Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
BREZTRI
AEROSPHERE is contraindicated in the following conditions:
Primary treatment of status asthmaticus or other acute
episodes of COPD or asthma where intensive measures are required [see Warnings
and Precautions (5.2)].
Hypersensitivity
to budesonide, glycopyrrolate, 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, 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 ?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. BREZTRI 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). BREZTRI 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.
5.2 Deterioration of Disease and Acute Episodes
Additions
and/or revisions underlined:
BREZTRI
AEROSPHERE should not be initiated in patients with acutely deteriorating COPD or
asthma, which may be a life-threatening condition. BREZTRI AEROSPHERE has
not been studied in patients with acutely deteriorating COPD or asthma.
The use of BREZTRI 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
BREZTRI AEROSPHERE.
…
Acute
symptoms should be treated with either an inhaled short-acting beta2-agonist/corticosteroid
combination (asthma only) or an inhaled short-acting beta2-agonist
(COPD or asthma).
…
When
prescribing BREZTRI 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
(COPD or asthma) and instruct the patient on how it should be used.
5.7
Transferring Patients from Systemic Corticosteroid Therapy
Additions
and/or revisions underlined:
…
Although
BREZTRI AEROSPHERE may provide control of COPD or asthma 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 COPD or asthma 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 COPD or asthma
exacerbation.
Patients
requiring oral corticosteroids should be weaned slowly from systemic
corticosteroid use after transferring to BREZTRI AEROSPHERE. Prednisone
reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg
on a weekly basis during therapy with BREZTRI AEROSPHERE. Lung function (forced
expiratory volume in 1 second [FEV1] or morning peak expiratory flow
[PEF]), beta-agonist use, and COPD or asthma 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 BREZTRI AEROSPHERE routinely (e.g., via stadiometry) [see Use in Specific Populations (8.4)].
5.15 Glaucoma and Cataracts,
Worsening of Narrow-Angle Glaucoma
Additions
and/or revisions underlined:
Glaucoma,
increased intraocular pressure, and cataracts have been reported in patients
with COPD or asthma following the long-term administration of ICS or with
use of inhaled anticholinergics.
…
6
Adverse Reactions
Additions and/or
revisions underlined:
- Growth effects in pediatric patients [see
Warnings and Precautions (5.14)]
6.1 Clinical
Trials Experience
Additions
and/or revisions underlined:
Table
2 title revised: Adverse Reactions
Occurring at an Incidence of greater than or equal to 2% of Subjects with COPD
and More Common in BREZTRI AEROSPHERE Compared to GFF MDI and/or BFF MDI (ETHOS)
Chronic
Obstructive Pulmonary Disease
The
safety of BREZTRI AEROSPHERE in COPD is based on the safety data from
one 52-week exacerbation trial (ETHOS) and one 24-week lung function
trial with a 28-week safety extension study, resulting in up to 52 weeks of
treatment (KRONOS). In ETHOS and KRONOS, a total of 2783
subjects have received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6
mcg [see Clinical Studies (14.1)].
In
ETHOS and KRONOS, subjects received one of the following
treatments: BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, glycopyrrolate and formoterol
fumarate (GFF MDI 18 mcg/9.6 mcg), or budesonide and formoterol fumarate (BFF
MDI 320 mcg/9.6 mcg). Each treatment was administered twice daily.
In
ETHOS, a 52-week, randomized, double-blind clinical trial, a total of
2144 subjects with COPD received at least 1 dose of BREZTRI AEROSPHERE 320
mcg/18 mcg/9.6 mcg (mean age: 64.7 years, 84.9% Caucasian, 59.7% male across
all treatments) [see Clinical Studies
(14.1)].
In
KRONOS, a 24-week, randomized, double-blind clinical trial, with a
28-week long-term safety extension resulting in up to 52 weeks of treatment, a
total of 639 subjects received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18
mcg/9.6 mcg (mean age: 65.2 years, 50.1% Caucasian, 71.2% male across all
treatments) [see Clinical Studies
(14.1)].
