A1,
A2,
B,
C1,
C2,
D,
E,
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Serevent Diskus Warnings, Precautions, Pregnancy, Nursing, Abuse - Salmeterol Xinafoate (inhalation powder)
Serevent Diskus Warnings, Precautions, Pregnancy, Nursing, Abuse - Salmeterol Xinafoate (inhalation powder)
WARNINGS
IMPORTANT INFORMATION: SEREVENT DISKUS SHOULD NOT BE INITIATED
IN PATIENTS WITH SIGNIFICANTLY WORSENING OR
ACUTELY DETERIORATING ASTHMA, WHICH MAY BE A LIFE-THREATENING CONDITION.
Serious acute respiratory
events, including fatalities, have been reported, both in the United
States and worldwide, when SEREVENT has been initiated in this situation.
Although it is not possible from these reports to determine whether
SEREVENT contributed to these adverse events or simply failed to
relieve the deteriorating asthma,
the use of SEREVENT DISKUS in this setting is inappropriate.
SEREVENT DISKUS SHOULD NOT BE USED TO
TREAT ACUTE SYMPTOMS. It is crucial to inform patients of this and
prescribe an inhaled,
short-acting beta2-agonist for this purpose as well as warn them
that increasing inhaled beta2-agonist use is a signal
of deteriorating asthma.
SEREVENT DISKUS IS NOT A SUBSTITUTE FOR INHALED OR
ORAL CORTICOSTEROIDS. Corticosteroids
should not be stopped or reduced when SEREVENT DISKUS is initiated.
(See PATIENT INFORMATION
and the accompanying PATIENT'S INSTRUCTIONS FOR USE.)
1. Do Not Introduce SEREVENT DISKUS as a Treatment for Acutely
Deteriorating Asthma: SEREVENT DISKUS is intended for the
maintenance treatment of asthma
(see INDICATIONS AND USAGE)
and should not be introduced in acutely deteriorating asthma, which
is a potentially life-threatening condition. There are no data demonstrating
that SEREVENT DISKUS provides greater efficacy
than or additional efficacy
to inhaled, short-acting beta2-agonists in patients with worsening
asthma. Serious acute
respiratory events,
including fatalities, have been reported, both in the United States
and worldwide, in patients receiving SEREVENT. In
most cases, these have occurred in patients with severe asthma
(e.g., patients with a history
of corticosteroid
dependence, low pulmonary
function, intubation,
mechanical ventilation, frequent hospitalizations, or previous life-threatening
acute asthma
exacerbations) and/or in some patients in whom asthma
has been acutely deteriorating (e.g., unresponsive to usual medications;
increasing need for inhaled,
short-acting beta2-agonists; increasing need
for systemic corticosteroids;
significant increase
in symptoms; recent emergency
room visits; sudden or
progressive deterioration
in pulmonary function). However, they have occurred in a few patients
with less severe asthma as well. It was not possible from these
reports to determine whether SEREVENT contributed to these events
or simply failed to relieve
the deteriorating asthma.
2. Do Not Use SEREVENT DISKUS to Treat Acute Symptoms:
An inhaled, short-acting beta2-agonist, not SEREVENT DISKUS, should
be used to relieve acute
asthma symptoms. When
prescribing SEREVENT DISKUS, the physician
must also provide the patient
with an inhaled, short-acting beta2-agonist (e.g., albuterol) for
treatment of symptoms
that occur acutely, despite regular
twice-daily (morning and evening) use of SEREVENT DISKUS.
When beginning treatment
with SEREVENT DISKUS, 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 drugs and use them only for symptomatic
relief of acute
asthma symptoms (see
PATIENT INFORMATION).
3. Watch for Increasing Use of Inhaled, Short-Acting Beta2-Agonists,
Which Is a Marker of Deteriorating Asthma: Asthma may deteriorate
acutely over a period
of hours or chronically over several days or longer. If the patient's
inhaled, short-acting beta2-agonist becomes less effective or the
patient needs more inhalations
than usual, this may be a marker of destabilization of asthma. In
this setting, the patient
requires immediate reevaluation with reassessment of the treatment
regimen, giving special consideration to the possible need
for corticosteroids. If the patient uses four or more inhalations
per day of an inhaled, short-acting
beta2-agonist for 2 or more consecutive days, or if more than one
canister (200 inhalations per canister) of inhaled, short-acting
beta2-agonist is used in an 8-week period in conjunction with SEREVENT
DISKUS, then the patient
should consult the physician
for reevaluation. Increasing the daily dosage
of SEREVENT DISKUS in this situation
is not appropriate. SEREVENT DISKUS should not be used more frequently
than twice daily (morning and evening) at the recommended dose of
one inhalation.
