Included as part of the PRECAUTIONS section.
Long-acting beta2-adrenergic agonists, such as
formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of
asthma-related death. Currently available data are inadequate to determine
whether concurrent use of inhaled corticosteroids or other long-term asthma
control drugs mitigates the increased risk of asthma-related death from LABA.
Because of this risk, use of FORADIL AEROLIZER for the
treatment of asthma without concomitant use of a long-term asthma control
medication, such as an inhaled corticosteroid, is contraindicated. Once asthma
control is achieved and maintained, assess the patient at regular intervals and
step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss
of asthma control, and maintain the patient on a long-term asthma control
medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for
patients whose asthma is adequately controlled on low or medium dose inhaled
Pediatric and Adolescent Patients
Available data from controlled clinical trials suggest
that LABA increase the risk of asthma-related hospitalization in pediatric and
adolescent patients. For pediatric and adolescent patients with asthma who
require addition of a LABA to an inhaled corticosteroid, a fixed-dose
combination product containing both an inhaled corticosteroid and LABA should
ordinarily be considered to ensure adherence with both drugs. In cases where
use of a separate long-term asthma control medication (e.g. inhaled
corticosteroid) and LABA is clinically indicated, appropriate steps must be
taken to ensure adherence with both treatment components. If adherence cannot
be assured, a fixed-dose combination product containing both an inhaled
corticosteroid and LABA is recommended.
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 long-acting beta2-adrenergic
agonists, including formoterol. No study adequate to determine whether the rate
of asthma-related death is increased with FORADIL AEROLIZER has been conducted.
Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL
AEROLIZER than in those who received placebo [see ADVERSE REACTIONS].
The sizes of these studies were not adequate to precisely quantify the
differences in serious asthma exacerbation rates between treatment groups.
The studies described above enrolled patients with
asthma. No studies have been conducted that were adequate to determine whether
the rate of death in patients with COPD is increased by long-acting beta2-adrenergic
Deterioration of Disease and Acute Episodes
FORADIL AEROLIZER should not be initiated in patients with
significantly worsening, acutely deteriorating, or potentially life-threatening
episodes of asthma or COPD. The use of FORADIL AEROLIZER in this setting is not
appropriate [see INDICATIONS AND USAGE].
Asthma may deteriorate acutely over a period of hours or
chronically over several days or longer. It is important to watch for signs of
worsening asthma, such as increasing use of inhaled, short-acting beta2-adrenergic
agonists or a significant decrease in peak expiratory flow (PEF) or lung
function. Such findings require immediate evaluation. Patients should be
advised to seek immediate attention should their condition deteriorate.
Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in
this situation is not appropriate. FORADIL AEROLIZER should not be used more
frequently than twice daily (morning and evening) at the recommended dose.
FORADIL AEROLIZER should not be used to treat acute
symptoms. FORADIL AEROLIZER has not been studied in the relief of acute
symptoms and extra doses should not be used for that purpose. When prescribing
FORADIL AEROLIZER, the physician should also provide the patient with an
inhaled, short-acting beta2-agonist for treatment of symptoms that occur
acutely, despite regular twice-daily (morning and evening) use of FORADIL
AEROLIZER. Patients should also be cautioned that increasing inhaled beta2-agonist
use is a signal of deteriorating asthma [see Information for Patients and
the accompanying Medication Guide.]
When beginning treatment with FORADIL AEROLIZER, patients
who have been taking inhaled, short-acting beta2agonists 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 symptoms.
FORADIL AEROLIZER is not a substitute for corticosteroids
There are no data demonstrating that FORADIL has any
clinical anti-inflammatory effect and therefore it cannot be expected to take
the place of corticosteroids. Corticosteroids should not be stopped or reduced
at the time FORADIL AEROLIZER is initiated. Patients who already require oral
or inhaled corticosteroids for treatment of asthma should be continued on this
type of treatment even if they feel better as a result of initiating FORADIL
AEROLIZER. Any change in corticosteroid dosage, in particular a reduction,
should be made ONLY after clinical evaluation [see PATIENT INFORMATION].