The
incidence of adverse reactions from the 52-week trial (ETHOS) is
presented in Table 2 for subjects treated with BREZTRI AEROSPHERE 320 mcg/18
mcg/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, or BFF MDI 320 mcg/9.6 mcg.
…
In
24-week data from KRONOS, adverse reactions that occurred in subjects
treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (n=639) at an incidence
of greater than or equal to 2% included dysphonia (3.1%) and muscle
spasms (3.3%).
Asthma
The
safety of BREZTRI AEROSPHERE for the maintenance treatment of asthma is based
on the pooled safety data from two, 24 to 52-week, clinical trials (KALOS and
LOGOS) [see Clinical Studies (14.2)].
In the KALOS and LOGOS pooled safety population, a total of 1179 subjects with
asthma received at least one dose of BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg.
The mean duration of exposure to BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg
twice daily was 45 weeks, with 678 (57%) subjects treated for at least 52
weeks.
The
incidence of adverse reactions (greater than or equal to 2%) from the 24 to
52-week trials (KALOS and LOGOS) is presented in Table 3 for subjects treated
with BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg or BFF MDI 320 mcg/9.6 mcg.
…
Additional Adverse Reactions
Other adverse reactions that have been associated
with one or more of the individual components of BREZTRI AEROSPHERE include: gastroesophageal
reflux disease, dysphonia, oropharyngeal pain, renal and urinary tract
infection, …
7
Drug Interactions
7.6 Beta-adrenergic Receptor Blocking Agents
Additions
and/or revisions underlined:
Beta-adrenergic
receptor antagonists (beta-blockers) and BREZTRI AEROSPHERE may interfere with
the effect of each other when administered concurrently. Beta-blockers not only
block the therapeutic effects of beta2-agonists, but may produce
severe bronchospasm in COPD and asthma patients. Therefore, patients with
COPD or asthma should not normally be treated with beta-blockers. However,
under certain circumstances, e.g., as prophylaxis after myocardial infarction, there
may be no acceptable alternatives to the use of beta-blockers in patients with
COPD or asthma. In this setting, cardioselective beta-blockers could be
considered, although they should be administered with caution.
7.7 Anticholinergics
Additions
and/or revisions underlined:
There
is a potential for an additive interaction with concomitantly used
anticholinergic medications. Therefore, avoid coadministration of BREZTRI
AEROSPHERE with other anticholinergic-containing drugs as this may lead to an
increase in anticholinergic adverse effects [see
Warnings and Precautions (5.9, 5.10) and Adverse Reactions (6.1)].
8
Use in Specific Populations
8.1 Pregnancy
Additions
and/or revisions underlined:
…
Glycopyrrolate
alone, administered by the subcutaneous route in rats and rabbits, did not
cause structural abnormalities or affect fetal survival at exposures
approximately 1350 and 2700 times from MRHDID, respectively.
Glycopyrrolate had no effects on the physical, functional, and behavioral
development of rat pups with exposures up to 1350 times the MRHDID.
…
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.
…
Glycopyrrolate
In
an embryo-fetal development study in pregnant rats dosed during the period of
organogenesis from gestation days 6 to 17, glycopyrrolate produced no
structural abnormalities or effects on fetal survival; however, slight
reductions of fetal body weight in the presence of maternal toxicity at the
highest tested dose that was 1350 times the MRHDID (on a mcg/m2
basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Fetal body weights
were unaffected with doses up to 135 times the MRHDID (on a mcg/m2 basis
with maternal subcutaneous doses up to 1000 mcg/kg/day). Maternal toxicity was
observed with doses 135 times the MRHDID and higher (on a mcg/m2
basis with maternal subcutaneous doses of 1000 mcg/kg/day and higher).
