Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
SYMBICORT
AEROSPHERE is contraindicated in the following conditions:
Primary treatment of status asthmaticus or other acute
episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)].
Hypersensitivity
to budesonide, formoterol, or any of the excipients [see Warnings and Precautions (5.11) and Description (11)].
5
Warnings and Precautions
5.1 Serious Asthma-Related Events –
Hospitalizations, Intubations and Death
Newly added information:
Newly added Table 1; please refer to label for
complete information
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 greater than or equal to 12 years: one trial
compared budesonide/formoterol to budesonide; one trial compared fluticasone
propionate/salmeterol inhalation powder to fluticasone propionate inhalation
powder; and one trial compared mometasone furoate/formoterol to mometasone
furoate. The fourth trial included pediatric patients 4 to 11 years of age and
compared fluticasone propionate/salmeterol inhalation powder to fluticasone
propionate inhalation powder. SYMBICORT AEROSPHERE is not indicated for
patients 4 to 11 years of age. 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.
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:
0.73, 2.27). SYMBICORT AEROSPHERE is not indicated for use in pediatric
patients aged 11 years and younger.
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.
5.2 Deterioration of Disease and Acute Episodes
Additions and/or revisions underlined:
SYMBICORT AEROSPHERE should not be initiated in
patients with acutely deteriorating asthma or COPD, which may be a
life-threatening condition. SYMBICORT AEROSPHERE has not been studied in
patients with acutely deteriorating asthma or COPD. The initiation of
SYMBICORT AEROSPHERE 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 additional
therapeutic options. Patients should not use more than 2 inhalations twice
daily (morning and evening) of SYMBICORT AEROSPHERE.
SYMBICORT AEROSPHERE should not be used for the
relief of acute symptoms, i.e., as rescue therapy for the treatment of acute
episodes of bronchospasm. SYMBICORT AEROSPHERE has not been studied in the
relief of acute symptoms and extra doses should not be used for that purpose.
Acute symptoms should be treated with either an inhaled short-acting
beta2-agonist/corticosteroid combination (asthma only) or an inhaled
short-acting beta2-agonist (asthma or COPD).
When beginning treatment with SYMBICORT AEROSPHERE,
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 and use them only for symptomatic relief of acute
respiratory symptoms. When prescribing SYMBICORT AEROSPHERE, the healthcare
provider should also prescribe either an inhaled short-acting
beta2-agonist/corticosteroid combination (asthma only) or an inhaled, short
acting beta2-agonist (asthma or COPD) and instruct the patient on how it
should be used.
5.3 Avoid Excessive Use of SYMBICORT AEROSPHERE, and Avoid
Use with Other Long-acting Beta2-agonists
Subsection Title Revised
5.7 Transferring Patients from Systemic Corticosteroid Therapy
Additions and/or revisions underlined:
…
Although SYMBICORT AEROSPHERE may provide control of
asthma or COPD symptoms during these episodes, in recommended doses it
supplies less than normal physiological amounts of glucocorticoid systemically
and does not provide the mineralocorticoid activity that is necessary for
coping with these emergencies.
During periods of stress, a severe asthma attack
or a severe COPD exacerbation, patients who have been withdrawn from systemic
corticosteroids should be instructed to resume oral corticosteroids (in large
doses) immediately and to contact their healthcare practitioner for further instruction.
These patients should also be instructed to carry a warning card indicating that
they may need supplementary systemic corticosteroids during periods of stress, a
severe asthma attack or a severe COPD exacerbation.
Patients requiring oral corticosteroids should be
weaned slowly from systemic corticosteroid use after transferring to SYMBICORT
AEROSPHERE. Prednisone reduction can be accomplished by reducing the daily
prednisone dose by 2.5 mg on a weekly basis during therapy with SYMBICORT AEROSPHERE.
Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist
use, and asthma or COPD symptoms should be carefully monitored during
withdrawal of oral corticosteroids. In addition, patients should be observed
for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude,
weakness, nausea and vomiting, and hypotension.
5.14 Effect on Growth
Newly
added subsection:
Orally inhaled corticosteroids may cause a reduction
in growth velocity when administered to pediatric patients. Monitor the growth
of pediatric patients receiving SYMBICORT AEROSPHERE routinely (e.g., via
stadiometry). To minimize the systemic effects of orally inhaled
corticosteroids, including SYMBICORT AEROSPHERE, titrate each patient's dose to
the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2) and Use
in Specific Populations (8.4)].
