Included as part of the PRECAUTIONS section.
- Data from a large placebo-controlled trial in subjects
with asthma showed that LABAs may increase the risk of asthma-related death.
Data are not available to determine whether the rate of death in patients with
COPD is increased by LABAs.
- A 28-week, placebo-controlled US trial comparing the
safety of another LABA (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 vs. 3/13,179 in
subjects treated with placebo; RR 4.37, 95% CI: 1.25, 15.34). The increased risk
of asthma-related death is considered a class effect of LABAs, including
formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE.
- No trial adequate to determine whether the rate of
asthma-related deaths is increased in patients treated with BEVESPI AEROSPHERE
has been conducted. The safety and efficacy of BEVESPI AEROSPHERE in patients
with asthma have not been established. BEVESPI AEROSPHERE is not indicated for
the treatment of asthma.
Deterioration Of Disease And Acute Episodes
BEVESPI AEROSPHERE should not be initiated in patients
with acutely deteriorating COPD, which may be a life-threatening condition.
BEVESPI AEROSPHERE has not been studied in patients with acutely deteriorating
COPD. The use of BEVESPI AEROSPHERE in this setting is inappropriate.
BEVESPI AEROSPHERE should not be used for the relief of
acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of
bronchospasm. BEVESPI 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 an inhaled short-acting beta2-agonist.
When beginning BEVESPI AEROSPHERE, patients who have been
taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four
times a day) should be instructed to discontinue the regular use of these
medicines and use them only for symptomatic relief of acute respiratory
symptoms. When prescribing BEVESPI AEROSPHERE, the healthcare provider should
also prescribe an inhaled, short acting beta2-agonist and instruct the patient
on how it should be used. Increasing inhaled beta2-agonist use is a signal of
deteriorating disease for which prompt medical attention is indicated.
COPD may deteriorate acutely over a period of hours or
chronically over several days or longer. If BEVESPI AEROSPHERE no longer
controls the symptoms of bronchoconstriction, or the patient's inhaled,
short-acting beta2-agonist becomes less effective, or the patient needs more
inhalations of short-acting beta2-agonist than usual, these may be markers of
deterioration of disease. In this setting, a re-evaluation of the patient and
the COPD treatment regimen should be undertaken at once. Increasing the daily
dosage of BEVESPI AEROSPHERE beyond the recommended dose is not appropriate in
Excessive Use Of BEVESPI And Use With Other Long-Acting
As with other inhaled medicines containing beta2-agonists,
BEVESPI AEROSPHERE should not be used more often than recommended, at higher
doses than recommended, or in conjunction with other medications containing
LABAs, as an overdose may result. Clinically significant cardiovascular effects
and fatalities have been reported in association with excessive use of inhaled
sympathomimetic medicines. Patients using BEVESPI AEROSPHERE should not use
another medicine containing a LABA for any reason [see DRUG INTERACTIONS].
As with other inhaled medicines, BEVESPI AEROSPHERE can
produce paradoxical bronchospasm, which may be life threatening. If paradoxical
bronchospasm occurs following dosing with BEVESPI AEROSPHERE, it should be
treated immediately with an inhaled, short-acting bronchodilator, BEVESPI
AEROSPHERE should be discontinued immediately, and alternative therapy should
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions have been reported
after administration of glycopyrrolate or formoterol fumarate, the components
of BEVESPI AEROSPHERE. If signs suggesting allergic reactions occur, in
particular, angioedema (including difficulties in breathing or swallowing,
swelling of tongue, lips and face), urticaria, or skin rash, BEVESPI AEROSPHERE
should be stopped at once and alternative treatment should be considered.
Formoterol fumarate, like other beta2-agonists, can produce
a clinically significant cardiovascular effect in some patients as measured by
increases in pulse rate, systolic or diastolic blood pressure, or symptoms [see
CLINICAL PHARMACOLOGY]. If such effects occur, BEVESPI AEROSPHERE may need
to be discontinued. In addition, beta-agonists have been reported to produce
electrocardiographic changes, such as flattening of the T wave, prolongation of
the QTc interval, and ST segment depression, although the clinical significance
of these findings is unknown.
