Included as part of the "PRECAUTIONS" Section
[See BOX WARNING]
Data from a large placebo-controlled study in asthma patients showed that long-acting beta2 -adrenergic
agonists 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 long-acting beta2 -adrenergic agonists.
A 28-week, placebo-controlled US study comparing 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; RR 4.37, 95%
CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the longacting
beta2 -adrenergic agonists, including PERFOROMIST Inhalation Solution. No study adequate to
determine whether the rate of asthma related death is increased in patients treated with PERFOROMIST
Inhalation Solution has been conducted. The safety and efficacy of PERFOROMIST in patients with
asthma have not been established. All LABA, including PERFOROMIST, are contraindicated in patients
with asthma without the use of a long-term asthma control medication. [see CONTRAINDICATIONS].
Clinical studies with formoterol fumarate administered as a dry powder inhaler suggested a higher
incidence of serious asthma exacerbations in patients who received formoterol than in those who
received placebo. The sizes of these studies were not adequate to precisely quantify the differences in
serious asthma exacerbation rates between treatment groups.
Deterioration Of Disease And Acute Episodes
PERFOROMIST Inhalation Solution should not be initiated in patients with acutely deteriorating COPD,
which may be a life-threatening condition. PERFOROMIST Inhalation Solution has not been studied in
patients with acutely deteriorating COPD. The use of PERFOROMIST Inhalation Solution in this setting
PERFOROMIST Inhalation Solution should not be used for the relief of acute symptoms, i.e., as rescue
therapy for the treatment of acute episodes of bronchospasm. PERFOROMIST Inhalation Solution 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 PERFOROMIST Inhalation Solution, patients who have been taking inhaled, shortacting
beta2 -agonists on a regular basis (e.g., four 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 PERFOROMIST Inhalation Solution, the healthcare provider should also prescribe
an inhaled, short-acting beta2 -agonist and instruct the patient 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
PERFOROMIST Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the
patient’s inhaled, short-acting beta2 -agonist becomes less effective or the patient needs more inhalation
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 PERFOROMIST Inhalation Solution beyond the recommended 20 mcg twice daily
dose is not appropriate in this situation.
Excessive Use And Use With Other Long-Acting Beta2 -Agonists
As with other inhaled beta2 -adrenergic drugs, PERFOROMIST Inhalation Solution should not be used
more often, at higher doses than recommended, or in conjunction with other medications containing
long-acting beta2 -agonists, as an overdose may result. Clinically significant cardiovascular effects and
fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
As with other inhaled beta2 -agonists, PERFOROMIST Inhalation Solution can produce paradoxical
bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, PERFOROMIST
Inhalation Solution should be discontinued immediately and alternative therapy instituted.
PERFOROMIST Inhalation Solution, like other beta2 -agonists, can produce a clinically significant
cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic
blood pressure, and/or symptoms. If such effects occur, PERFOROMIST Inhalation Solution may need
to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as
flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical
significance of these findings is unknown. Therefore, PERFOROMIST Inhalation Solution, like other
sympathomimetic amines, should be used with caution in patients with cardiovascular disorders,
especially coronary insufficiency, cardiac arrhythmias, and hypertension.
PERFOROMIST Inhalation Solution, like other sympathomimetic amines, should be used with caution in
patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to
sympathomimetic amines. Doses of the related beta2 -agonist albuterol, when administered intravenously,
have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Hypokalemia And Hyperglycemia
Beta-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. Beta-agonist medications may produce transient hyperglycemia in some patients.
Clinically significant changes in serum potassium and blood glucose were infrequent during clinical
studies with long-term administration of PERFOROMIST Inhalation Solution at the recommended dose.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of PERFOROMIST Inhalation
Solution, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and
Patient Counseling Information
Patients should be informed that long acting beta agonist, such as PERFOROMIST, increase the
risk of asthma-related death. All LABA, including PERFOROMIST, should not be used in
patients with asthma without use of a long-term asthma control medication.
Acute Exacerbations Or Deteriorations
PERFOROMIST Inhalation Solution is not indicated for 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 (the healthcare provider should provide the patient with such medication and instruct the
patient in how it should be used). Patients should be instructed to seek medical attention if their
symptoms worsen despite recommended doses of PERFOROMIST Inhalation Solution, if PERFOROMIST Inhalation Solution treatment becomes less effective, or if they need more inhalations
of a short-acting beta2 -agonist than usual.
Patients should not stop using PERFOROMIST Inhalation Solution unless told to do so by a healthcare
provider because symptoms may get worse. Patients should not inhale more than the prescribed number
of vials at any one time. The daily dosage of PERFOROMIST Inhalation Solution should not exceed
one vial twice daily (40 mcg total daily dose). Excessive use of sympathomimetics may cause
significant cardiovascular effects, and may be fatal.
Patients who have been taking inhaled, short-acting beta2 -agonists (e.g., albuterol) on a regular basis
should be instructed to discontinue the regular use of these products and use them only for symptomatic
relief of acute symptoms. PERFOROMIST Inhalation Solution should not be used in conjunction with
other inhaled medications containing long-acting beta2 -agonists. Patients should be warned not to stop
or change the dose of other concomitant COPD therapy without medical advice, even if symptoms
improve after initiating treatment with PERFOROMIST Inhalation Solution.
Common Adverse Reactions With Beta2 -Agonists
Patients should be informed that treatment with beta2 -agonists may lead to adverse reactions that include
palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor,
nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high
blood sugar, high blood acid, or trouble sleeping [see ADVERSE REACTIONS].