5.15 Glaucoma and Cataracts
Additions and/or revisions underlined:
Glaucoma, increased intraocular pressure, and
cataracts have been reported in patients with asthma and COPD following
the long-term administration of ICS, including budesonide, a component of
SYMBICORT AEROSPHERE. Therefore, close monitoring is warranted in patients with
a change in vision or with history of increased intraocular pressure, glaucoma,
and/or cataracts. Consider referral to an ophthalmologist in patients who
develop ocular symptoms.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
Newly added Table
2; please refer to label for complete information
Asthma
The safety of SYMBICORT AEROSPHERE in asthma
is based on the safety data from two clinical trials, with durations of 12
weeks (LITHOS) and 24 weeks (VATHOS), respectively. In LITHOS, a total of 357
adult and pediatric patients aged 12 years and older with asthma were
randomized; 179 patients received at least 1 dose of SYMBICORT AEROSPHERE 160
mcg/9.6 mcg. In VATHOS, a total of 585 adult and pediatric patients aged 13
years and older were randomized; 88 patients received at least 1 dose of
SYMBICORT AEROSPHERE 160 mcg/9.6 mcg and 163 patients received at least 1 dose
of SYMBICORT AEROSPHERE 320 mcg/9.6 mcg [see Clinical Studies (14.1)].
Table 2 includes adverse reactions that occurred at
an incidence of ?2% with SYMBICORT AEROSPHERE and more commonly than in the
budesonide (BD MDI) group with twice-daily dosing in VATHOS.
Adverse
Reactions in LITHOS
In the LITHOS trial, an adverse reaction that
occurred at an incidence of at least 2% and more frequently in patients treated
with SYMBICORT AEROSPHERE 160 mcg/9.6 mcg compared to patients treated with BD
MDI 160 mcg was upper respiratory tract infection at 3.4% and 2.9%,
respectively.
Chronic Obstructive Pulmonary Disease
The safety of SYMBICORT AEROSPHERE in COPD is based
on the safety data from two clinical trials, with
durations of 24 weeks (TELOS) and 12-52 weeks (SOPHOS), respectively. In TELOS
and SOPHOS, a total of 1274 patients with COPD received at least 1 dose
of SYMBICORT AEROSPHERE 320 mcg/9.6 mcg [see Clinical Studies (14.2)].
In the two trials,
adult patients were
treated with SYMBICORT AEROSPHERE 320 mcg/9.6 mcg twice daily (TELOS mean age:
64 years [range: 40 to 81 years], 97% White, 61% male; SOPHOS: mean age 65
years [range: 40 to 80 years], 83% White, 57% male)
[see Clinical Studies
(14.2)]. The incidence of common adverse reactions in TELOS is shown in
Table
3.
7
Drug Interactions
Additions
and/or revisions underlined:
7.6 Beta-Adrenergic Receptor Blocking Agents
Beta-adrenergic
receptor antagonists (beta-blockers) and SYMBICORT AEROSPHERE may interfere
with the effect of each other when administered concurrently. Beta-blockers
(including eye drops) not only block the therapeutic effects of beta2-agonists,
but may produce severe bronchospasm in asthma and COPD patients.
Therefore, patients with asthma or COPD 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 or COPD. In this setting,
cardioselective beta-blockers could be considered, although they should be
administered with caution.
8
Use in Specific Populations
8.1 Pregnancy
…
The
background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth
defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical
Considerations
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.
…
8.4 Pediatric Use
Additions and/or revisions underlined:
The
safety and effectiveness of SYMBICORT AEROSPHERE have been established for
the treatment of asthma in pediatric patients 12 years of age and older.
Use of SYMBICORT AEROSPHERE in this indication is supported by evidence from
two adequate and well-controlled trials (LITHOS and VATHOS) in patients 12
years of age and older with asthma. In the LITHOS and VATHOS trials, 15 pediatric
patients 12 to 17 years of age were treated with SYMBICORT AEROSPHERE twice
daily [see Adverse Reactions (6.1) and
Clinical Studies (14.1)].
