DATA FROM A LARGE PLACEBO-CONTROLLED SAFETY STUDY THAT WAS STOPPED EARLY SUGGEST THAT SALMETEROL MAY BE ASSOCIATED WITH RARE SERIOUS ASTHMA EPISODES OR ASTHMA-RELATED DEATHS. Data from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further suggest that the risk might be greater in African American patients. These results led to stopping the study prematurely (see CLINICAL TRIALS: Asthma: Salmeterol Multi-center Asthma Research Trial). The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk. Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect.
Findings similar to the SMART study findings were reported in a prior 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence of asthma-related death was numerically, though not statistically, greater in patients with asthma treated with salmeterol (42 mcg twice daily) versus albuterol (180 mcg 4 times daily) added to usual asthma therapy.
SEREVENT INHALATION AEROSOL 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 Inhalation Aerosol has been initiated in this situation.
Although it is not possible from these reports to determine whether SEREVENT Inhalation Aerosol contributed to these adverse events or simply failed to relieve the deteriorating asthma, the use of SEREVENT Inhalation Aerosol in this setting is inappropriate.
SEREVENT INHALATION AEROSOL SHOULD NOT BE USED TO TREAT ACUTE SYMPTOMS. It is crucial to inform patients of this and prescribe an inhaled, short-acting beta 2 -agonist for this purpose as well as warn them that increasing inhaled beta 2 -agonist use is a signal of deteriorating asthma.
SEREVENT INHALATION AEROSOL IS NOT A SUBSTITUTE FOR INHALED OR ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced when SEREVENT Inhalation Aerosol is initiated.
(See PRECAUTIONS: Information for Patients and the PATIENT'S INSTRUCTIONS FOR USE accompanying the product.)
1. Do Not Introduce SEREVENT Inhalation Aerosol as a Treatment for Acutely Deteriorating Asthma: SEREVENT Inhalation Aerosol 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 Inhalation Aerosol 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 Inhalation Aerosol. 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 lifethreatening 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, shortacting 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 Inhalation Aerosol contributed to these events or simply failed to relieve the deteriorating asthma.
2. Do Not Use SEREVENT Inhalation Aerosol to Treat Acute Symptoms: An inhaled, short-acting beta2-agonist, not SEREVENT Inhalation Aerosol, should be used to relieve acute asthma or COPD symptoms. When prescribing SEREVENT Inhalation Aerosol, 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 Inhalation Aerosol.
When beginning treatment with SEREVENT Inhalation Aerosol, 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 or COPD symptoms (see PRECAUTIONS: Information for Patients).
3. Watch for Increasing Use of Inhaled, Short-Acting Beta 2 -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 SEREVENT Inhalation Aerosol, then the patient should consult the physician for reevaluation. Increasing the daily dosage of SEREVENT Inhalation Aerosol in this situation is not appropriate. SEREVENT Inhalation Aerosol should not be used more frequently than twice daily (morning and evening) at the recommended dose of 2 inhalations.
4. Do Not Use SEREVENT Inhalation Aerosol 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 Inhalation Aerosol has a clinical anti-inflammatory 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 SEREVENT Inhalation Aerosol. Any change in corticosteroid dosage should be made ONLY after clinical evaluation (see PRECAUTIONS: Information for Patients).
5. Do Not Exceed Recommended Dosage: As with other inhaled beta2-adrenergic drugs, SEREVENT Inhalation Aerosol 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: SEREVENT Inhalation Aerosol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, SEREVENT Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.
7. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of SEREVENT Inhalation Aerosol, as demonstrated by rare 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 rarely in patients receiving SEREVENT Inhalation Aerosol.
SEREVENT Inhalation Aerosol, 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 Inhalation Aerosol 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 Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
1. Use With Spacer or Other Devices: The safety and effectiveness of SEREVENT Inhalation Aerosol when used with a spacer or other devices have not been adequately studied.
2. 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. SEREVENT Inhalation Aerosol, 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 ECGs have been seen infrequently in individual patients in controlled clinical studies with salmeterol.
3. 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 Inhalation Aerosol 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 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 Inhalation Aerosol at recommended doses.
