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prison Serevent Diskus Generic Name: Salmeterol (sal ME te role) Brand Name: Serevent Diskus Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings Breastfeeding Warnings User Reviews Support Group Q & A Pricing & Coupons Warning In people with asthma, long-acting puffers (inhalers) like this medicine (Serevent Diskus) raise the chance of asthma-related deaths. Talk with the doctor. Long-acting puffers (inhalers) like this medicine may raise the chance of asthma-related hospital stays in children and teens. Talk with the doctor. Do not use this medicine (Serevent Diskus) to treat asthma if you are not using a long-term asthma-control drug like a breathed-in steroid. Do not use this drug to treat asthma if your asthma is well controlled by a long-term asthma-control drug. Uses of Serevent Diskus: It is used to treat asthma. It is used to treat COPD (chronic obstructive pulmonary disease). It is used to prevent exercise-induced breathing problems. This medicine is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor. Slideshow Short Of Breath? 11 Reasons Why This Could Be A Cause For Concern What do I need to tell my doctor BEFORE I take Serevent Diskus? If you have an allergy to salmeterol or any other part of this medicine. If you have a milk allergy. If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs. If you are taking or will be taking another drug like this one. If you are taking any of these drugs: Atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, or telithromycin. This is not a list of all drugs or health problems that interact with this medicine (Serevent Diskus). Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor. What are some things I need to know or do while I take Serevent Diskus? Tell all of your health care providers that you take this medicine (Serevent Diskus). This includes your doctors, nurses, pharmacists, and dentists. If you have high blood sugar (diabetes), this medicine may sometimes raise blood sugar. Talk with your doctor about how to keep your blood sugar under control. Have your blood pressure checked often. Talk with your doctor. Call your doctor right away if your breathing problems get worse, if your rescue inhaler does not work as well, or if you need to use your rescue inhaler more often. Do not take more of this medicine (Serevent Diskus) or use it more often than you have been told. Deaths have happened when too much of this type of drug has been taken. Talk with your doctor. Use with care in children. Talk with the doctor. If you are 65 or older, use this medicine with care. You could have more side effects. Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine (Serevent Diskus) while you are pregnant. Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby. How is this medicine (Serevent Diskus) best taken? Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely. Follow how to use as you have been told by the doctor or read the package insert. To gain the most benefit, do not miss doses. Keep using this medicine (Serevent Diskus) as you have been told by your doctor or other health care provider, even if you feel well. For breathing in only by a puffer (inhaler) into the lungs. Have your puffer (inhaler) use checked with your doctor at each visit. Read and follow facts on how to use the puffer. Make sure you use the puffer the right way. Do not take the device apart or wash it. Do not use it with a spacer. Do not breathe out into the device. Close the device after each dose. Do not open the device unless a dose is being used. If using to prevent exercise-induced breathing problems, use at least 30 minutes before exercise. Do not take another dose for at least 12 hours. What do I do if I miss a dose? Skip the missed dose and go back to your normal time. Do not take 2 doses at the same time or extra doses. Do not use more than 2 doses a day. Dosage Information (comprehensive) What are some side effects that I need to call my doctor about right away? WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect: Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat. Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit. Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal. Chest pain or pressure or a fast heartbeat. A heartbeat that does not feel normal. Very nervous and excitable. Very bad headache. Very bad dizziness or passing out. Shakiness. Fever. Seizures. Very upset stomach or throwing up. Feeling very tired or weak. Not able to sleep. This medicine can cause very bad breathing problems right after you take a dose. Sometimes, this may be life-threatening. If you have trouble breathing, breathing that is worse, wheezing, or coughing after using this medicine, use a rescue inhaler and get medical help right away. What are some other side effects of Serevent Diskus? All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away: Headache. Nose and throat irritation. Stuffy nose. Runny nose. These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch. Side Effects (complete list) If OVERDOSE is suspected: If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened. How do I store and/or throw out Serevent Diskus? Store at room temperature. Store in foil pouch until ready for use. After opening, throw away any part not used after 6 weeks or when the indicator reads zero, whichever comes first. Protect from heat. Protect from light. Store in a dry place. Do not store in a bathroom. Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets. Check with your pharmacist about how to throw out unused drugs. Consumer Information Use and Disclaimer If your symptoms or health problems do not get better or if they become worse, call your doctor. Do not share your drugs with others and do not take anyone else's drugs. Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor. Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins. This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine (Serevent Diskus) is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider. If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened. This information should not be used to decide whether or not to take this medicine (Serevent Diskus) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine (Serevent Diskus). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine. Review Date: November 1, 2017 Next Side Effects Print this page Add to My Med List More about Serevent Diskus (salmeterol) Side Effects During Pregnancy or Breastfeeding Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: adrenergic bronchodilators Consumer resources Serevent Serevent Diskus inhalation Serevent (Advanced Reading) Serevent Diskhaler Disk (Advanced Reading) Serevent Diskus (Advanced Reading) ... +3 more Professional resources Serevent (FDA) Serevent Diskus (FDA) Salmeterol Xinafoate (AHFS Monograph) Related treatment guides Asthma, Maintenance Bronchospasm Prophylaxis COPD, Maintenance} Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA WADA Class Anti-Doping Classification Serevent Diskus Rating No Reviews - Be the first! 9.5 /10 No Reviews - Be the first! 9.5 Rate it! Manufacturer GlaxoSmithKline Drug Class Adrenergic bronchodilators Related Drugs COPD, Maintenance Symbicort , Spiriva , albuterol , ProAir HFA , Advair Diskus , ipratropium , Breo Ellipta , Ventolin , More... Asthma, Maintenance Symbicort , albuterol , fluticasone , montelukast , ProAir HFA , Singulair , Advair Diskus , budesonide , More... Bronchospasm Prophylaxis albuterol , montelukast , ProAir HFA , Singulair , Ventolin , Ventolin HFA , Proventil , Proventil HFA , More...} } and have become