Therefore, BEVESPI AEROSPHERE should be used with caution
in patients with cardiovascular disorders, especially coronary insufficiency,
cardiac arrhythmias, and hypertension.
BEVESPI AEROSPHERE, like all medications 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-agonist albuterol, when
administered intravenously, have been reported to aggravate pre-existing
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 [see CLINICAL
PHARMACOLOGY]. The decrease in serum potassium is usually transient, not
requiring supplementation. Beta2-agonist medicines may produce transient
hyperglycemia in some patients. In two clinical trials of 24-weeks and a
28-week safety extension study evaluating BEVESPI AEROSPHERE in subjects with
COPD, there was no evidence of a treatment effect on serum glucose or
Worsening Of Narrow-Angle Glaucoma
BEVESPI AEROSPHERE should be used with caution in
patients with narrow-angle glaucoma. Prescribers and patients should be alert
for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or
discomfort, blurred vision, visual halos or colored images in association with
red eyes from conjunctival congestion and corneal edema). Instruct patients to
consult a physician immediately should any of these signs or symptoms develop.
Worsening Of Urinary Retention
BEVESPI AEROSPHERE should be used with caution in patients
with urinary retention. Prescribers and patients should be alert for signs and
symptoms of urinary retention (e.g., difficulty passing urine, painful
urination), especially in patients with prostatic hyperplasia or bladder-neck
obstruction. Instruct patients to consult a physician immediately should any of
these signs or symptoms develop.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide and Instructions for Use)
Asthma-Related Death: Inform patients that LABAs,
such as formoterol fumarate, one of the active ingredients in BEVESPI
AEROSPHERE, increase the risk of asthma-related death. BEVESPI AEROSPHERE is
not indicated for the treatment of asthma.
Not for Acute Symptoms: Inform patients that
BEVESPI AEROSPHERE is not meant to relieve acute symptoms of COPD and extra
doses should not be used for that purpose. Advise them to treat acute symptoms
with a rescue inhaler such as albuterol. Provide patients with such medicine and
instruct them in how it should be used.
Instruct patients to seek medical attention immediately
if they experience any of the following:
- Symptoms get worse
- Need for more inhalations than usual of their rescue
Patients should not stop therapy with BEVESPI AEROSPHERE
without physician/provider guidance since symptoms may recur after
Do Not Use Additional Long-Acting Beta2-Agonists:
Instruct patients to not use other medicines containing a LABA. Patients should
not use more than the recommended dose of BEVESPI AEROSPHERE.
Instruct patients who have been taking inhaled,
short-acting beta2-agonists on a regular basis to discontinue the regular use
of these products and use them only for the symptomatic relief of acute symptoms.
Paradoxical Bronchospasm: As with other inhaled
medicines, BEVESPI AEROSPHERE can cause paradoxical bronchospasm. If
paradoxical bronchospasm occurs, instruct patients to discontinue BEVESPI
Risks Associated With Beta2-Agonist Therapy: Inform
patients of adverse effects associated with beta2-agonists, such as
palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct
patients to consult a physician immediately should any of these signs or
Worsening of Narrow Angle Glaucoma: Instruct
patients to be alert for signs and symptoms of acute narrow-angle glaucoma
(e.g., eye pain or discomfort, blurred vision, visual halos or colored images
in association with red eyes from conjunctival congestion and corneal edema).
Instruct patients to consult a physician immediately should any of these signs
or symptoms develop.
Worsening of Urinary Retention: Instruct patients
to be alert for signs and symptoms of urinary retention (e.g., difficulty
passing urine, painful urination). Instruct patients to consult a physician
immediately should any of these signs or symptoms develop.
Instructions For Administering BEVESPI AEROSPHERE
It is important for patients to understand how to
correctly administer BEVESPI AEROSPHERE [see Instructions for Use].
Inform patients to use 2 inhalations of BEVESPI
AEROSPHERE orally twice daily (2 inhalations in the morning and 2 inhalations
in the evening).