Excessive Use and Use with Other Long-Acting Beta2-Agonists
FORADIL AEROLIZER should not be used more often or at doses
higher than recommended, or in conjunction with other medications containing
LABA, as an overdose may result. Patients using FORADIL AEROLIZER should not
use an additional LABA (e.g. salmeterol xinafoate, arformoterol tartrate) for
any reason. Fatalities have been reported in association with excessive use of
inhaled sympathomimetic drugs in patients with asthma. The exact cause of death
is unknown, but cardiac arrest following an unexpected development of a severe
acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data
from clinical trials with FORADIL AEROLIZER suggest that the use of doses
higher than recommended is associated with an increased risk of serious asthma
exacerbations [see ADVERSE REACTIONS].
As with other inhaled beta2-agonists, formoterol can produce
paradoxical bronchospasm that may be life-threatening. If paradoxical
bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and
alternative therapy instituted.
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. Fatalities have been
reported in association with excessive use of inhaled sympathomimetic drugs [see
Formoterol fumarate, like other beta2-agonists, can produce
a clinically significant cardiovascular effect in some patients as measured by
increases in pulse rate, blood pressure, and/or symptoms. Although such effects
are uncommon after administration of FORADIL AEROLIZER at recommended doses, if
they occur, the drug 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, formoterol fumarate, like
other sympathomimetic amines, should be used with caution in patients with
cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after
administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic
reactions, urticaria, angioedema, rash, and bronchospasm.
FORADIL AEROLIZER contains lactose, which contains trace
levels of milk proteins. Allergic reactions to products containing milk
proteins may occur in patients with severe milk protein allergy.
Formoterol fumarate, like other sympathomimetic amines,
should be used with caution in patients with cardiovascular disorders,
especially coronary insufficiency, cardiac arrhythmias, and hypertension; in
patients with convulsive disorders or thyrotoxicosis; and in patients who are
unusually responsive to sympathomimetic amines. Doses of the related beta2agonist
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. The decrease in serum potassium is usually transient, not requiring supplementation.
Clinically significant changes in blood glucose and/or serum
potassium were infrequent during clinical studies with long-term administration
of FORADIL AEROLIZER at the recommended dose.
Inappropriate route of administration
FORADIL capsules should ONLY be used with the AEROLIZER
Inhaler and SHOULD NOT be swallowed. FORADIL capsules should always be stored
in the blister, and only removed IMMEDIATELY before use.
Patient Counseling Information
See FDA-approved patient
labeling (Medication Guide and Instructions for Use)
Patients should be instructed to
read the accompanying Medication Guide with each new prescription and refill.
The complete text of the Medication Guide is reprinted at the end of this
document. Patients should be given the following information:
Patients should be informed
that long-acting beta2-adrenergic agonists (LABA), including formoterol, the
active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related
death and may increase the risk of asthma-related hospitalizations in pediatric
and adolescent patients. Currently available data are inadequate to determine
whether concurrent use of inhaled corticosteroids or other long-term asthma
control drugs mitigates the increased risk of asthma- related death from LABA.
Patients should be informed
that FORADIL AEROLIZER should not be the only therapy for the treatment of
asthma and must only be used as additional therapy when a long-term asthma
control medication (e.g., inhaled corticosteroids) do not adequately control asthma
symptoms. Patients should be informed that when FORADIL AEROLIZER is added to
their treatment regimen they must continue to use their long-term asthma
Not for Acute Symptoms
FORADIL AEROLIZER is not indicated
to relieve acute asthma symptoms or exacerbations of COPD and extra doses
should not be used for that purpose. Acute symptoms should be treated with an
inhaled, short-acting, beta2-agonist (the health-care provider should prescribe
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, if FORADIL AEROLIZER treatment becomes less effective, or if
they need more inhalations of a short-acting beta2-agonist than usual. Patients
should not inhale more than the contents of one capsule at any one time. The
daily dosage of FORADIL AEROLIZER should not exceed one capsule twice daily (24
mcg total daily dose).
Required Concomitant Therapy
Patients with asthma should be
advised that FORADIL AEROLIZER must always be used with a long-term asthma
control medication such as an inhaled corticosteroid.
FORADIL AEROLIZER should not be
used as a substitute for oral or inhaled corticosteroids. The dosage of these
medications should not be changed and they should not be stopped without
consulting the physician, even if the patient feels better after initiating
treatment with FORADIL AEROLIZER.