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which means that [0.001).:<0.001). Safe usage with maintenance of efficacy for periods up to 1 year has been documented. SEREVENT DISKUS and SEREVENT (salmeterol xinafoate) Inhalation Aerosol were compared to placebo in 2 additional randomized, double-blind clinical trials in adolescent and adult patients with mild-to-moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of exercise-induced bronchospasm (EIB). Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate patients with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all patients. In a randomized, double-blind, controlled study (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial peak expiratory flow (PEF) (36% to 39% postdose increase from baseline) and FEV 1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebo-controlled study (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS. Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids : In 4 clinical trials in adult and adolescent patients with asthma (N = 1,922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose. Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled patients (ages 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalational Aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher dose beclomethasone dipropionate group). Two randomized, double-blind, parallel-group clinical trials (N = 925) enrolled patients (ages 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2- to 4-week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer patients receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%). Exercise-Induced Bronchospasm : In 2 randomized, single-dose, crossover studies in adolescents and adults with EIB (N = 53), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes to exercise. For many patients, this protective effect against prior EIB was still apparent up to 8.5 hours following a single dose. Table 2. Results of 2 Exercise-Induced Bronchospasm Studies in Adolescents and Adults Placebo (N = 52) SEREVENT DISKUS (N = 52) n % Total n % Total 0.5-Hour % Fall in FEV 1 postdose> <10% 15 29 31 60 exercise> /=10%, <20% 3 6 11 21 challenge> /=20% 34 65 10 19 Mean maximal % fall in FEV 1 (SE) -25% (1.8) -11% (1.9) 8.5-Hour % Fall in FEV 1 postdose <10% 12 23 26 50 exercise> /=10%, <20% 7 13 12 23 challenge> /=20% 33 63 14 27 Mean maximal % fall in FEV 1 (SE) -27% (1.5) -16% (2.0) In 2 randomized studies in children 4 to 11 years old with asthma and EIB (N = 50), 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. Salmeterol Multi-center Asthma Research Trial : The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta 2 -agonist-naive patients with asthma (average age of 39 years, 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol, 42 mcg twice daily over 28 weeks) compared to placebo when added to usual asthma therapy. The primary endpoint was the combined number of respiratory-related deaths or respiratory-related life-threatening experiences (intubation and mechanical ventilation). Secondary endpoints included combined asthma-related deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355). Due to the low rate of primary events in the study, the findings of the planned interim analysis were not conclusive. However, analyses of secondary endpoints suggested that patients receiving salmeterol may be at increased risk for some of these events compared to patients receiving placebo. The analysis for the total population showed a relative risk of 1.40 (95% CI 0.91, 2.14) for the primary endpoint in the salmeterol group relative to the placebo group (50 out of 13,176 vs. 36 out of 13,179, respectively). In the total population, a higher number of asthma-related deaths (13 vs. 3, RR 4.37, 95% CI 1.25, 15.34) and combined asthma-related deaths or life-threatening experiences (37 vs. 22, RR 1.71, 95% CI 1.01, 2.89) occurred in patients treated with salmeterol than those treated with placebo. The analysis of the African American subgroup showed a relative risk of 4.10 (95% CI 1.54, 10.90) for the primary endpoint in patients treated with salmeterol relative to those treated with placebo (20 out of 2,366 vs. 5 out of 2,319, respectively). In African Americans, a higher number of asthma-related deaths (7 vs. 1, RR 7.26, 95% CI 0.89, 58.94) and combined asthma-related deaths or life-threatening experiences (19 vs. 4, RR 4.92, 95% CI 1.68, 14.45) occurred in patients treated with salmeterol than those treated with placebo. Analysis of the Caucasian population showed a relative risk of 1.05 (95% CI 0.62, 1.76) for the primary endpoint for those treated with salmeterol relative to those treated with placebo (29 out of 9,281 vs. 28 out of 9,361, respectively). In Caucasians, a higher number of asthma-related deaths (6 vs. 1, RR 5.82, 95% CI 0.70, 48.37) occurred in patients treated with salmeterol than in patients treated with placebo. In Caucasians, the relative risk was 1.08 (17 vs. 16, 95% CI 0.55, 2.14) for combined asthma-related deaths or life-threatening experiences in patients treated with salmeterol relative to placebo. The numbers of patients from other ethnic groups were too small to draw any conclusions in these populations. Even through SMART did not reach predetermined stopping criteria for the total population, the study was stopped due to the findings in African American patients and difficulties in enrollment. Chronic Obstructive Pulmonary Disease: In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (N = 336) compared to placebo (N = 366) in patients with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group studies of 24 weeks' duration and were