Serevent Drug Information

• should be administered by the orally inhaled route only. More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects. Patients using SEREVENT DISKUS should not use additional LABA for any reason. [See Warnings and Precautions ( 5.4 , 5.6 ).]
• For oral inhalation only. ( 2 )
• Treatment of asthma in patients aged 4 years and older: 1 inhalation twice daily in addition to concomitant treatment with an ICS. ( 2.1 )
• EIB: 1 inhalation at least 30 minutes before exercise. ( 2.2 )
• Maintenance treatment of bronchospasm associated with COPD: 1 inhalation twice daily. ( 2.3 ) 2.1 Asthma LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death [see Warnings and Precautions ( 5.1 )]. Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma younger than 18 years who require addition of a LABA to an ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an ICS and a LABA is recommended. For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be reevaluated. If symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief. 2.2 Exercise-Induced Bronchospasm Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include an ICS. One inhalation of SEREVENT DISKUS at least 30 minutes before exercise has been shown to protect patients against EIB. When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years. Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB. 2.3 Chronic Obstructive Pulmonary Disease For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart.

• LABA, including salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death. Data from a large 28-week placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions ( 5.1 ), Clinical Studies ( 14.1 )] . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions (incidence ≥5%) are:
• Asthma: Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis. ( 6.1 )
• COPD: Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience in Asthma Adult and Adolescent Subjects Aged 12 Years and Older Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 trials. Table 1. Adverse Reactions with SEREVENT DISKUS with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma a a Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group. Adverse Event Percent of Subjects SEREVENT DISKUS 50 mcg Twice Daily (n = 149) Albuterol Inhalation Aerosol 180 mcg 4 Times Daily (n = 150) Placebo (n = 152) Ear, nose, and throat Nasal/sinus congestion, pallor 9 8 6 Rhinitis 5 4 4 Neurological Headache 13 12 9 Respiratory Asthma 3 <1 1 Tracheitis/bronchitis 7 3 4 Influenza 5 5 2 Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at ≥3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials. Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with SEREVENT DISKUS compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance. Pediatric Subjects Aged 4 to 11 Years Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 4 to 11 years with asthma. Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group. Table 2. Adverse Reaction Incidence in Two 12-Week Pediatric Clinical Trials in Subjects with Asthma Adverse Event Percent of Subjects SEREVENT DISKUS 50 mcg Twice Daily (n = 211) Albuterol Inhalation Aerosol 200 mcg 4 Times Daily (n = 115) Placebo (n = 215) Ear, nose, and throat Ear signs and symptoms 4 9 3 Pharyngitis 6 3 3 Neurological Headache 17 20 14 Respiratory Asthma 4 <1 2 Skin Skin rashes 4 2 3 Urticaria 3 2 0 The following events were reported at an incidence of >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 ICS, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of ICS. Laboratory Test Abnormalities Elevation of hepatic enzymes was reported in ≥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. 6.2 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 a Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group. 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 Additional Adverse Reactions Other adverse reactions occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥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. 6.3 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.

• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of cardiovascular effects. ( 7.1 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system. ( 7.2 )
• Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 )
• Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 ) 7.1 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. 7.2 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. 7.3 Beta-adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, 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. 7.4 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.

Pregnancy Risk Summary The available data from published epidemiological studies and case reports with use of SEREVENT DISKUS in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Beta‑agonists may interfere with uterine contractility. There are clinical considerations in pregnant women with asthma (see Clinical Considerations). Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta‑adrenoceptor stimulation at maternal doses approximately 50 times the maximum recommended human daily inhaled dose (MRHDID) on an AUC basis. These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures.

No such effects occurred at an oral salmeterol dose approximately 20 times the MRHDID (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Severe asthma during pregnancy has been associated with maternal mortality, fetal mortality, or both. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor and Delivery: There are no adequate and well-controlled human studies that have evaluated the effects of SEREVENT DISKUS during labor and delivery. 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. Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not established an association with SEREVENT DISKUS use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The available studies have methodologic limitations, including retrospective data collection and inconsistent comparator groups. Animal Data: In 3 embryofetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1,000 mcg/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 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,000 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day). In 2 embryofetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal toxicity or embryofetal effects at doses up to 973 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). In a peri- and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 973 times the MRHDID (on a mcg/m 2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors.

Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

Pediatric Use Available data from controlled clinical trials suggest that LABA used as monotherapy 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 ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs . 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 . 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 . 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% ) and the placebo group (0.12% ; relative risk: 1.0 ). All-cause hospitalization, however, was increased in the salmeterol group (2% ) versus the placebo group (less than 1% ; relative risk: 2.1 ). 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 ICS. 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.

• Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated [see Warnings and Precautions ( 5.1 )] . The use of SEREVENT DISKUS is contraindicated in the following conditions:
• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions ( 5.2 )]
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to salmeterol or any of the excipients [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.3 ), Description ( 11 )]
• Asthma: Without concomitant use of an ICS. ( 4 )
• Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures. ( 4 )
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to salmeterol or any of the excipients. ( 4 )

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.