4. Do Not Use SEREVENT DISKUS as a Substitute for Oral or
Inhaled Corticosteroids: The use of beta-adrenergic agonist
bronchodilators alone may not be adequate to control
asthma in many patients.
Early consideration should be given to adding anti-inflammatory
agents, e.g., corticosteroids. There are no
data demonstrating that SEREVENT DISKUS has a clinical
anti-inflammatory effect and could be expected to take
the place of, or reduce
the dose of, corticosteroids.
Patients who already require oral
or inhaled corticosteroids for treatment
of asthma should be continued
on a suitable dose to maintain
clinical stability
even if they feel better as a result of initiating SEREVENT DISKUS.
Any change in corticosteroid
dosage should be made
ONLY after clinical evaluation
(see PATIENT INFORMATION).
5. Do Not Exceed Recommended Dosage: As with other
inhaled beta2-adrenergic drugs, SEREVENT DISKUS should not be used
more often or at higher doses than recommended. Fatalities have
been reported in association with excessive use of inhaled sympathomimetic
drugs. Large doses of inhaled or oral
salmeterol (12 to 20 times the recommended dose) have been associated
with clinically significant
prolongation of the QTc
interval, which has
the potential for
producing ventricular
arrhythmias.
6. Paradoxical Bronchospasm: Inhalation of salmeterol
xinafoate can produce paradoxical bronchospasm,
which may be life threatening.
If paradoxical bronchospasm
occurs, SEREVENT DISKUS should be discontinued immediately and alternative
therapy instituted.
7. Immediate Hypersensitivity Reactions: Immediate
hypersensitivity reactions may occur after
administration of SEREVENT DISKUS, as demonstrated by cases of urticaria,
angioedema, rash, and bronchospasm.
8. Upper Airway Symptoms: Symptoms of laryngeal
spasm, irritation, or swelling, such
as stridor and choking,
have been reported in patients receiving SEREVENT DISKUS.
SEREVENT DISKUS, like all other beta-adrenergic agonists, can produce
a clinically significant
cardiovascular effect
in some patients as measured by pulse
rate, blood pressure, and/or symptoms.
Although such effects are
uncommon after administration
of SEREVENT DISKUS at recommended doses, if they occur, the drug
may need to be discontinued.
In addition, beta-agonists have been reported to produce electrocardiogram
(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, SEREVENT DISKUS,
like all sympathomimetic amines, should be used with caution in
patients with cardiovascular
disorders, especially coronary
insufficiency, cardiac
arrhythmias, and hypertension.
PRECAUTIONS
General
1. Cardiovascular and Other Effects: No
effect on the cardiovascular
system is usually seen
after the administration
of inhaled salmeterol at recommended doses, but the cardiovascular
and central nervous
system effects seen with all sympathomimetic
drugs (e.g., increased blood pressure, heart
rate, excitement) can occur after use of salmeterol and may require
discontinuation of the drug. Salmeterol, like all 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.
As has been described with other beta-adrenergic agonist
bronchodilators, clinically significant
changes in systolic
and/or diastolic blood
pressure, pulse rate, and electrocardiograms have been seen infrequently
in individual patients in controlled clinical
studies with salmeterol.
2. Metabolic Effects: Doses of the related beta2-adrenoceptor
agonist albuterol, when administered intravenously, have been reported
to aggravate preexisting diabetes
mellitus and ketoacidosis. No
effects on glucose have
been seen with SEREVENT DISKUS at recommended doses. Beta-adrenergic
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 seen rarely during clinical
studies with long-term administration of SEREVENT DISKUS at recommended
doses.
Information for Patients
See PATIENT INFORMATION
section.
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In an 18-month carcinogenicity study in CD-mice, salmeterol xinafoate
at oral doses of 1.4 mg/kg
and above (approximately 20 times the maximum recommended daily
inhalation dose
in adults and children based on comparison of the area
under the plasma concentration
versus time curves [AUCs])
caused a dose-related increase in the incidence
of smooth muscle hyperplasia,
cystic glandular hyperplasia,
leiomyomas of the uterus,
and cysts in the ovaries. The incidence
of leiomyosarcomas was not statistically significant. No tumors
were seen at 0.2 mg/kg (approximately 3 times the maximum
recommended daily inhalation
doses in adults and children based on comparison of the AUCs).
In a 24-month oral and
inhalation carcinogenicity
study in Sprague Dawley rats, salmeterol caused a
dose-related increase in the incidence
of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg
and above (approximately 60 times the maximum recommended daily
inhalation dose
in adults andapproximately 30 times the maximum recommended daily
inhalation dose
in children on a mg/m2 basis). No
tumors were seen at 0.21 mg/kg (approximately 20 times the maximum
recommended daily inhalation
dose in adults and approximately
9 times the maximum recommended daily inhalation
dose in children on a mg/m2
basis). These findings in rodents are similar to those reported
previously for other beta-adrenergic agonist
drugs. The relevance of these findings to human
use is unknown.