identical in design, patient entrance criteria, and overall conduct. Figure 2 displays the integrated 2-hour postdose FEV 1 results from the 2 clinical trials. The percent change in FEV 1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for patient withdrawals during the study, Endpoint (last evaluable FEV 1 ) data are provided. Patients receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV 1 at Endpoint (216 mL, 20%) compared to placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment. Onset of Action and Duration of Effect : The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of patients (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV 1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 3, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 3 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours. Indications and Usage Asthma: SEREVENT DISKUS is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta 2 -agonists. It is not indicated for patients whose asthma can be managed by occasional use of inhaled, short-acting beta 2 -agonists. SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm in patients 4 years of age and older. SEREVENT DISKUS may be used alone or in combination with inhaled or systemic corticosteroid therapy. Chronic Obstructive Pulmonary Disease: SEREVENT DISKUS is indicated for the long-term, twice-daily (morning and evening) administration in the maintenance treatment of bronchospasm associated with COPD (including emphysema and chronic bronchitis). Contraindications SEREVENT DISKUS is contraindicated in patients with a history of hypersensitivity to salmeterol or any other component of the drug product (see DESCRIPTION and ADVERSE REACTIONS : Observed During Clinical Practice : Non-Site Specific ). Warnings 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 beta 2 -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 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 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 DISKUS IS NOT A SUBSTITUTE FOR INHALED OR ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced when SEREVENT DISKUS is initiated. (See PRECAUTIONS : Information for Patients and the Patient's Instructions for Use accompanying the product.) 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 beta 2 -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 beta 2 -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. Do Not Use SEREVENT DISKUS to Treat Acute Symptoms: An inhaled, short-acting beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute asthma or COPD symptoms. When prescribing SEREVENT DISKUS, the physician must also provide the patient with an inhaled, short-acting beta 2 -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 beta 2 -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 ). Watch for Increasing Use of Inhaled, Short-Acting Beta 2 -Agonists, Which Is a Marker of Deteriorating Asthma or COPD: The patient's condition may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient's inhaled, short-acting beta 2 -agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in PEF or lung function, these may be markers of destabilization of their disease. 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 beta 2 -agonist for 2 or more consecutive days, or if more than 1 canister (200 inhalations per canister) of inhaled, short-acting beta 2 -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 1 inhalation. 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 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 PRECAUTIONS : Information for Patients ). Do Not Exceed Recommended Dosage: As with other inhaled beta 2 -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. Paradoxical Bronchospasm: As with other inhaled asthma and COPD medications, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated with a short-acting, inhaled bronchodilator; SEREVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of SEREVENT DISKUS, 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 in patients receiving SEREVENT DISKUS. Cardiovascular Disorders: 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 beta 2 -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: 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. 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. 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). Patients should not stop therapy with SEREVENT DISKUS for asthma or COPD without physician/provider guidance since symptoms may worsen after discontinuation. 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. 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 beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -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 beta 2 -agonist for 2 or more days consecutively Use of more than 1 canister (200 inhalations per canister) of an inhaled, short-acting beta 2 -agonist in an 8-week period. 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. Patients should be cautioned regarding adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. When patients are prescribed SEREVENT DISKUS, other medications for asthma and COPD should be used only as directed by the physician. SEREVENT DISKUS should not be used with a spacer device. Patients who are pregnant or nursing should contact the physician about the use of SEREVENT DISKUS. 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. 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 Beta 2 -Agonists: In two 12-week, repetitive-dose adolescent and adult clinical trials in patients with asthma (N = 149), the mean daily need for additional beta 2 -agonist in patients using SEREVENT DISKUS was approximately 1 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 beta 2 -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 FEV 1 and no increase in occurrence of cardiovascular adverse events. In 2 clinical trials in patients with COPD, the mean daily need for additional beta 2 -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 exh this college


