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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