Common Adverse Reactions
Patients should be informed that
treatment with beta2-agonists may lead to adverse events which include
palpitations, chest pain, rapid heart rate, tremor or nervousness.
The active ingredient of FORADIL
(formoterol fumarate) is a long-acting, bronchodilator used for the treatment
of asthma, including nocturnal asthma, for the prevention of exercise-induced
bronchospasm, and for the maintenance treatment of bronchoconstriction in
patients with Chronic Obstructive Pulmonary Disease including chronic
bronchitis and emphysema. FORADIL AEROLIZER provides bronchodilation for up to
12 hours. Patients should be advised not to increase the dose or frequency of
FORADIL AEROLIZER without consulting the prescribing physician. Patients should
be warned not to stop or reduce concomitant asthma therapy without medical
For asthma and COPD, the usual
dose is one FORADIL capsule inhaled through the AEROLIZER inhaler 2 times each
day (morning and evening). The 2 doses should be about 12 hours apart. Patients
should be advised not to use other LABA when using FORADIL AEROLIZER.
When FORADIL AEROLIZER is used for
the prevention of EIB, the contents of one capsule should be taken at least 15
minutes prior to exercise. Additional doses of FORADIL AEROLIZER should not be
used for 12 hours. Prevention of EIB has not been studied in patients who are
receiving chronic FORADIL AEROLIZER administration twice daily and these
patients should not use additional FORADIL AEROLIZER for prevention of EIB.
Instructions for Administration
It is important for patients to
understand how to correctly administer FORADIL capsules using the AEROLIZER
Inhaler and how FORADIL should be used in relation to other asthma medications
they are taking (see the accompanying Medication Guide).
Patients should be instructed that
FORADIL capsules should only be administered via the AEROLIZER device and the
AEROLIZER device should not be used for administering other medications. The
contents of FORADIL capsules are for oral inhalation only and must not be
Patients should be informed never
to use FORADIL AEROLIZER with a spacer and never to exhale into the device.
Patients should avoid exposing the
FORADIL capsules to moisture and should handle the capsules with dry hands. The
AEROLIZER Inhaler should never be washed and should be kept dry. The patient
should always use the new AEROLIZER Inhaler that comes with each refill.
Patients should be told that in
rare cases, the gelatin capsule might break into small pieces. These pieces should
be retained by the screen built into the AEROLIZER Inhaler. However, it remains
possible that rarely, tiny pieces of gelatin might reach the mouth or throat
after inhalation. The capsule is less likely to shatter when pierced if:
storage conditions are strictly followed, capsules are removed from the blister
immediately before use, and the capsules are only pierced once.
Women should be advised to contact
their physician if they become pregnant or if they are nursing.
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 mg/kg and above in the drinking water study and at 20
mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC
exposure approximately 450 times human exposure at the maximum recommended
human dose [MRHD]). In the dietary study, the incidence of benign ovarian
theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure
at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the
MRHD). 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 mg/kg
and above in the drinking water study, but not at doses up to 50 mg/kg (AUC
exposure approximately 590 times human exposure at the MRHD) in the dietary
study. The incidence of hepatocarcinomas was increased in the dietary study at
doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up
to 5 mg/kg in either males or females (AUC exposure approximately 60 times
human exposure at the MRHD). Also in the dietary study, the incidence of
uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and
above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human
exposure at the MRHD). 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 mg/kg (approximately
1,200 times the MRHD on a mcg/m2 basis).
Use In Specific Populations
Pregnancy Category C
Teratogenic Effects: There are no adequate and
well-controlled studies of FORADIL AEROLIZER in pregnant women. Animal
reproduction studies of formoterol fumarate in rats and rabbits revealed
evidence of teratogenicity as well as other developmental toxic effects.