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photographs Serevent Diskus (inhalation) Generic Name: salmeterol (inhalation) (sal MEE ter all) Brand Name: Serevent Diskus Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings Breastfeeding Warnings User Reviews Support Group Q & A Pricing & Coupons What is Serevent Diskus (salmeterol inhalation)? Salmeterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Salmeterol inhalation is used to prevent asthma attacks or exercise-induced bronchospasm. Salmeterol inhalation is also used to treat chronic obstructive pulmonary disease (COPD) including emphysema and chronic bronchitis. Salmeterol inhalation may also be used for purposes not listed in this medication guide. Slideshow Prednisone: 12 Things You Should Know What is the most important information I should know about Serevent Diskus (salmeterol inhalation)? Do not use salmeterol inhalation to treat an asthma attack that has already begun. Salmeterol may increase the risk of asthma-related death. Use only the prescribed dose of this medication, and do not use it for longer than your doctor recommends. Follow all patient instructions for safe use. Talk with your doctor about your individual risks and benefits of using salmeterol inhalation. If you use salmeterol inhalation for asthma, you must use it together with another long-term asthma control medication. Seek medical attention if you think any of your asthma medications are not working as well as usual. What should I discuss with my healthcare provider before using Serevent Diskus (salmeterol inhalation)? You should not use this medication if you are allergic to salmeterol or to milk proteins. To make sure salmeterol inhalation is safe for you, tell your doctor if you have: a food or drug allergy; heart disease or high blood pressure; epilepsy or other seizure disorder; diabetes; a thyroid disorder; or liver disease. FDA pregnancy category C. It is not known whether salmeterol inhalation will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether salmeterol inhalation passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. Salmeterol can increase the risk of asthma-related hospitalization in children and teenagers. It is very important that children using salmeterol inhalation for asthma use it together with another long-term asthma control medication. Do not give this medication to a child younger than 4 years old. How should I use Serevent Diskus (salmeterol inhalation)? Salmeterol may increase the risk of asthma-related death. Use only the prescribed dose of this medication, and do not use it for longer than your doctor recommends. Follow all patient instructions for safe use. Tell your doctor if your symptoms do not improve after 1 week of treatment. Do not use salmeterol inhalation to treat an asthma attack that has already begun. It will not work fast enough. Use only a fast-acting inhalation medication. Asthma is often treated with a combination of different drugs. If you use salmeterol inhalation to treat asthma, you must use it together with another asthma control medication. Use all of your medications as directed by your doctor. Talk with your doctor if your medications do not seem to work as well in treating or preventing attacks. Do not change your doses or medication schedule without advice from your doctor. Serevent Diskus is a powder form of salmeterol inhalation that comes with a special inhaler device preloaded with blister packs containing measured doses of the medicine. The device opens and loads a blister each time you use the inhaler. This device is not to be used with a spacer. Use salmeterol inhalation regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely. Do not stop using salmeterol inhalation without first talking to your doctor. Your asthma symptoms may get worse after you stop using the medication. If you also use a steroid medication, do not stop using the steroid suddenly or you may have unpleasant withdrawal symptoms. Talk with your doctor about taking less and less of the steroid before stopping completely. Seek medical attention if you think any of your asthma medications are not working as well as usual. An increased need for medication could be an early sign of a serious asthma attack. If you use a peak flow meter at home, call your doctor if your numbers are lower than normal. Store at room temperature away from moisture, heat, and sunlight. Do not try to clean or take apart the Diskus device. Throw it away 6 weeks after you have taken it out of the foil pouch, or if the dose indicator shows a zero, whichever comes first. Each Diskus device contains 60 doses. What happens if I miss a dose? Use the medication as soon as you remember, then wait 12 hours before using the medication again. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose. What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. What should I avoid while using Serevent Diskus (salmeterol inhalation)? Do not use a second form of salmeterol (such as Advair) or use a similar inhaled bronchodilator such as formoterol or arformoterol (Foradil, Perforomist, Symbicort, or Brovana) unless your doctor has told you to. Do not exhale or blow into the Diskus device. Do not take the device apart or allow it to get wet. Serevent Diskus (salmeterol inhalation) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have: worsening asthma symptoms, or other breathing problems after using this medication; muscle cramps, sleep problems (insomnia), tremors; chest pain, fast or irregular heartbeats, feeling light-headed, fainting, or seizure (convulsions); low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling); or high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss). Common side effects may include: headache; flu symptoms; joint or muscle pain; throat irritation, cough; or stuffy or runny nose. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Side Effects (complete list) What other drugs will affect Serevent Diskus (salmeterol inhalation)? Tell your doctor about all medicines you use, and those you start or stop using during your treatment with salmeterol inhalation, especially: an antidepressant--nefazodone; an antibiotic--clarithromycin, telithromycin; antifungal medication--itraconazole, ketoconazole, voriconazole; a beta blocker--carvedilol, labetalol, nadolol, metoprolol, penbutolol, pindolol, propranolol, sotalol, timolol; hepatitis C medications--boceprevir, telaprevir; HIV/AIDS medication--atazanavir, cobicistat, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir. This list is not complete. Other drugs may interact with salmeterol, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Next Side Effects Print this page Add to My Med List More about Serevent Diskus (salmeterol) Side Effects During Pregnancy or Breastfeeding Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: adrenergic bronchodilators Consumer resources Serevent Serevent Diskus Serevent (Advanced Reading) Serevent Diskhaler Disk (Advanced Reading) Serevent Diskus (Advanced Reading) ... +3 more Professional resources Serevent (FDA) Serevent Diskus (FDA) Salmeterol Xinafoate (AHFS Monograph) Related treatment guides Asthma, Maintenance Bronchospasm Prophylaxis COPD, Maintenance Where can I get more information? Your pharmacist can provide more information about salmeterol inhalation. Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. Disclaimer: Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist. Copyright 1996-2012 Cerner Multum, Inc. Version: 13.04. Date modified: December 03, 2017 Last reviewed: July 15, 2013} Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA WADA Class Anti-Doping Classification Manufacturer GlaxoSmithKline Drug Class Adrenergic bronchodilators Related Drugs COPD, Maintenance Symbicort , Spiriva , albuterol , ProAir HFA , Advair Diskus , ipratropium , Breo Ellipta , Ventolin , More... Asthma, Maintenance Symbicort , albuterol , fluticasone , montelukast , ProAir HFA , Singulair , Advair Diskus , budesonide , More... Bronchospasm Prophylaxis albuterol , montelukast , ProAir HFA , Singulair , Ventolin , Ventolin HFA , Proventil , Proventil HFA , More... Serevent Diskus Rating No Reviews - Be the first! 9.5 /10 No Reviews - Be the first! 9.5 Rate it! Related Questions & Answers Asthma -- Maintenance - is it safe to suddenly stop taking serevent diskus? Serevent Diskus - What is the cost of this medicine without insurance? Read more questions} } come across


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problem [1:<1 2 Skin Skin rashes 4 2 3 Urticaria 3 2 0 The following events were reported at an incidence of greater than 1% in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism. In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of inhaled corticosteroids. Laboratory Test Abnormalities Elevation of hepatic enzymes was reported in greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium. Clinical Trials Experience in Chronic Obstructive Pulmonary Disease Two multicenter, 24-week, placebo-controlled U.S. trials evaluated twice-daily doses of Serevent Diskus in subjects with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo). Table 3. Adverse Reactions with Serevent Diskus with 3% Incidence in U.S. Controlled Clinical Trials in Subjects with Chronic Obstructive Pulmonary Disease a Adverse Event Percent of Subjects Serevent Diskus 50 mcg Twice Daily (n = 341) Placebo (n = 576) Cardiovascular Hypertension 4 2 Ear, nose, and throat Throat irritation 7 6 Nasal congestion/blockage 4 3 Sinusitis 4 2 Ear signs and symptoms 3 1 Gastrointestinal Nausea and vomiting 3 3 Lower respiratory Cough 5 4 Rhinitis 4 2 Viral respiratory infection 5 4 Musculoskeletal Musculoskeletal pain 12 10 Muscle cramps and spasms 3 1 Neurological Headache 14 11 Dizziness 4 2 Average duration of exposure (days) 138.5 128.9 a Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of greater than or equal to 3% in the group receiving Serevent Diskus and were more common in the group receiving Serevent Diskus than in the placebo group. Additional Adverse Reactions Other adverse reactions occurring in the group receiving Serevent Diskus that occurred at a frequency of greater than or equal to 1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes. Adverse reactions to salmeterol are similar in nature to those seen with other selective beta 2 -adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm. Laboratory Abnormalities There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of salmeterol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to salmeterol or a combination of these factors. In extensive U.S. and worldwide postmarketing experience with salmeterol, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating [see Warnings and Precautions (5.2)] , but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events. Cardiovascular Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis. Non-Site Specific Very rare anaphylactic reaction in patients with severe milk protein allergy. Respiratory Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation. Drug Interactions Inhibitors of Cytochrome P450 3A4 Salmeterol is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Serevent Diskus is not recommended because increased cardiovascular adverse effects may occur. In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and C max increased 1.4-fold). Three (3) subjects were withdrawn due to beta 2 -agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Serevent Diskus 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. 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, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. Non Potassium-Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non potassium-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 Serevent Diskus with non potassium-sparing diuretics. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C. There are no adequate and well-controlled trials with Serevent Diskus in pregnant women. Beta 2 -agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, Serevent Diskus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking Serevent Diskus. No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the maximum recommended human daily inhalation dose (MRHDID) (on a mg/m 2 basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg/day and higher), fetal toxic effects were observed 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 such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 10 mg/kg/day). Salmeterol crossed the placenta following oral administration to mice and rats. Labor and Delivery There are no well-controlled human trials 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. Since there are no data from controlled trials on the use of Serevent Diskus by nursing mothers, caution should be exercised when Serevent Diskus is administered to a nursing woman. Pediatric Use 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 a LABA should ordinarily be used to ensure adherence with both drugs [see Indications and Usage (1.1), Warnings and Precautions (5.1)] . The safety and efficacy of Serevent Diskus in adolescents (aged 12 years and older) have been established based on adequate and well-controlled trials conducted in adults and adolescents [see Clinical Studies (14.1)] . A large 28-week placebo-controlled U.S. trial comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies (14.1)] . Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]). The safety and efficacy of Serevent Diskus have been evaluated in over 2,500 subjects 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. In 2 randomized, double-blind, controlled clinical trials of 12 weeks duration, Serevent Diskus 50 mcg was administered to 211 pediatric subjects 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 peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV 1 ). Serevent Diskus was effective in demographic subgroups (gender and age) of the population. In 2 randomized trials in children aged 4 to 11 years 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 subjects. Geriatric Use Of the total number of adult and adolescent subjects with asthma who received Serevent Diskus in chronic dosing clinical trials, 209 were aged 65 years and older. Of the total number of subjects with COPD who received Serevent Diskus in chronic dosing clinical trials, 167 were aged 65 years and older and 45 were aged 75 years and older. No apparent differences in the safety of Serevent Diskus were observed when geriatric subjects were compared with younger subjects in clinical trials. As with other beta 2 -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 beta-agonists. Data from the trials in subjects with COPD suggested a greater effect on FEV 1 of Serevent Diskus in subjects younger than 65 years, as compared with subjects aged 65 years and older. However, based on available data, no adjustment of dosage of Serevent Diskus in geriatric patients is warranted. Hepatic Impairment Formal pharmacokinetic studies using Serevent Diskus have not been conducted in patients with hepatic impairment. Since salmeterol is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored. Overdosage The expected signs and symptoms with overdosage of Serevent Diskus are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with Serevent Diskus can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of Serevent Diskus. Treatment consists of discontinuation of Serevent Diskus together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Serevent Diskus. Cardiac monitoring is recommended in cases of overdosage. Serevent Diskus Description The active component of Serevent Diskus is salmeterol xinafoate, a beta 2 -adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure: Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C 25 H 37 NO 4 C 11 H 8 O 3 . It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water. Serevent Diskus is a teal green plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, Serevent Diskus delivers 47 mcg of salmeterol base per blister when tested at a flow rate of 60 L/min for 2 seconds. In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Serevent Diskus - Clinical Pharmacology Mechanism of Action Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta 2 -adrenoceptors than albuterol. Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3 ,5 -adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D 2 , from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness. Pharmacodynamics Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5.6, 5.10)] . The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (n = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol inhalation powder (n = 67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted. In 24-week clinical studies in patients with COPD, the incidence of clinically significant abnormalities on the predose ECGs at Weeks 12 and 24 in patients who received salmeterol 50 mcg was not different compared with placebo. No effect of treatment with salmeterol 50 mcg was observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 91) and after 12 weeks of therapy (n = 74). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar for patients receiving either salmeterol or placebo [see Adverse Reactions (6.1)] . Concomitant Use of Serevent Diskus with Other Respiratory Medications Short-acting Beta 2 -agonists: In two 12-week repetitive-dose clinical trials in adult and adolescent subjects with asthma (N = 149), the mean daily need for additional beta 2 -agonist in subjects using Serevent Diskus was approximately 1 inhalations/day. Twenty-six percent (26%) of the subjects 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 subjects 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 subjects who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta 2 -agonist with Serevent Diskus has not been established. In 29 subjects 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 FEV 1 and no increase in occurrence of cardiovascular adverse events. In 2 clinical trials in subjects with COPD, the mean daily need for additional beta 2 -agonist for subjects using Serevent Diskus was approximately 4 inhalations/day. Twenty-four percent (24%) of subjects using Serevent Diskus averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day. Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving salmeterol has not been completely evaluated. In 1 clinical trial in subjects with asthma, 87 subjects receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 subjects receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the subjects on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol. In 2 clinical trials in subjects with COPD, 39 subjects receiving Serevent Diskus concurrently with a theophylline product had adverse event rates similar to those in 302 subjects 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. Cromoglycate: In clinical trials, inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently. Pharmacokinetics Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Absorption Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses. Distribution The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. Metabolism Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces. An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro. Elimination In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days. Drug Interactions Inhibitors of Cytochrome P450 3A4: Ketoconazole: In a placebo-controlled crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Erythromycin: In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol C max at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P> <0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for 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 and 25 times the MRHDID for adults and children, respectively, on a mg/m 2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, 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 rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m 2 basis). Animal Toxicology and/or Pharmacology Preclinical Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown. Clinical Studies Asthma The initial trials supporting the approval of Serevent Diskus for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, Serevent Diskus is currently indicated only as concomitant therapy with an inhaled corticosteroid [see Indications and Usage (1.1)] . Adult and Adolescent Subjects Aged 12 Years and Older In 2 randomized double-blind trials, Serevent Diskus