the numbers will change to red to remind the patient to contact their
pharmacist for a refill of medication or consult their physician for a
prescription refill. When the dose counter reaches 0, the background will
change to solid red. Inform patients to discard AirDuo Digihaler when the dose
counter displays 0, 30 days after opening the foil pouch or after the
expiration date on the product, whichever comes first.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Fluticasone propionate demonstrated no tumorigenic
potential in mice at oral doses up to 1000 mcg/kg (approximately 10 times the MRHDID
for adults on a mcg/m² basis) for 78 weeks or in rats at inhalation doses up to
57 mcg/kg (approximately equivalent to the MRHDID for adults on a mcg/m² basis)
for 104 weeks.
Fluticasone propionate did not induce gene mutation in
prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was
seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse
Fertility and reproductive performance were unaffected in
male and female rats at subcutaneous doses up to 50 mcg/kg (approximately
equivalent to the MRHDID for adults on a mcg/m² basis).
In an 18-month carcinogenicity study in CD-mice,
salmeterol at oral doses of 1400 mcg/kg and above (approximately 240 times the
MRHDID on a mcg/m² basis) caused a dose-related increase in the incidence of
smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the
uterus, and ovarian cysts. No tumors were seen at 200 mcg/kg (approximately 35
times the MRHDID on a mcg/m² basis).
In a 24 month oral and inhalation carcinogenicity study
in Sprague Dawley rats, salmeterol caused a dose related increase in the
incidence of mesovarian leiomyomas and ovarian cysts at doses of 680 mcg/kg and
above (approximately 240 times the MRHDID on a mcg/m² basis). No tumors were
seen at 210 mcg/kg (approximately 75 times the MRHDID on a mcg/m² basis). These
findings in rodents are similar to those reported previously for other beta
adrenergic agonist drugs. The relevance of these findings to human use is unknown.
Salmeterol produced no detectable or reproducible
increases in microbial and mammalian gene mutation in vitro. No clastogenic
activity occurred in vitro in human lymphocytes or in vivo in a rat
Fertility and reproductive performance were unaffected in
male and female rats at oral doses up to 2000 mcg/kg (approximately 690 times
the MRHDID for adults on a mcg/m² basis).
Use In Specific Populations
There are no randomized clinical studies of AirDuo
Digihaler or individual monoproducts, fluticasone propionate and salmeterol, in
pregnant women. There are clinical considerations with the use of AirDuo
Digihaler in pregnant women [see Clinical Considerations]. Animal
reproduction studies are available with the combination of fluticasone
propionate and salmeterol as well as individual components. In animals,
teratogenicity characteristic of corticosteroids, decreased fetal body weight
and/or skeletal variations, in rats, mice, and rabbits were observed with
subcutaneously administered maternal toxic doses of fluticasone propionate less
than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m² basis
[see Data]. However, fluticasone propionate administered via inhalation
to rats decreased fetal body weight, but did not induce teratogenicity at a
maternal toxic dose less than the MRHDID on a mcg/m² basis [see Data].
Experience with oral corticosteroids suggests that rodents are more prone to
teratogenic effects from corticosteroids than humans. Oral administration of
salmeterol to pregnant rabbits caused teratogenicity characteristic of
beta-adrenoceptor stimulation at maternal doses approximately 700 times the
MRHDID on a mcg/m² basis. These adverse effects generally occurred at large
multiples of the MRHDID when salmeterol was administered by the oral route to
achieve high systemic exposures. No such effects occurred at an oral salmeterol
dose approximately 420 times the MRHDID [see Data].
The estimated 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
Fluticasone Propionate And Salmeterol
In an embryo/fetal development study with pregnant rats
that received the combination of subcutaneous administration of fluticasone
propionate and oral administration of salmeterol at doses of 0/1000, 30/0,
10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone
propionate/salmeterol) during the period of organogenesis, findings were generally
consistent with the individual monoproducts and there was no exacerbation of
expected fetal effects. Omphalocele, increased embryo/fetal deaths, decreased
body weight, and skeletal variations were observed in rat fetuses, in the
presence of maternal toxicity, when combining fluticasone propionate at a dose
approximately 2 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous
dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times
the MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day).