Instruct patients to prime BEVESPI AEROSPHERE before
using it for the first time. Instruct patients to prime BEVESPI AEROSPHERE by
releasing 4 sprays into the air away from their face, shaking well before each
spray. Inform patients that BEVESPI AEROSPHERE must be re-primed when the
inhaler has not been used for more than 7 days. Instruct patients to re-prime
BEVESPI AEROSPHERE by releasing 2 sprays into the air away from their face,
shaking well before each spray.
Inform patients that it is very important to clean
BEVESPI AEROSPHERE 1 time each week so that medicine will not build up and
block the spray through the mouthpiece [see INSTRUCTIONS FOR USE].
Instruct patients to clean BEVESPI AEROSPHERE by taking the canister out of the
actuator, running warm water through the actuator, and allowing the actuator to
air-dry overnight. Instruct patients to insert the canister back into the
actuator after it is dry, and to re-prime BEVESPI AEROSPHERE. Instruct patients
to re-prime BEVESPI AEROSPHERE by releasing 2 sprays into the air away from
their face, shaking well before each spray.
Inform patients that if they miss a dose of BEVESPI
AEROSPHERE, they should take their next dose at the usual time. Instruct
patients to not use BEVESPI AEROSPHERE more often or more puffs than they have
Instruct patients not to spray BEVESPI AEROSPHERE in
their eyes. Inform patients that if they accidentally get BEVESPI AEROSPHERE in
their eyes, to rinse their eyes with water, and if redness or irritation
persists, to consult their healthcare provider.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of BEVESPI AEROSPHERE which contains
glycopyrrolate and formoterol fumarate. The data described below for the
individual components apply to BEVESPI AEROSPHERE.
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of inhaled glycopyrrolate or any other
formulations of glycopyrrolate.
Glycopyrrolate was not mutagenic in the bacterial reverse
mutation assay, the in vitro mammalian cell micronucleus assay in TK6 cells or
the in vivo micronucleus assay in rats.
In reproduction studies in rats, dietary administration of
glycopyrrolate resulted in diminished rates of conception in a dose-related
manner. Other studies in dogs suggest that this may be due to diminished
seminal secretion which is evident at high doses of glycopyrrolate.
Long-term studies were conducted in mice using oral
administration and rats using inhalation administration to evaluate the
carcinogenic potential of formoterol fumarate.
In a 24-month carcinogenicity study in CD-1 mice,
formoterol fumarate at oral doses of 0.1 mg/kg and above [approximately 25
times the maximum recommended human daily inhalation dose (MRHDID) on a mg/m² basis]
caused a dose-related increase in the incidence of uterine leiomyomas.
In a 24-month carcinogenicity study in Sprague-Dawley
rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma
were observed at the inhaled dose of 130 mcg/kg (approximately 65 times the
MRHDID on a mcg/m² basis). No tumors were seen at 22 mcg/kg (approximately 10
times the MRHDID on a mcg/m² basis).
Other beta-agonist drugs have similarly demonstrated
increases in leiomyomas of the genital tract in female rodents. The relevance
of these findings to human use is unknown.
Formoterol fumarate was not mutagenic or clastogenic in
Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome
aberration test in human lymphocytes, and rat micronucleus test.
A reduction in fertility and/or reproductive performance
was identified in male rats treated with formoterol at an oral dose of 15 mg/kg
(approximately 7600 times the MRHDID on a mg/m² basis). In a separate study
with male rats treated with an oral dose of 15 mg/kg (approximately 7600 times
the MRHDID on a mg/m² basis), there were findings of testicular tubular atrophy
and spermatic debris in the testes and oligospermia in the epididymides. No
such effect was seen at 3 mg/kg (approximately 1500 times the MRHDID on a mg/m²
basis). No effect on fertility was detected in female rats at doses up to 15
mg/kg (approximately 7600 times the MRHDID on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C. There are no adequate and
well-controlled trials of BEVESPI AEROSPHERE or its individual components,
glycopyrrolate and formoterol fumarate, in pregnant women. Because animal
reproduction studies are not always predictive of human response, BEVESPI
AEROSPHERE should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. Women should be advised to contact
their physicians if they become pregnant while taking BEVESPI AEROSPHERE.
