Dosage Form: inhalation powder, oral powder
FULL PRESCRIBING INFORMATION
WARNING: ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, the active ingredient in SEREVENT® DISKUS®, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT® Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 patients on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.
Because of this risk, use of Serevent Diskus for the treatment of asthma without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use Serevent Diskus only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serevent Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: 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. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) 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 inhaled corticosteroid and a LABA is recommended.
Indications and Usage for Serevent Diskus
Treatment of Asthma
Serevent Diskus is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, 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, 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 a long-term asthma control medication, such as an inhaled corticosteroid, 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 a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serevent Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: 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. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) 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 inhaled corticosteroid and a LABA is recommended.
Important Limitation of Use: Serevent Diskus is NOT indicated for the relief of acute bronchospasm.
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 a long-term asthma control medication, such as an inhaled corticosteroid.
Maintenance Treatment of Chronic Obstructive Pulmonary Disease
Serevent Diskus is indicated for the long-term twice-daily (morning and evening) administration in the maintenance treatment of bronchospasm associated with 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.
Serevent Diskus Dosage and Administration
Serevent Diskus should be administered by the orally inhaled route only.
For both asthma and COPD, adverse effects are more likely to occur with higher doses of salmeterol, and more frequent administration or administration of a larger number of inhalations (more than 1 inhalation twice daily) is not recommended. Patients using Serevent Diskus should not use additional LABA for any reason. [See Warnings and Precautions (5.4, 5.6).]
Asthma
LABA, such as salmeterol, the active ingredient in Serevent Diskus, 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 a long-term asthma control medication, such as an inhaled corticosteroid is contraindicated. Use Serevent Diskus only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serevent Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age 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. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) 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 inhaled corticosteroid 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 (morning and evening, 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 beta2-agonist should be taken for immediate relief.
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 a long-term asthma control medication, such as an inhaled corticosteroid. 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 adolescents and adults 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.
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 (morning and evening, approximately 12 hours apart).
Dosage Forms and Strengths
Disposable teal green device with 60 blisters containing salmeterol (50 mcg) as an oral inhalation powder formulation. An institutional pack containing 28 blisters is also available.
Contraindications
Because of the risk of asthma-related death and hospitalization, use of Serevent Diskus for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated [see Warnings and Precautions (5.1)].
Serevent Diskus is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)].
Serevent Diskus is contraindicated in patients with severe hypersensitivity to milk proteins [see Warnings and Precautions (5.7), Adverse Reactions (6.3), Description (11)].
Warnings and Precautions
Asthma-Related Death
LABA, such as salmeterol, the active ingredient in Serevent Diskus, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.
Because of this risk, use of Serevent Diskus for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use Serevent Diskus only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serevent Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: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. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) 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 inhaled corticosteroid and a LABA is recommended.
The Salmeterol Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US study 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 patients receiving salmeterol [see Clinical Studies (14.1)]. Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART study are considered a class effect.
A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients 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 studies enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by LABA.
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 patients 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 beta2-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 beta2-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 inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily (morning and evening) 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 beta2-agonist, not Serevent Diskus, should be used to relieve acute symptoms such as shortness of breath. When prescribing Serevent Diskus, the physician must also provide the patient with an inhaled, short-acting beta2-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 beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
Serevent Diskus is Not a Substitute for Corticosteroids
There are no data demonstrating that Serevent Diskus has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with Serevent Diskus in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating Serevent Diskus. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.
Excessive Use of Serevent Diskus and Use With Other Long-Acting Beta2-Agonists
As with other inhaled beta2-adrenergic drugs, Serevent Diskus should not be used more often or at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Serevent Diskus should not use an additional LABA (e.g., formoterol fumarate, arformoterol tartrate) for any reason.
Paradoxical Bronchospasm and Upper Airway Symptoms
As with other inhaled medications, Serevent Diskus can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Serevent Diskus, it should be treated immediately with an inhaled, short-acting bronchodilator; Serevent Diskus should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving Serevent Diskus.
