Serevent
salmeterol xinafoate · Powder, Metered · Oral, Respiratory (inhalation)
Uses
1 INDICATIONS AND USAGE SEREVENT DISKUS is a LABA indicated for:
• Treatment of asthma in patients aged 4 years and older with an ICS. ( 1.1 )
• Prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. ( 1.2 )
• Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). ( 1.3 ) Important limitation of use: Not indicated for relief of acute bronchospasm. ( 1.1 , 1.3 ) 1.1 Treatment of Asthma SEREVENT DISKUS is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with an ICS in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal 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 )] . Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated [see Contraindications ( 4 )] . 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 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. 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. Important Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm. 1.2 Prevention of Exercise-Induced Bronchospasm SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. 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. 1.3 Maintenance Treatment of Chronic Obstructive Pulmonary Disease SEREVENT DISKUS is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis). Important Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
Dosage and administration
2 DOSAGE AND ADMINISTRATION SEREVENT DISKUS 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.
Dosage forms and strengths
Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains salmeterol 50 mcg per blister. Inhalation powder: Inhaler containing salmeterol (50 mcg) as a powder formulation for oral inhalation. ( 3 )
Contraindications
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 )
Warnings and precautions
• LABA as monotherapy (without ICS) for asthma increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe for asthma only as concomitant therapy with an inhaled corticosteroid. ( 5.1 )
• Do not initiate in acutely deteriorating asthma or COPD. Do not use to treat acute symptoms. ( 5.2 )
• Not a substitute for corticosteroids. Patients with asthma must take a concomitant ICS. ( 5.3 )
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.4 )
• If paradoxical bronchospasm occurs, discontinue SEREVENT DISKUS and institute alternative therapy. ( 5.5 )
• Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. ( 5.6 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.9 )
• Be alert to hypokalemia and hyperglycemia. ( 5.10 ) 5.1 Asthma-Related Death LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death. When LABA are used in fixed - dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. 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 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. 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. The Salmeterol Multicenter Asthma Research Trial (SMART) was a large 28-week placebo-controlled U.S. trial comparing the safety of salmeterol (SEREVENT Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies ( 14.1 )] . Given the similar basic mechanisms of action of beta 2 -agonists, the findings seen in the SMART trial are considered a class effect. A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy. The SNS and SMART trials enrolled subjects with asthma. Available data do not suggest an increased risk of death with use of LABA in patients with COPD. 5.2 Deterioration of Disease and Acute Episodes SEREVENT DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. SEREVENT DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of SEREVENT DISKUS in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. 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, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta 2 -agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional ICS or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of SEREVENT DISKUS. SEREVENT DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath. When prescribing SEREVENT DISKUS, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms. When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or 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.
Side effects
6 ADVERSE REACTIONS 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.
Drug interactions
• 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.
Use in specific populations
Hepatic impairment: Monitor patients for signs of increased drug exposure. ( 8.6 ) 8.1 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. 8.2 Lactation Risk Summary There is no information regarding the presence of salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Salmeterol is detected in rat milk (see Data) . Salmeterol concentrations in human plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be low [see Clinical Pharmacology ( 12.3 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEREVENT DISKUS and any potential adverse effects on the breastfed child from SEREVENT DISKUS or from the underlying maternal condition. Data Animal Data: Oral administration of salmeterol at a dose of 10,000 mcg/kg/day to lactating rats resulted in measurable levels in milk. 8.4 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 [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.
Pregnancy
8.1 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
8.4 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 [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 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.
Geriatric use
8.5 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.
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.
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 the 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. Salmeterol chemical structure
Mechanism of action
12.1 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.
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING SEREVENT DISKUS is supplied as a disposable teal green plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0521-00). Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children. SEREVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard SEREVENT DISKUS 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Asthma-Related Death Inform patients that salmeterol when used alone increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Inform patients that SEREVENT DISKUS should not be the only therapy for the treatment of asthma and must only be used as additional therapy when ICS do not adequately control asthma symptoms. Inform patients that when SEREVENT DISKUS is added to their treatment regimen they must continue to use their ICS. Not for Acute Symptoms Inform patients that SEREVENT DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used. Instruct patients to seek medical attention immediately if they experience any of the following:
• 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 lung function as outlined by the physician Tell patients they should not stop therapy with SEREVENT DISKUS without physician/provider guidance since symptoms may recur after discontinuation. Not a Substitute for Corticosteroids Advise all patients with asthma that they must also continue regular maintenance treatment with an ICS if they are taking SEREVENT DISKUS. 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. Do Not Use Additional Long-acting Beta 2 -agonists Instruct patients not to use other LABA. Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. Patients should discontinue SEREVENT DISKUS if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take SEREVENT DISKUS. Risks Associated with Beta-agonist Therapy Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Treatment of Exercise-Induced Bronchospasm Patients using SEREVENT DISKUS for the treatment of EIB should not use additional doses for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB. Trademarks are owned by or licensed to the GSK group of companies. GlaxoSmithKline Durham, NC 27701 ©2022 GSK group of companies or its licensor. SRD:17PI
Label text from the FDA structured product label by GlaxoSmithKline LLC (revised Oct 10, 2022). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Salmeterol Xinafoate in 1 product
Serevent NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0173-0521 | Salmeterol Xinafoate 50 ug/1 Powder, Metered | GlaxoSmithKline LLC | NDA |
Frequently asked questions
What is Serevent used for?
1 INDICATIONS AND USAGE SEREVENT DISKUS is a LABA indicated for: • Treatment of asthma in patients aged 4 years and older with an ICS. ( 1.1 ) • Prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. ( 1.2 ) • Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). ( 1.3 ) Important limitation of use: Not indicated for…
What are the side effects of Serevent?
6 ADVERSE REACTIONS 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… See the full label for the complete list.
Who makes Serevent?
Serevent is listed by 1 labeler in the FDA NDC directory, including GlaxoSmithKline LLC.