Salmeterol produced no detectable
or reproducible increases in microbial and mammalian gene
mutation in vitro.
No clastogenic
activity occurred in
vitro in human lymphocytes
or in vivo in a rat micronucleus
test. No effects on fertility
were identified in male
and female rats treated
with salmeterol at oral
doses up to 2 mg/kg (approximately 170 times the maximum recommended
daily inhalation
dose in adults on a mg/m2
basis).
Pregnancy
Teratogenic Effects: Pregnancy Category C. No
teratogenic effects occurred in rats at oral
doses up to 2 mg/kg (approximately 170 times the maximum
recommended daily inhalation
dose in adults on a mg/m2
basis). In pregnant
Dutch rabbits administered oral doses of 1 mg/kg and above
(approximately 50 times the maximum
recommended daily inhalation
dose in adults based on
comparison of the AUCs), salmeterol exhibited fetal
toxic effects characteristically
resulting from beta-adrenoceptor stimulation. These included precocious
eyelid openings, cleft
palate, sternebral fusion, limb
and paw flexures, and delayed ossification
of the frontal cranial bones. No
significant effects
occurred at an oral dose
of 0.6 mg/kg (approximately 20 times the maximum
recommended daily inhalation
dose in adults based on
comparison of the AUCs).
New Zealand White rabbits were less sensitive
since only delayed ossification of the frontal
bones was seen at an oral
dose of 10 mg/kg (approximately
1700 times the maximum
recommended daily inhalation
dose in adults on a mg/m2
basis). Extensive use of other beta-agonists has provided no evidence
that these class effects
in animals are relevant to their use in humans. There are no
adequate and well-controlled studies with SEREVENT DISKUS in pregnant
women. SEREVENT DISKUS should be used during pregnancy only if the
potential benefit
justifies the potential
risk to the fetus.
Use in Labor and Delivery
There are no well-controlled
human studies that have
investigated effects of salmeterol on preterm
labor or labor
at term. Because of the potential for beta-agonist interference
with uterine contractility,
use of SEREVENT DISKUS for relief
of bronchospasm
during labor should be
restricted to those patients in whom the benefits clearly outweigh
the Risks.
Nursing Mothers
Plasma levels of salmeterol after inhaled therapeutic
doses are very low. In rats,
salmeterol xinafoate is excreted in the milk. However, since there
are no data from controlled trials on the use of SEREVENT by nursing
mothers, a decision should be made whether to discontinue nursing
or to discontinue the drug,
taking into account the importance of the drug
to the mother. Caution should be exercised when salmeterol xinafoate
is administered to a nursing
woman.
Pediatric Use
The safety and efficacy
of salmeterol inhalation
powder has been evaluated
in over 2500 patients aged
4 to 11 years with asthma,
346 of whom were administered salmeterol inhalation
powder for 1 year. Based
on available data, no adjustment
of salmeterol dosage
in pediatric patients
is warranted for either asthma
or EIB (see DOSAGE AND ADMINISTRATION).
In two randomized, double-blind, controlled clinical
trials of 12 weeks’ duration, salmeterol 50-mcg powder
was administered to 211 pediatric
asthma patients who did and who did not receive concurrent inhaled
corticosteroids. The efficacy
of salmeterol inhalation
powdersalmeterol powder
was demonstrated over the 12-week treatment
period with respect to
peak expiratory flow
and FEV1. Salmeterol inhalation
powderSalmeterol powder
was effective in demographic subgroups (gender and age) of the population.
Salmeterol was effective when coadministered with other inhaled
asthma medications, such
as short-acting bronchodilators and inhaled corticosteroids. Salmeterol
inhalation powderSalmeterol
powder was well tolerated
in the pediatric population, and there were no
safety issues identified specific to the administration
of salmeterol inhalation
powdersalmeterol powder to pediatric
patients.
In two randomized studies in children 4 to 11 years old with asthma
and EIB, a single 50-mcg dose
of salmeterol inhalation
powdersalmeterol powder significantly prevented EIB when dosed 30
minutes prior to exercise, with protection lasting up to 11.5 hours
in repeat testing following this single-dose in many patients.
Geriatric Use
Of the total number
of patients who received salmeterol inhalation
powder in adolescent
and adult chronic
dosing clinical trials,
209 were 65 years of age
and older. No apparent
differences in the efficacy
and safety of SEREVENT inhalation
powder were observed
when geriatric patients were compared with younger patients in clinical
trials. As with other beta2-agonists,
however, special caution should be observed when using SEREVENT
inhalation powder in geriatric patients who have concomitant
cardiovascular
disease that could be adversely affected by this class
of drug. Based on available data, no
adjustment of salmeterol
dosage in geriatric patients
is warranted.
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