was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV 1 , actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent inhaled corticosteroids. The efficacy of Serevent Diskus was demonstrated over the 12-week period with no change in effectiveness over this time period (Figure 1). There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect was noted in these trials. FEV 1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days. Figure 1. Serial 12-Hour FEV 1 from Two 12-Week Clinical Trials in Subjects with Asthma First Treatment Day Last Treatment Day (Week 12) Table 4 shows the treatment effects seen during daily treatment with Serevent Diskus for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma. Table 4. Daily Efficacy Measurements in Two 12-Week Clinical Trials (Combined Data) Parameter Time Serevent Diskus Albuterol Inhalation Aerosol Placebo No. of randomized subjects 149 148 152 Mean AM peak expiratory flow (L/min) Baseline 12 weeks 395 394 394 427 a 394 396 Mean % days with no asthma symptoms Baseline 12 weeks 13 12 14 33 21 20 Mean % nights with no awakenings Baseline 12 weeks 63 68 70 85 a 71 73 Rescue medications (mean no. of inhalations per day) Baseline 12 weeks 4.3 4.3 4.2 1.6 b 2.2 3.3 Asthma exacerbations (%) 15 16 14 a Statistically superior to placebo and albuterol ( P> <0.001). b Statistically superior to placebo ( P> <0.001). Maintenance of efficacy for periods up to 1 year has been documented. Serevent Diskus and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects with mild-to-moderate asthma. Serevent Diskus 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of Serevent Diskus and SEREVENT Inhalation Aerosol for the prevention of EIB. Therefore, while Serevent Diskus was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects. Subjects on Concomitant Inhaled Corticosteroids: In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to inhaled corticosteroid therapy was evaluated over a 24-week treatment period. The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose. Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled subjects (aged 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily. As compared with the doubled dose of BDP, the addition of SEREVENT years to come


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overview for [0.001:<0.05 versus albuterol. p> <0.001 versus placebo. Safe usage with maintenance of efficacy for periods up to 1 year has been documented. Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids In 4 clinical trials in adult and adolescent patients with asthma (N = 1,922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose. Two randomized, double-blind, parallel-group clinical trials (N = 997) enrolled patients (ages 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of Serevent Inhalation Aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the salmeterol group versus 17.9% in the higher-dose beclomethasone dipropionate group). Two randomized, double-blind, parallel-group clinical trials (N = 925) enrolled patients (ages 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2- to 4-week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of Serevent Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. Fewer patients receiving salmeterol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%). Salmeterol Multi-center Asthma Research Trial The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta 2 -agonist naive patients with asthma (average age of 39 years, 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SereventInhalation Aerosol, 42 mcg twice daily over 28 weeks) compared to placebo when added to usual asthma therapy. The primary endpoint was the combined number of respiratory-related deaths or respiratory-related life-threatening experiences (intubation and mechanical ventilation). Secondary endpoints included combined asthma-related deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355). Due to the low rate of primary events in the study, the findings of the planned interim analysis were not conclusive. However, analyses of secondary endpoints suggested that patients receiving salmeterol may be at increased risk for some of these events compared to patients receiving placebo. The analysis for the total population showed a relative risk of 1.40 (95% CI 0.91, 2.14) for the primary endpoint in the salmeterol group relative to the placebo group (50 out of 13,176 vs. 36 out of 13,179, respectively). In the total population, a higher number of asthma-related deaths (13 vs. 3, RR 4.37, 95% CI 1.25, 15.34) and combined asthma-related deaths or life-threatening experiences (37 vs. 22, RR 1.71, 95% CI 1.01, 2.89) occurred in patients treated with salmeterol than those treated with placebo. The analysis of the African American subgroup showed a relative risk of 4.10 (95% CI 1.54, 10.90) for the primary endpoint in patients treated with salmeterol relative to those treated with placebo (20 out of 2,366 vs. 5 out of 2,319, respectively). In African Americans, a higher number of asthma-related deaths (7 vs. 1, RR 7.26, 95% CI 0.89, 58.94) and combined asthma-related deaths or life-threatening experiences (19 vs. 4, RR 4.92, 95% CI 1.68, 14.45) occurred in patients treated with salmeterol than those treated with placebo. Analysis of the Caucasian population showed a relative risk of 1.05 (95% CI 0.62, 1.76) for the primary endpoint for those treated with salmeterol relative to those treated with placebo (29 out of 9,281 vs. 28 out of 9,361, respectively). In Caucasians, a higher number of asthma-related deaths (6 vs. 1, RR 5.82, 95% CI 0.70, 48.37) occurred in patients treated with salmeterol than in patients treated with placebo. In Caucasians, the relative risk was 1.08 (17 vs. 16, 95% CI 0.55, 2.14) for combined asthma-related deaths or life-threatening experiences in patients treated with salmeterol relative to placebo. The numbers of patients from other ethnic groups were too small to draw any conclusions in these populations. Even though SMART did not reach predetermined stopping criteria for the total population, the study was stopped due to the findings in African American patients and difficulties in enrollment. Exercise-Induced Bronchospasm Protection against exercise-induced bronchospasm (EIB) was examined in 3 controlled studies. Based on median values, patients who received Serevent Inhalation Aerosol had consistently less exercise-induced fall in FEV 1 than patients who received placebo, and they were protected for a longer period of time than patients who received albuterol (see Table 2). There were, however, some patients who were not protected from EIB