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8. Upper Airway Symptoms: Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS. 9. Cardiovascular Disorders: Text Continues Below
SEREVENT DISKUS, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 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 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.
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 SEREVENT DISKUS. SEREVENT DISKUS, 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. 2. Metabolic Effects: Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 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: Patients being treated with SEREVENT DISKUS should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use the DISKUS appropriately and how to use SEREVENT DISKUS in relation to other asthma or COPD medications they are taking. Patients should be given the following information: 1. The action of SEREVENT DISKUS may last up to 12 hours or longer. The recommended dosage (1 inhalation twice daily, morning and evening) should not be exceeded. 2. Most patients are able to taste or feel a dose delivered from SEREVENT DISKUS. However, whether or not patients are able to sense delivery of a dose, you should instruct them not to exceed the recommended dose of 1 inhalation twice daily, morning and evening. You should instruct them to contact you or the pharmacist if they have questions. 3. SEREVENT DISKUS 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 bronchodilator (the physician should provide the patient with such medication and instruct the patient in how it should be used). 4. Patients should not stop therapy with SEREVENT DISKUS for asthma or COPD without physician/provider guidance since symptoms may worsen after discontinuation. 5. When used for the treatment of EIB, 1 inhalation of SEREVENT DISKUS should be taken 30 minutes before exercise. Additional doses of SEREVENT should not be used for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB. 6. The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma or COPD: Decreasing effectiveness of inhaled, short-acting beta2-agonists Need for more inhalations than usual of inhaled, short-acting beta2-agonists Significant decrease in PEF or lung function as outlined by the physician 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 (200 inhalations per canister) of an inhaled, short-acting beta2-agonist in an 8-week period. 7. SEREVENT DISKUS 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 DISKUS. 8. Patients should be cautioned regarding adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. 9. When patients are prescribed SEREVENT DISKUS, other medications for asthma and COPD should be used only as directed by the physician. 10. SEREVENT DISKUS should not be used with a spacer device. 11. Patients who are pregnant or nursing should contact the physician about the use of SEREVENT DISKUS. 12. Effective and safe use of SEREVENT DISKUS includes an understanding of the way that it should be used: Never exhale into the DISKUS. Never attempt to take the DISKUS apart. Always activate and use the DISKUS in a level, horizontal position. Never wash the mouthpiece or any part of the DISKUS. KEEP IT DRY. Always keep the DISKUS in a dry place. Discard 6 weeks after removal from the moisture-protective foil overwrap pouch or after all blisters have been used (when the dose indicator reads “0”), whichever comes first. 13. For the proper use of SEREVENT DISKUS and to attain maximum benefit, the patient should read and follow carefully the Patient's Instructions for Use accompanying the product. Drug Interactions: Short-Acting Beta2-Agonists: In two 12-week, repetitive-dose adolescent and adult clinical trials in patients with asthma (N = 149), the mean daily need for additional beta2-agonist in patients using SEREVENT DISKUS was approximately 1½ inhalations/day. Twenty-six percent (26%) of the patients in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on 1 or more occasions. Nine percent (9%) of the patients in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among the 3 patients who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta2-agonist with SEREVENT DISKUS has not been established. In 29 patients who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events. In 2 clinical trials in patients with COPD, the mean daily need for additional beta2-agonist for patients using SEREVENT DISKUS was approximately 4 inhalations/day. Twenty-four percent (24%) of the patients using SEREVENT DISKUS in these trials averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular events was observed among patients who averaged 6 or more inhalations per day. 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 salmeterol when administered concurrently. Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving salmeterol 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 therapy with SEREVENT Inhalation Aerosol. In 2 clinical trials in patients with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 patients receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile. Beta-Adrenergic Receptor Blocking Agents: Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEREVENT DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD 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 or COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. Diuretics: 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 caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts at 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]). 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 55 times the maximum recommended daily inhalation dose in adults and approximately 25 times the maximum recommended daily inhalation dose in children on a mg/m 2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults and approximately 8 times the maximum recommended daily inhalation dose in children on a mg/m 2 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 160 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). Pregnancy: Teratogenic Effects: Pregnancy Category C. No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dose in adults on a mg/m 2 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 1,600 times the maximum recommended daily inhalation dose in adults on a mg/m 2 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. Salmeterol xinafoate crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 410 and 810 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). 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 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 salmeterol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue SEREVENT DISKUS, taking into account the importance of SEREVENT DISKUS to the mother. Caution should be exercised when SEREVENT DISKUS is administered to a nursing woman. Pediatric Use: The safety and efficacy of SEREVENT DISKUS has been evaluated in over 2,500 patients aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS for 1 year. Based on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric patients is warranted for either asthma or EIB (see DOSAGE AND ADMINISTRATION). In 2 randomized, double-blind, controlled clinical trials of 12 weeks’ duration, SEREVENT DISKUS 50-mcg was administered to 211 pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to PEF and FEV1. SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population. SEREVENT DISKUS was effective when coadministered with other inhaled asthma medications, such as short-acting bronchodilators and inhaled corticosteroids. SEREVENT DISKUS was well tolerated in the pediatric population, and there were no safety issues identified specific to the administration of SEREVENT DISKUS to pediatric patients. In 2 randomized studies in children 4 to 11 years old with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS 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 adolescent and adult patients with asthma who received SEREVENT DISKUS in chronic dosing clinical trials, 209 were 65 years of age and older. Of the total number of patients with COPD who received SEREVENT DISKUS in chronic dosing clinical trials, 167 were 65 years of age or older and 45 were 75 years of age or older. No apparent differences in the safety of SEREVENT DISKUS 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 DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Data from the trials in patients with COPD suggested a greater effect on FEV1 of SEREVENT DISKUS in the <65 years age-group, as compared with the 65 years age-group. However, based on available data, no adjustment of dosage of SEREVENT DISKUS in geriatric patients is warranted.
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