Instructions For Administration
It is important that patients understand how to use PERFOROMIST Inhalation Solution with a nebulizer
appropriately [see the accompanying PATIENT INFORMATION]. Patients should be instructed not to mix other
medications with PERFOROMIST Inhalation Solution or ingest PERFOROMIST Inhalation Solution.
Patients should throw the plastic dispensing container away immediately after use. Due to their small
size, the container and top pose a danger of choking to young children.
FDA-Approved Medication Guide
See the accompanying PATIENT INFORMATION.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and
dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at
doses of 15,000 mcg/kg and above in the drinking water study and at 20,000 mcg/kg in the dietary study
(AUC exposure approximately 2,300 times human exposure at the maximum recommended daily
inhalation dose), but not at dietary doses up to 5,000 mcg/kg (AUC exposure approximately 570 times
human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence
of benign ovarian theca-cell tumors was increased at doses of 500 mcg/kg (AUC exposure was
approximately 57 times human exposure at the maximum recommended daily inhalation dose) and above.
This finding was not observed in the drinking water study, nor was it seen in mice (see below).
In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses
of 69,000 mcg/kg (AUC exposure approximately 1000 times human exposure at the maximum
recommended daily inhalation dose) and above in the drinking water study, but not at doses up to 50,000
mcg/kg (AUC exposure approximately 750 times human exposure at the maximum recommended daily
inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary
study at doses of 20,000 and 50,000 mcg/kg in females (AUC exposures approximately 300 and 750
times human exposure at the maximum recommended daily inhalation dose, respectively) and 50,000
mcg/kg in males, but not at doses up to 5,000 mcg/kg (AUC exposure approximately 75 times human
exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence
of uterine leiomyomas and leiomyosarcomas was increased at doses of 2,000 mcg/kg (AUC exposure
was approximately 30 times human exposure at the maximum recommended daily inhalation dose) and
above. Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with
other beta-agonist drugs.
Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in
bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis
repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and
micronucleus tests in mice and rats.
Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3,000 mcg/kg
(approximately 730 times the maximum recommended daily inhalation powder dose in humans on a
Use In Specific Populations
There are limited available data with PERFOROMIST Inhalation Solution use in pregnant women to
inform a drug-associated risk of adverse developmental outcomes. Beta-agonists may interfere with
uterine contractility (see Clinical Considerations). In animal reproduction studies, oral administration of
formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits),
decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses
that produced exposures approximately 730 to 29,000 times the MRHD on a mg/m2 or AUC
basis.These adverse effects generally occurred at large multiples of the MRHD when formoterol
fumarate was administered by the oral route to achieve high systemic exposures. No effects were
observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure
approximately 300 times the MRHD (see Data).
The estimated 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 2-4% and 15-20%, respectively.
Labor or delivery
There are no adequate and well-controlled human studies that have studied the effects of
PERFOROMIST Inhalation Solution during labor and delivery. Because of the potential for betaagonists
interference with uterine contractility, use of PERFOROMIST Inhalation Solution during labor
should be restricted to those patients in whom the benefits clearly outweigh the risk.
In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of
organogenesis, formoterol fumarate did not cause malformations in either species. However, for
pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at
an exposure approximately 50 times the MRHD (on a mcg/m2 basis with maternal oral doses of 200
mcg/kg and higher) and decreased fetal weight at an exposure approximately 1,500 times the MRHD (on
a mcg/m2 basis with maternal oral doses of 6,000 mcg/kg and above). In a pre- and post-natal
development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused
stillbirth and neonatal mortality at an exposure approximately 1,500 times the MRHD (on a mcg/m2 basis
with maternal oral doses of 6,000 mcg/kg and above). However, no effects were observed in this study
at an exposure approximately 50 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 200
In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and
rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both
species. Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 730
times the MRHD (on a mcg/m2 basis with maternal oral doses of 3,000 mcg/kg/day and above).
Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 3,600
times the MRHD (on a mcg/m2 basis with a maternal oral dose of 15,000 mcg/kg/day). In another study
with rats, no teratogenic effects were observed with exposures up to approximately 300 times the
MRHD (on a mcg/m2 basis with a maternal inhalation dose of 1,200 mcg/kg/day). Subcapsular cysts on
the liver were observed in rabbit fetuses at an exposure approximately 29,000 times the MRHD (on a
mcg/m2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed
with exposures up to approximately 1,700 times the MRHD (on a mcg/m2 basis with a maternal oral
dose of 3,500 mcg/kg).
There are no well-controlled human studies of the use of PERFOROMIST Inhalation Solution in
nursing mothers. It is not known whether formoterol fumarate is excreted in human milk, or whether
there are effects on the breastfed infant or on the milk production.
In reproductive studies in rats formoterol was excreted in the milk (see Data).
The developmental and health benefits of breastfeeding should be considered along with the mother`s
clinical need for PERFOROMIST Inhalation Solution and any potential adverse effects on the breastfed
child from PERFOROMIST Inhalation Solution or from the underlying maternal condition.
In a pharmacokinetic study in rats formoterol was excreted in the milk. The amount of radioactive
labelled 3H-formoterol fumarate was less than 2% of that in the maternal plasma.
PERFOROMIST Inhalation Solution is not indicated for use in children. The safety and effectiveness
of PERFOROMIST Inhalation Solution in pediatric patients have not been established. The
pharmacokinetics of formoterol fumarate has not been studied in pediatric patients.
Of the 586 subjects who received PERFOROMIST Inhalation Solution in clinical studies, 284 were 65
years and over, while 89 were 75 years and over. Of the 123 subjects who received PERFOROMIST
Inhalation Solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects. Other reported clinical experience has not identified differences in responses between the
elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
The pharmacokinetics of PERFOROMIST Inhalation Solution has not been studied in elderly subjects.