after Serevent administration and others in whom protection against EIB decreased with continued administration over a period of 4 weeks. Clinical Trials/Time After Dose Treatment Placebo Serevent Inhalation Aerosol Albuterol Inhalation Aerosol Study A: 1st Dose 6 hours 37 9 * 12 hours 27 16 * Study A: 4th Week 6 hours 30 19 12 hours 24 12 Study B: 1 hour 37 0 * 2 * 6 hours 37 5 * 27 12 hours 34 6 * 33 Study C: 0.5 hour 43 16 * 8 * 2.5 hours 33 12 * 30 4.5 hours -- 12 36 6.0 hours -- 19 41 * Statistically superior to placebo (p 0.05). Statistically superior to albuterol (p 0.05). Chronic Obstructive Pulmonary Disease In 2 large randomized, double-blind studies, Serevent Inhalation Aerosol administered twice daily was compared with placebo and ipratropium bromide inhalation aerosol administered 4 times daily in patients with COPD (emphysema and chronic bronchitis), including patients who were reversible ( 12% and 200 mL increase in baseline FEV 1 after albuterol treatment) and nonreversible to albuterol. After a single 42-mcg dose of Serevent, significant improvement in pulmonary function (mean FEV 1 increase of 12% or more) occurred within 30 minutes, reached a peak within 4 hours on average, and persisted for 12 hours with no loss in effectiveness observed over a 12-week treatment period. Figure 2 displays serial 12-hour measurements of FEV 1 from these two 12-week trials for both the first and last treatment days. Figure 2. FEV 1 From 2 Large 12-Week Clinical Trials First Treatment Day * Ipratropium inhalation aerosol (or matching placebo) administered immediately following hour 6 assessment. Last Treatment Day (Week 12) * Ipratropium inhalation aerosol (or matching placebo) administered immediately following hour 6 assessment. Indications and Usage for Serevent Asthma Serevent Inhalation Aerosol is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta 2 -agonists. It should not be used in patients whose asthma can be managed by occasional use of inhaled, short-acting beta 2 -agonists. Serevent Inhalation Aerosol may be used alone or in combination with inhaled or systemic corticosteroid therapy. Serevent Inhalation Aerosol is also indicated for prevention of exercise-induced bronchospasm in patients 12 years of age and older. Chronic Obstructive Pulmonary Disease Serevent Inhalation Aerosol is indicated for long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchospasm associated with COPD (including emphysema and chronic bronchitis). Contraindications Serevent Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to salmeterol or any other component of the drug product (see DESCRIPTION). Warnings 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 beta 2 -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 beta 2 -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 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 beta 2 -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 beta 2 -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 beta 2 -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 beta 2 -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 beta 2 -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 beta 2 -agonist for 2 or more consecutive days, or if more than 1 canister (200 inhalations per canister) of inhaled, short-acting beta 2 -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 beta 2 -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. Precautions General 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 beta 2 -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 beta 2 -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 beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -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 beta 2 -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. Drug Interactions Short-Acting Beta 2 -Agonists 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. Methylxanthines 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/m 2 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/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 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/m 2 basis). Pregnancy Teratogenic Effects 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/m 2 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/m 2 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. Nursing Mothers 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. Pediatric Use The safety and effectiveness of Serevent Inhalation Aerosol in children younger than 12 years of age have not been established. Geriatric Use 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 FEV 1 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 beta 2 -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. Adverse Reactions Adverse reactions to salmeterol are similar in nature to reactions to other selective beta 2 -adrenoceptor agonists, i.e., tachycardia; palpitations;immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm (see WARNINGS); headache; tremor; nervousness; and paradoxical bronchospasm (see WARNINGS). Asthma Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of Serevent Inhalation Aerosol in patients 12 years of age and older with asthma. Table 3 reports the incidence of adverse events in these 2 studies. Table 3. Adverse Event Incidence in 2 Large 12-Week Clinical Trials in Patients With Asthma* Adverse Event Percent of Patients Placebo (N = 187) Serevent Inhalation Aerosol 42 mcg Twice Daily (N = 184) Albuterol Inhalation Aerosol 180 mcg 4 Times Daily (N = 185) Ear, nose, and throat Upper respiratory tract infection 13 14 16 * Nasopharyngitis 12 14 11 Disease of nasal cavity/sinus 4 6 1 Sinus headache 2 4> <1 Gastrointestinal Stomachache 0 4 0 Neurological Headache 23 28 27 Tremor 2 4 3 Respiratory Cough 6 7 3 Lower respiratory infection 2 4 2 * The only adverse event classified as serious was 1 case of upper respiratory tract infection in a patient treated with albuterol. Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in the group treated with Serevent Inhalation Aerosol and were more common in the group treated with Serevent Inhalation Aerosol than in the placebo group. Pharyngitis, allergic rhinitis, dizziness/giddiness, and influenza occurred at 3% or more but were equally common on placebo. Other events occurring in the group treated with Serevent Inhalation Aerosol at a frequency of 1% to 3% were as follows: Cardiovascular Tachycardia, palpitations. Ear, Nose, and Throat Rhinitis, laryngitis. Gastrointestinal Nausea, viral gastroenteritis, nausea and vomiting, diarrhea, a good thing about


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