Information for Patients
See illustrated PATIENT’S INSTRUCTIONS FOR USE. SHAKE WELL BEFORE USING.
It is important that patients understand how to use SEREVENT Inhalation Aerosol 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:
- Shake well before using.
- The action of SEREVENT Inhalation Aerosol may last up to 12 hours or longer. The recommended dosage (2 inhalations twice daily, morning and evening) should not be exceeded.
- SEREVENT 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).
- Patients should not stop SEREVENT therapy for asthma or COPD without physician/provider guidance since symptoms may recur after discontinuation.
- 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
- SEREVENT Inhalation Aerosol 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 SEREVENT Inhalation Aerosol.
- Patients should be cautioned regarding common adverse cardiovascular effects, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
- In patients receiving SEREVENT Inhalation Aerosol, other inhaled medications should be used only as directed by the physician.
- When using SEREVENT Inhalation Aerosol to prevent exercise-induced bronchospasm, patients should take the dose at least 30 to 60 minutes before exercise.
- Patients who are pregnant or nursing should contact the physician about the use of SEREVENT Inhalation Aerosol.
- Effective and safe use of SEREVENT Inhalation Aerosol includes an understanding of the way that it should be administered.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.
Corticosteroids and Cromoglycate
In clinical trials, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of SEREVENT Inhalation Aerosol when administered concurrently.
The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving SEREVENT Inhalation Aerosol has not been completely evaluated. In 1 clinical asthma trial, 87 patients receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 patients receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the patients on theophylline but were little affected by SEREVENT Inhalation Aerosol therapy.
Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as SEREVENT Inhalation Aerosol, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg and above (approximately 9 times the maximum recommended daily inhalation dose in adults based on comparison of the areas under the plasma concentration versus time curves [AUCs]) caused dose-related increases 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 (comparable to the maximum recommended human daily inhalation dose in adults based on comparison of the AUCs).
In a 24-month inhalation and oral 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/day and above (approximately 55 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). No tumors were seen at 0.21 mg/kg/day (approximately 15 times the maximum recommended human daily inhalation dose 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 xinafoate 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 orally with salmeterol xinafoate at doses up to 2 mg/kg (approximately 160 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis).
Pregnancy Category C. No teratogenic effects occurred in the rat at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 20 times the maximum recommended human daily inhalation dose in adults based on the comparison of the AUCs), salmeterol xinafoate 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 10 times the maximum recommended human 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 cranial bones was seen at oral doses of 10 mg/kg (approximately 1,600 times the maximum recommended human daily inhalation dose on a mg/m2 basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to use in humans. There are no adequate and well-controlled studies with SEREVENT Inhalation Aerosol in pregnant women. SEREVENT Inhalation Aerosol 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 Inhalation Aerosol for prevention of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in milk. However, since there is no experience with use of SEREVENT Inhalation Aerosol 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.
The safety and effectiveness of SEREVENT Inhalation Aerosol in children younger than 12 years of age have not been established.
Of the total number of patients who received SEREVENT Inhalation Aerosol in all asthma clinical studies, 241 were 65 years of age and older. Geriatric patients (65 years and older) with reversible obstructive airway disease were evaluated in 4 well-controlled studies of 3 weeks’ to 3 months’ duration. Two placebo-controlled, crossover studies evaluated twice-daily dosing with salmeterol for 21 to 28 days in 45 patients. An additional 75 geriatric patients were treated with salmeterol for 3 months in 2 large parallel-group, multicenter studies. These 120 patients experienced increases in AM and PM PEF and decreases in diurnal variation in PEF similar to responses seen in the total populations of the 2 latter studies. The adverse event type and frequency in geriatric patients were not different from those of the total populations studied.
In 2 large, randomized, double-blind, placebo-controlled 3-month studies involving patients with COPD, 133 patients using SEREVENT Inhalation Aerosol were 65 years and older. These patients experienced similar improvements in FEV1 as observed for patients younger than 65.
No apparent differences in the efficacy and safety of SEREVENT Inhalation Aerosol were observed when geriatric patients were compared with younger patients in asthma and COPD clinical trials. As with other beta2-agonists, however, special caution should be observed when using SEREVENT Inhalation Aerosol 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.