In
an embryo-fetal development study in pregnant rabbits dosed during the period
of organogenesis from gestation days 6 to 18, glycopyrrolate produced no
structural abnormalities or effects on fetal survival; however, slight
reductions of fetal body weight in the presence of maternal toxicity at the
highest tested dose that was 2700 times the MRHDID (on a mcg/m2
basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Fetal body weights
were unaffected with doses up to 270 times the MRHDID (on a mcg/m2
basis with maternal subcutaneous doses up to 1000 mcg/kg/day). Maternal
toxicity was observed with doses 270 times the MRHDID and higher (on a
mcg/m2 basis with maternal subcutaneous doses of 1000 mcg/kg/day and
higher).
In
a pre- and post-natal development study, pregnant female rats received
glycopyrrolate at doses of 100, 1000, and 10,000 mcg/kg/day from gestation day
6 through the lactation period. Pup body weight gain was slightly reduced from
birth through the lactation period at a dose 1350 times the MRHDID (on a
mcg/m2 basis with a maternal subcutaneous dose of 10,000
mcg/kg/day); however, pup body weight gain was unaffected after weaning. There
were no treatment-related effects on the physical, functional, and behavioral
development of pups with doses up to 1350 times the MRHDID (on a mcg/m2
basis with maternal subcutaneous doses up to 10,000 mcg/kg/day). Maternal
toxicity was observed from gestation days 6 to 18 with doses 135 times
the MRHDID and higher (on a mcg/m2 basis with maternal subcutaneous
doses of 1000 mcg/kg/day and higher).
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of BREZTRI AEROSPHERE
have been established for the maintenance treatment of asthma in pediatric
patients 12 years of age and older. Use
of BREZTRI AEROSPHERE for this indication is supported by evidence from two
adequate and well-controlled studies (KALOS and LOGOS) in adults and pediatric
patients 12 years of age and older, in which 30 pediatric patients 12 years to
less than 18 years of age were treated with BREZTRI AEROSPHERE 320 mcg/36
mcg/9.6 mcg twice daily by oral inhalation [see
Adverse Reactions (6.1) and Clinical Studies (14.2)].
The safety and effectiveness of BREZTRI AEROSPHERE
in pediatric patients less than 12 years of age have not been established.
Controlled clinical studies have shown that ICS
agents, including budesonide, one of the components of BREZTRI 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)].
8.5 Geriatric Use
Additions
and/or revisions underlined:
Based on available data, no adjustment of the dosage
of BREZTRI AEROSPHERE in geriatric patients is necessary, but greater
sensitivity in some older individuals cannot be ruled out.
In the COPD trials, ETHOS and KRONOS, 1100
subjects and 343 subjects, respectively, aged 65 years and older were
administered BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg twice daily [see Clinical Studies (14.1)]. In both
trials, no overall differences in safety or effectiveness were observed between
these subjects and younger subjects.
In the asthma trials, KALOS and LOGOS, 141 subjects
and 124 subjects, respectively, aged 65 years and older were administered
BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg twice daily [see Clinical Studies (14.2)]. In both trials, no overall
differences in safety or effectiveness were observed between these subjects and
younger subjects.
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 BREZTRI AEROSPHERE,
there is not a significant increase in the risk of these events [see Warnings and Precautions (5.1)].
Not
for Treatment of Acute Symptoms
Inform
patients that BREZTRI AEROSPHERE is not meant to relieve acute symptoms of COPD
or asthma and extra doses should not be used for that purpose. 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 [see Warnings and Precautions (5.2)]. 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.
…
Effect
on Growth
Inform
patients that orally inhaled corticosteroids, a component of BREZTRI
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
…
Asthma:
Do not use BREZTRI
AEROSPHERE:
…
Read the
step-by-step instructions for using BREZTRI AEROSPHERE in the Instructions
for Use provided with this Patient Information leaflet.
…
BREZTRI AEROSPHERE
can cause serious side effects, including:
…
The most common side
effects of BREZTRI AEROSPHERE include:
…
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