The rat no observed adverse effect level (NOAEL) was observed when combining
fluticasone propionate at a dose 0.6 times the MRHDID (on a mcg/m² basis at a
maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at
approximately 350 times the MRHDID (on a mcg/m² basis at a maternal oral dose
of 1000 mcg/kg/day).
In an embryo/fetal development study with pregnant mice
that received the combination of subcutaneous administration of fluticasone
propionate and oral administration of salmeterol at doses of 0/1400, 40/0,
10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone
propionate/salmeterol) during the period of organogenesis, findings were
generally consistent with the individual monoproducts and there was no
exacerbation of expected fetal effects. Cleft palate, fetal death, increased
implantation loss, and delayed ossification were observed in mouse fetuses when
combining fluticasone propionate at a dose approximately 1.4 times the MRHDID
(on a mcg/m² basis at a maternal subcutaneous dose of 150 mcg/kg/day) and
salmeterol at a dose approximately 1470 times the MRHDID (on a mcg/m² basis at
a maternal oral dose of 10,000 mcg/kg/day). No developmental toxicity was
observed at combination doses of fluticasone propionate up to approximately 0.8
times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 40
mcg/kg) and doses of salmeterol up to approximately 420 times the MRHDID (on a
mcg/m² basis at a maternal oral dose of 1400 mcg/kg).
In embryo/fetal development studies with pregnant rats
and mice dosed by the subcutaneous route throughout the period of
organogenesis, fluticasone propionate was teratogenic in both species.
Omphalocele, decreased body weight, and skeletal variations were observed in
rat fetuses, in the presence of maternal toxicity, at a dose approximately 2
times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 100
mcg/kg/day). The rat NOAEL was observed at approximately 0.6 times the MRHDID
(on a mcg/m² basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft
palate and fetal skeletal variations were observed in mouse fetuses at a dose
approximately 0.5 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose
approximately 0.16 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 15 mcg/kg/day).
In an embryo/fetal development study with pregnant rats
dosed by the inhalation route throughout the period of organogenesis,
fluticasone propionate produced decreased fetal body weights and skeletal
variations, in the presence of maternal toxicity, at a dose approximately 0.5
times the MRHDID (on a mcg/m² basis with a maternal inhalation dose of 25.7
mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was
observed with a dose approximately 0.1 times the MRHDID (on a mcg/m² basis with
a maternal inhalation dose of 5.5 mcg/kg/day).
In an embryo/fetal development study in pregnant rabbits
that were dosed by the subcutaneous route throughout organogenesis, fluticasone
propionate produced reductions of fetal body weights, in the presence of
maternal toxicity at doses approximately 0.02 times the MRHDID and higher (on a
mcg/m² basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).
Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at
a dose approximately 0.2 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses
with a dose approximately 0.004 times the MRHDID (on a mcg/m² basis with a
maternal subcutaneous dose of 0.08 mcg/kg/day).
In a pre- and post-natal development study in pregnant
rats dosed by the subcutaneous route from late gestation through delivery and
lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was
not associated with decreases in pup body weight, and had no effects on
developmental landmarks, learning, memory, reflexes, or fertility at doses up to
approximate equivalence to the MRHDID (on a mcg/m² basis with maternal
subcutaneous doses up to 50 mcg/kg/day).
Fluticasone propionate crossed the placenta following
subcutaneous administration to mice and rats and oral administration to
In three embryo/fetal development studies, pregnant
rabbits received oral administration of salmeterol at doses ranging from 100 to
10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits
administered salmeterol doses approximately 700 times the MRHDID (on a mcg/m² basis
at maternal oral doses of 1000 mcg/kg/day and higher), fetal toxic effects were
observed characteristically resulting from beta-adrenoceptor stimulation. These
included precocious eyelid openings, cleft palate, sternebral fusion, limb and
paw flexures, and delayed ossification of the frontal cranial bones. No such
effects occurred at a salmeterol dose approximately 420 times the MRHDID (on a
mcg/m² basis at a maternal oral dose of 600 mcg/kg/day). New Zealand White
rabbits were less sensitive since only delayed ossification of the frontal
cranial bones was seen at a salmeterol dose approximately 7,000 times the
MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day).