Controlled
clinical studies have shown that ICS agents, including budesonide, one of the
components of SYMBICORT AEROSPHERE, may cause a reduction in growth velocity in
pediatric patients. The effects of long-term treatment of pediatric patients
with ICS on final adult height are not known. The potential growth effects of
prolonged treatment should be weighed against the clinical benefits obtained [see Warnings and Precautions (5.14)].
The safety and effectiveness of SYMBICORT
AEROSPHERE have not been established in pediatric patients younger than 12
years of age.
8.5 Geriatric Use
Additions
and/or revisions underlined:
There
were 66 patients and 112 patients 65 years of age and older in the asthma
trials LITHOS and VATHOS, respectively [see
Clinical Studies (14.1)]. Of the total number of SYMBICORT
AEROSPHERE-treated patients in these trials, 32 (18%) in LITHOS and 50 (20%) in
VATHOS were 65 years of age and older, while 9 (2.6%) patients in LITHOS and 10
(1.7%) patients in VATHOS were 75 years of age and older. No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects, but greater sensitivity in some older individuals cannot be
ruled out.
There
were 1229 patients and 999 patients 65 years of age and older in the COPD
trials TELOS and SOPHOS, respectively [see
Clinical Studies (14.2)]. Of the total number of SYMBICORT
AEROSPHERE-treated patients in these trials, 333 (51%) in TELOS and 347 (56%)
in SOPHOS were 65 years of age and older, while 65 (10%) patients in TELOS and
87 (14%) patients in SOPHOS were 75 years of age and older. No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects, but greater sensitivity in some older individuals cannot be
ruled out.
Based
on available data for SYMBICORT AEROSPHERE or its active components, no
adjustment of dosage of SYMBICORT AEROSPHERE in geriatric patients is
warranted.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
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 SYMBICORT
AEROSPHERE, there is not a significant increase in risk of these events.
Not
for Treatment of Acute Symptoms
Inform
patients that SYMBICORT AEROSPHERE is not used to relieve acute symptoms
of asthma or COPD and extra doses should not be used for that purpose [see Warnings and Precautions (5.2)].
Advise patients to treat acute symptoms with an inhaled, short-acting
beta2-agonist/corticosteroid for asthma or, an inhaled, short-acting
beta2-agonist for asthma or COPD. Provide patients with such medication and
instruct them on how it should be used.
Instruct
patients to seek medical attention immediately if they experience any of the
following:
- Decreasing
effectiveness of inhaled, short-acting beta2-agonist/corticosteroid
combination, or inhaled, short-acting beta2-agonists.
- Need
for more inhalations than usual of inhaled, short-acting beta2-agonist/corticosteroid
combination, or inhaled, short-acting beta2-agonists.
- Significant
decrease in lung function as outlined by the health care practitioner.
Tell
patients they should not stop therapy with SYMBICORT AEROSPHERE without
physician/provider guidance since symptoms may recur after discontinuation.
…
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
[see Warnings and
Precautions (5.13)].
Effect on Growth
Inform
patients that orally inhaled corticosteroids, a component of SYMBICORT
AEROSPHERE, may cause a reduction in growth velocity when administered to
pediatric patients. Healthcare providers should closely follow the growth of
pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.14)].
PATIENT
INFORMATION
Additions and/or revisions underlined:
What
is SYMBICORT AEROSPHERE?
…
Do
not use SYMBICORT AEROSPHERE:
- to treat sudden severe symptoms of asthma or COPD.
…
What
are the possible side effects of SYMBICORT AEROSPHERE? SYMBICORT AEROSPHERE can
cause serious side effects, including:
…
slowed growth in
children. A
child’s growth should be checked regularly while using SYMBICORT AEROSPHERE.
new or worsened
eye problems including glaucoma and cataracts. You should have
regular eye exams while using SYMBICORT AEROSPHERE.
- changes in
laboratory blood values, including high levels of blood sugar (hyperglycemia)
and low levels of potassium (hypokalemia). Low levels of potassium may cause
symptoms of muscle spasm, muscle weakness, or abnormal heart rhythm.
The most common
side effects of SYMBICORT AEROSPHERE include:
People with
asthma:
pain or swelling of your nose or throat
(nasopharyngitis)
joint pain (arthralgia)
gout
COVID-19
high blood pressure
hay fever (allergic rhinitis)
diarrhea
bronchitis
influenza like illness
upper respiratory tract infection
People with COPD:
…
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