Because there are no adequate and well-controlled studies in pregnant women,
FORADIL AEROLIZER should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Formoterol fumarate administered
throughout organogenesis did not cause malformations in rats or rabbits
following oral administration. When given to rats throughout organogenesis,
oral doses equal to or greater than 80 times the maximum recommended human dose
(MRHD) for adults (on a mcg/m2 basis for maternal doses of 0.2 mg/kg
and above) delayed ossification of the fetus and doses equal to or greater than
2,400 times the MRHD for adults (on a mcg/m2 basis for maternal
doses of 6 mg/kg and above) decreased fetal weight. Formoterol fumarate has
been shown to cause stillbirth and neonatal mortality at oral doses equal to or
greater than 2,400 times the MRHD for adults (on a mcg/m2 basis for
maternal doses of 6 mg/kg and above) in rats receiving the drug during the late
stage of pregnancy. These effects, however, were not produced at a dose equal
to 80 times the MRHD for adults (on a mcg/m2 basis for a maternal
dose of 0.2 mg/kg).
In another testing laboratory,
formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical
hernia, a malformation, was observed in rat fetuses at oral doses equal to or
greater than 1,200 times the MRHD for adults (on a mcg/m2 basis for
maternal doses of 3 mg/kg/day and above). Brachygnathia, a skeletal
malformation, was observed for rat fetuses at an oral dose equal to 6,100 times
the MRHD for adults (on a mcg/m2 basis for a maternal dose of 15 mg/kg/day).
In another study in rats, no teratogenic effects were seen at inhalation doses
up to 500 times the MRHD for adults (on a mcg/m2 basis for maternal
doses up to 1.2 mg/kg/day). Subcapsular cysts on the liver were observed for
rabbit fetuses at an oral dose equal to 49,000 times the MRHD for adults (on a
mcg/m2 basis for a maternal dose of 60 mg/kg). No teratogenic
effects were observed at oral doses up to 3,000 times the MRHD for adults (on a
mcg/m2 basis for maternal doses up to 3.5 mg/kg).
Labor and Delivery
There are no adequate and
well-controlled human studies that have investigated the effects of FORADIL
AEROLIZER during labor and delivery.
Because beta-agonists may
potentially interfere with uterine contractility, FORADIL AEROLIZER should be
used during labor only if the potential benefit justifies the potential risk.
Formoterol fumarate has been shown
to cause stillbirth and neonatal mortality at oral doses equal to or greater
than 2,400 times the MRHD for adults (on a mcg/m2 basis for maternal
doses of 6 mg/kg and above) in rats receiving the drug for several days at the
end of pregnancy. These effects were not produced at a dose 80 times the MRHD
for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg).
In reproductive studies in rats,
formoterol was excreted in the milk. It is not known whether formoterol is
excreted in human milk, but because many drugs are excreted in human milk,
caution should be exercised if FORADIL AEROLIZER is administered to nursing
women. There are no well-controlled human studies of the use of FORADIL
AEROLIZER in nursing mothers.
Available data from controlled
clinical trials suggest that LABA increase the risk of asthma-related
hospitalization in pediatric and adolescent patients. For pediatric and
adolescent patients with asthma who require addition of a LABA to an inhaled
corticosteroid, a fixed-dose combination product containing both an inhaled
corticosteroid and LABA should ordinarily be used to ensure adherence with both
drugs [see INDICATIONS AND USAGE and WARNINGS AND PRECAUTIONS].
A total of 776 children 5 years of
age and older with asthma were studied in three multiple-dose controlled
clinical trials. Of the 512 children who received formoterol, 508 were 5-12
years of age, and approximately one third were 5-8 years of age [see ADVERSE
A total of 25 pediatric patients,
4-11 years of age, were studied in two well-controlled single-dose clinical
The safety and effectiveness of
FORADIL AEROLIZER in pediatric patients below 5 years of age has not been
established [see Clinical Trials, and ADVERSE REACTIONS].
Of the total number of patients
who received FORADIL AEROLIZER in adolescent and adult chronic dosing asthma
clinical trials, 318 were 65 years of age or older and 39 were 75 years of age
and older. Of the 811 patients who received FORADIL AEROLIZER in two pivotal
multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%)
were 65 years of age or older while 62 (7.6%) were 75 years of age or older. No
overall differences in safety or effectiveness were observed between these
subjects and younger subjects. A slightly higher frequency of chest infection
was reported in the 39 asthma patients 75 years of age and older, although a
causal relationship with FORADIL has not been established. 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.