CONTRAINDICATIONS
Salmeterol xinafoate is contraindicated in patients with a history of hypersensitivity to
salmeterol or any of its components.
WARNINGS
IMPORTANT INFORMATION: SALMETEROL XINAFOATE 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
salmeterol xinafoate has been initiated in this situation.
Although it is not possible from these reports to determine whether salmeterol
xinafoate contributed to these adverse events or simply failed to relieve the
deteriorating asthma, the use of salmeterol xinafoate in this setting is
inappropriate.
SALMETEROL XINAFOATE 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.
SALMETEROL XINAFOATE IS NOT A SUBSTITUTE FOR INHALED OR
ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced
when salmeterol xinafoate is initiated.
(See PRECAUTIONS, Information for the Patient and Patient's Instructions for
Use.)
Do Not Introduce Salmeterol Xinafoate as a Treatment for Acutely Deteriorating
Asthma
Salmeterol xinafoate 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 salmeterol xinafoate 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 salmeterol xinafoate. 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 salmeterol xinafoate contributed to these events or simply failed to
relieve the deteriorating asthma.
Do Not Use Salmeterol Xinafoate to Treat Acute Symptoms
An inhaled, short-acting beta2-agonist, not salmeterol xinafoate, should be used to relieve
acute asthma symptoms (and COPD symptoms for the inhalation aerosol). When
prescribing salmeterol xinafoate, 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 salmeterol xinafoate.
When beginning treatment with salmeterol xinafoate, patients who have been taking
inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 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 (or COPD symptoms for the inhalation
aerosol). (See PRECAUTIONS, Information for the Patient).
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 4 or more inhalations per day of an inhaled,
short-acting beta2-agonist for 2 or more consecutive days, or if more than 1 canister
(200 inhalations per canister) of inhaled, short-acting beta2-agonist is used in an 8 week
period in conjunction with salmeterol xinafoate, then the patient should consult the
physician for reevaluation. Increasing the daily dosage of salmeterol xinafoate in this
situation is not appropriate. Salmeterol xinafoate should not be used more
frequently than twice daily (morning and evening) at the recommended dose of 1
inhalation for salmeterol xinafoate inhalation powder and 2 inhalations for
salmeterol xinafoate inhalation aerosol.
Do Not Use Salmeterol Xinafoate 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 antiinflammatory
agents, e.g., corticosteroids. There are no data demonstrating that salmeterol xinafoate
has a clinical antiinflammatory effect and could be expected to take the place of
corticosteroids. 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 salmeterol xinafoate. Any change in corticosteroid dosage should be made
ONLY after clinical evaluation (see PRECAUTIONS, Information for the Patient).
Do Not Exceed Recommended Dosage
As with other inhaled beta2-adrenergic drugs, salmeterol xinafoate 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 (12-20 times the recommended dose) have been associated with
clinically significant prolongation of the QTc interval, which has the potential for producing
ventricular arrhythmias.
Paradoxical Bronchospasm
Inhalation of salmeterol xinafoate can produce paradoxical bronchospasm, which may be
life-threatening. If paradoxical bronchospasm occurs, salmeterol xinafoate should be
discontinued immediately and alternative therapy instituted. For Salmeterol Xinafoate
Inhalation Aerosol Only: It should be recognized that paradoxical bronchospasm, when
associated with inhaled formulations, frequently occurs with the first use of a new canister
or vial.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of salmeterol
xinafoate, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.
Upper Airway Symptoms
Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have
been reported rarely in patients receiving salmeterol xinafoate.
Salmeterol xinafoate, 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
salmeterol xinafoate 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, salmeterol xinafoate, like all sympathomimetic amines, should be
used with caution in patients with cardiovascular disorders, especially coronary
insufficiency, cardiac arrhythmias, and hypertension.
PRECAUTIONS
General
Use with Spacer or Other Devices
Salmeterol Xinafoate Inhalation Aerosol: The safety and effectiveness of salmeterol
xinafoate inhalation aerosol when used with a spacer or other devices have not been
adequately studied.
Cardiovascular and Other Effects
No effect on the cardiovascular system is usually seen after the administration of inhaled
salmeterol in 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.
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 salmeterol xinafoate 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 salmeterol xinafoate at
recommended doses.
Information for the Patient
Salmeterol Xinafoate Inhalation Aerosol
See illustrated Patient's Instructions for Use. SHAKE WELL BEFORE USING.
It is important that patients understand how to use the drug inhalation device
appropriately and how it should be used in relation to other asthma or COPD
medications they are taking. Patients should be given the following information:
1. Shake well before using.
2. The action of salmeterol xinafoate inhalation aerosol may last up to 12 hours or
longer. The recommended dosage (2 inhalations twice daily, morning and evening)
should not be exceeded.
3. Salmeterol xinafoate inhalation aerosol is not meant to relieve acute asthma or
COPD symptoms and extra doses should not be used for that purpose. Acute
symptoms should be treated with an inhaled, short-acting beta2-agonist such as
albuterol (the physician should provide the patient with such medication and
instruct the patient in how it should be used).
4. Patients should not stop salmeterol xinafoate inhalation aerosol therapy for
COPD without physician/provider guidance since symptoms may recur after
discontinuation.
5. The physician should be notified immediately if any of the following situations
occur, which may be a sign of seriously worsening asthma:
Decreasing effectiveness of inhaled, short-acting beta2-agonists.