Glycopyrrolate: There was no evidence of teratogenic effects in rats and
rabbits at approximately 18,000 and 270 times, respectively, the maximum
recommended human daily inhalation dose (MRHDID) in adults (on a mg/m² basis at
a maternal oral dose of 65 mg/kg/day in rats and at a maternal intramuscular
injection dose of 0.5 mg/kg in rabbits).
Single-dose studies in humans found that very small
amounts of glycopyrrolate passed the placental barrier.
Formoterol Fumarate: Formoterol fumarate has been shown to be teratogenic,
embryocidal, to increase pup loss at birth and during lactation, and to
decrease pup weights in rats and teratogenic in rabbits. These effects were
observed at approximately 1,500 (rats) and 61,000 (rabbits) times the MRHDID
(on a mg/m² basis at maternal oral doses of 3 mg/kg/day and above in rats and
60 mg/kg/day in rabbits). Umbilical hernia was observed in rat fetuses at
approximately 1,500 times the MRHDID (on a mg/m² basis at maternal oral doses
of 3 mg/kg/day and above). Prolonged pregnancy and fetal brachygnathia was
observed in rats at approximately 7600 times the MRHDID (on a mg/m² basis at an
oral maternal dose of 15 mg/kg/day in rats). In another study in rats, no
teratogenic effects were seen at approximately 600 times the MRHDID (on a mg/m²
basis at maternal inhalation doses up to 1.2 mg/kg/day in rats).
Subcapsular cysts on the liver were observed in rabbit
fetuses at an oral dose approximately 61,000 times the MRHDID (on a mg/m² basis
at a maternal oral dose of 60 mg/kg/day in rabbits). No teratogenic effects
were observed at approximately 3600 times the MRHDID (on a mg/m² basis at
maternal oral doses up to 3.5 mg/kg/day).
Labor And Delivery
There are no well-controlled human trials that have
investigated the effects of BEVESPI AEROSPHERE on preterm labor or labor at
term. Because beta2-agonists may potentially interfere with uterine
contractility, BEVESPI AEROSPHERE should be used during labor only if the
potential benefit justifies the potential risk.
It is not known whether BEVESPI AEROSPHERE is excreted in
human milk. Because many drugs are excreted in human milk and because
formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, has
been detected in the milk of lactating rats, caution should be exercised when
BEVESPI AEROSPHERE is administered to a nursing woman. Since there are no data
from controlled trials on the use of BEVESPI AEROSPHERE by nursing mothers, a
decision should be made whether to discontinue nursing or to discontinue BEVESPI
AEROSPHERE, taking into account the importance of BEVESPI AEROSPHERE to the
BEVESPI AEROSPHERE is not indicated for use in children.
The safety and effectiveness of BEVESPI AEROSPHERE in the pediatric population
have not been established.
Based on available data, no adjustment of the dosage of
BEVESPI AEROSPHERE in geriatric patients is necessary, but greater sensitivity
in some older individuals cannot be ruled out.
The confirmatory trials of BEVESPI AEROSPHERE for COPD
included 1,680 subjects aged 65 and older and, of those, 290 subjects were aged
75 and older. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects.
Formal pharmacokinetic studies using BEVESPI AEROSPHERE
have not been conducted in patients with hepatic impairment. However, since
formoterol fumarate is predominantly cleared by hepatic metabolism, impairment
of liver function may lead to accumulation of formoterol fumarate in plasma.
Therefore, patients with hepatic disease should be closely monitored.
Formal pharmacokinetic studies using BEVESPI AEROSPHERE
have not been conducted in patients with renal impairment. In patients with
severe renal impairment (creatinine clearance of ≤ 30 mL/min/1.73 m²) or
end-stage renal disease requiring dialysis, BEVESPI AEROSPHERE should be used
if the expected benefit outweighs the potential risk [see CLINICAL