In two embryo/fetal development studies, pregnant rats
received salmeterol by oral administration at doses ranging from 100 to 10,000
mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal
toxicity or embryo/fetal effects at doses up to 3500 times the MRHDID (on a
mcg/m² basis at maternal oral doses up to 10,000 mcg/kg/day).
In a peri-and post-natal development study in pregnant
rats dosed by the oral route from late gestation through delivery and lactation,
salmeterol at a dose 3500 times the MRHDID (on mcg/m² basis with a maternal
oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of
Salmeterol xinafoate crossed the placenta following oral
administration to mice and rats.
There are no available data on the presence of
fluticasone propionate or salmeterol in human milk, the effects on the
breastfed child, or the effects on milk production. Other corticosteroids have
been detected in human milk. However, fluticasone propionate and salmeterol
concentrations in plasma after inhaled therapeutic doses are low and therefore
concentrations in human breast milk are likely to be correspondingly low [see CLINICAL
PHARMACOLOGY]. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for AirDuo Digihaler
and any potential adverse effects on the breastfed child from AirDuo Digihaler
or from the underlying maternal condition.
Subcutaneous administration of tritiated fluticasone
propionate at a dose in lactating rats approximately 0.2 times the MRHDID for
adults (on a mcg/m² basis) resulted in measurable levels in milk. Oral
administration of salmeterol at a dose in lactating rats approximately 2900
times the MRHDID for adults (on a mcg/m² basis) resulted in measurable levels
The safety and effectiveness of AirDuo Digihaler in the
treatment of asthma in pediatric patients aged 12 years and older whose asthma
(1) is inadequately controlled on a long term asthma control medication or (2)
warrants initiation of treatment with both an ICS and a LABA has been
established. Use of AirDuo Digihaler for this indication was supported by
evidence from two adequate and well-controlled trials in pediatric patients 12
years old and older with persistent symptomatic asthma despite ICS or ICS/LABA
therapy (Trials 1 and 2) [see Clinical Studies]. In these trials, 58
adolescents received fluticasone propionate/salmeterol MDPI one inhalation
The safety and effectiveness of AirDuo Digihaler in
pediatric patients below the age of 12 years have not been established.
Inhaled corticosteroids, including fluticasone
propionate, a component of AirDuo Digihaler, may cause a reduction in growth
velocity in adolescents [see WARNINGS AND PRECAUTIONS]. The growth of
pediatric patients receiving ICS, including AirDuo Digihaler, should be
If an adolescent on any corticosteroid appears to have
growth suppression, the possibility that he/she is particularly sensitive to
this effect of corticosteroids should be considered. In such patients, the
potential growth effects of prolonged ICS treatment should be weighed against
the clinical benefits obtained. To minimize the systemic effects of ICS,
including AirDuo Digihaler, each patient should be titrated to the lowest
strength that effectively controls his/her asthma [see DOSAGE AND
No overall differences in safety or effectiveness were
observed in data collected in 54 subjects aged 65 years and older versus
younger subjects who were treated with fluticasone propionate/salmeterol MDPI
in placebo-controlled Phase 2 and 3 asthma studies.
Formal pharmacokinetic studies using AirDuo Digihaler
have not been conducted in patients with hepatic impairment. However, since
both fluticasone propionate and salmeterol are predominantly cleared by hepatic
metabolism [see CLINICAL PHARMACOLOGY], impairment of liver function may
lead to accumulation of fluticasone propionate and salmeterol in plasma.
Therefore, patients with hepatic impairment should be closely monitored.
Formal pharmacokinetic studies using AirDuo Digihaler
have not been conducted in patients with renal impairment.