Need for more inhalations than usual of inhaled, short-acting beta2-agonists.
Use of 4 or more inhalations per day of a short-acting beta2-agonist for 2 or
more days consecutively.
Use of more than one 200 inhalation canister of an inhaled, short-acting
beta2-agonist (e.g., albuterol) in an 8 week period.
6. Salmeterol xinafoate inhalation aerosolshould 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 salmeterol xinafoate inhalation aerosol.
7. Patients should be cautioned regarding common adverse cardiovascular effects,
such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
8. In patients receiving salmeterol xinafoate inhalation aerosol, other inhaled
medications should be used only as directed by the physician.
9. When using salmeterol xinafoate inhalation aerosol to prevent exercise-induced
bronchospasm, patients should take the dose at least 30-60 minutes before
exercise.
10. If you are pregnant or nursing, contact your physician about use of salmeterol
xinafoate inhalation aerosol.
11. Effective and safe use of salmeterol xinafoate inhalation aerosol includes an
understanding of the way that it should be administered.
For Salmeterol Xinafoate Inhalation Powder
See illustrated Patient's Instructions for Use.
It is important that patients understand how to use the drug inhalation device
appropriately and how it should be used in relation to other asthma medications they are
taking. Patients should be given the following information:
1. The action of salmeterol xinafoate inhalation powder may last up to 12 hours or
longer. The recommended dosage (1 inhalations twice daily, morning and evening)
should not be exceeded.
2. Salmeterol xinafoate inhalation powder is not meant to relieve acute asthma
symptoms and extra doses should not be used for that purpose. Acute symptoms
should be treated with an inhaled, short-acting beta2-agonist such as albuterol (the
physician should provide the patient with such medication and instruct the patient in
how it should be used).
3.
When used for the treatment of EIB, 1 inhalation of salmeterol xinafoate
inhalation powder should be taken 30 minutes before exercise.
Additional doses of salmeterol xinafoate inhalation powder should not be
used for 12 hours.
Patients who are receiving salmeterol xinafoate inhalation powder twice
daily should not use additional salmeterol xinafoate inhalation powder for
prevention of EIB.
4. The physician should be notified immediately if any of the following situations
occur, which may be a sign of seriously worsening asthma:
Decreasing effectiveness of inhaled, short-acting beta2-agonists.
Need for more inhalations than usual of inhaled, short-acting beta2-agonists.
Use of 4 or more inhalations per day of a short-acting beta2-agonist for 2 or
more days consecutively.
Use of more than 1 canister of an inhaled, short-acting beta2-agonist (e.g.,
albuterol) in an 8 week period (i.e., canister with 200 inhalations).
5. Salmeterol xinafoate inhalation powder 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 salmeterol xinafoate inhalation
powder.
6. Patients should be cautioned regarding common adverse cardiovascular effects,
such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
7. In patients receiving salmeterol xinafoate inhalation powder, other inhaled
medications should be used only as directed by the physician.
8. Salmeterol xinafoate inhalation powder should not be used with a spacer.
9. If you are pregnant or nursing, contact your physician about use of salmeterol
xinafoate inhalation powder.
10. Effective and safe use of the inhalation device includes an understanding of the
way that it should be used:
Never exhale into the inhalation device.
Always activate and use the inhalation device in a level, horizontal position.
Never wash the mouthpiece or any part of the inhalation device. KEEP IT
DRY.
Carcinogenesis, Mutagenesis, and 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 for salmeterol xinafoate inhalation powder, and
approximately 9 times the maximum recommended daily inhalation dose in adults for
salmeterol xinafoate inhalation aerosol 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, and leiomyomas in
the uterus and cysts in the ovaries. The incidence of leiomyosarcomas was not statistically
significant. No tumors were seen at 0.2 mg/kg per day (approximately 3 times the
maximum recommended daily inhalation doses in adults and children for salmeterol
xinafoate inhalation powder, and comparable to the maximum recommended daily
inhalation dose in adults for salmeterol xinafoate inhalation aerosol based on comparison
of the AUCs).
In a 24 month oral and inhalation carcinogenicity study in Sprague Dawley rats,
salmeterol caused dose-related increases in the incidence of mesovarian leiomyomas and
ovarian cysts at inhalation and oral doses of 0.68 mg/kg per day and above
(approximately 60 times the maximum recommended daily inhalation dose in adults and
approximately 30 times the maximum recommended daily inhalation dose in children with
the inhalation powder, and approximately 55 times the maximum recommended human
daily inhalation dose in adults with the inhalation aerosol, on a mg/m2 basis). No tumors
were seen at 0.21 mg/kg per day (approximately 20 times the maximum recommended
daily inhalation dose in adults and 9 times the maximum recommended daily inhalation
dose in children with the inhalation powder; and approximately 15 times the maximum
recommended human daily inhalation dose with the inhalation aerosol in adults, 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 of up to 2 mg/kg
(approximately 170 times the maximum recommended daily inhalation dose with the
inhalation powder and approximately 160 times the maximum recommended human daily
inhalation dose in adults with the inhalation aerosol, on a mg/m2 basis).
Pregnancy, Teratogenic Effects, Pregnancy Category C
No teratogenic effects occurred in rats at oral doses of up to