Cardiovascular and Central Nervous System Effects
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, Serevent Diskus, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of Serevent Diskus, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take Serevent Diskus [see Contraindications (4)].
Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
Because of the potential for drug interactions and the potential for increased risk of cardiovascular adverse events, the concomitant use of Serevent Diskus with strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended [see Drug Interactions (7.1)].
Coexisting Conditions
Serevent Diskus, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Hypokalemia and Hyperglycemia
Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with Serevent Diskus at recommended doses.
Adverse Reactions
LABA, including salmeterol, the active ingredient in Serevent Diskus, increase the risk of asthma-related death. Data from a large 28-week placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. Available data from controlled clinical trials suggest that LABA 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.
Clinical Trials Experience in Asthma
Adult and Adolescent Patients Aged 12 Years and Older: Two multicenter, 12-week, controlled studies evaluated twice-daily doses of Serevent Diskus in patients aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 studies.
| Adverse Event | Percent of Patients | ||
Placebo (N = 152) | Serevent Diskus 50 mcg Twice Daily (N = 149) | Albuterol Inhalation Aerosol 180 mcg 4 Times Daily (N = 150) | |
| Ear, nose, and throat | |||
| Nasal/sinus congestion, pallor | 6 | 9 | 8 |
| Rhinitis | 4 | 5 | 4 |
| Neurological | |||
| Headache | 9 | 13 | 12 |
| Respiratory | |||
| Asthma | 1 | 3 | <1 |
| Tracheitis/bronchitis | 4 | 7 | 3 |
| Influenza | 2 | 5 | 5 |
Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving Serevent Diskus and were more common than in the placebo group.
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 patients with asthma treated with Serevent Diskus compared with patients 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 Patients Aged 4 to 11 Years: Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of Serevent Diskus in patients 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% or greater in the group receiving Serevent Diskus and were more common than in the placebo group.
| Adverse Event | Percent of Patients | ||
Placebo (N = 215) | Serevent Diskus 50 mcg Twice Daily (N = 211) | Albuterol Inhalation Aerosol 200 mcg 4 Times Daily (N = 115) | |
| Ear, nose, and throat | |||
| Ear signs and symptoms | 3 | 4 | 9 |
| Pharyngitis | 3 | 6 | 3 |
| Neurological | |||
| Headache | 14 | 17 | 20 |
| Respiratory | |||
| Asthma | 2 | 4 | <1 |
| Skin | |||
| Skin rashes | 3 | 4 | 2 |
| Urticaria | 0 | 3 | 2 |
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 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 ≥1% of patients in clinical trials. The elevations were transient and did not lead to discontinuation from the studies. 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, controlled studies have evaluated twice-daily doses of Serevent Diskus in patients with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, patient entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 studies (total N = 341 for salmeterol and 576 for placebo).
| Adverse Event | Percent of Patients | |
Placebo (N = 576) | Serevent Diskus 50 mcg Twice Daily (N = 341) | |
| Cardiovascular | ||
| Hypertension | 2 | 4 |
| Ear, nose, and throat | ||
| Throat irritation | 6 | 7 |
| Nasal congestion/blockage | 3 | 4 |
| Sinusitis | 2 | 4 |
| Ear signs and symptoms | 1 | 3 |
| Gastrointestinal | ||
| Nausea and vomiting | 3 | 3 |
| Lower respiratory | ||
| Cough | 4 | 5 |
| Rhinitis | 2 | 4 |
| Viral respiratory infection | 4 | 5 |
| Musculoskeletal | ||
| Musculoskeletal pain | 10 | 12 |
| Muscle cramps and spasms | 1 | 3 |
| Neurological | ||
| Headache | 11 | 14 |
| Dizziness | 2 | 4 |
| Average duration of exposure (days) | 128.9 | 138.5 |
aTable 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater 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 events 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 beta2-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 US 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
In a drug interaction study in 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-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. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended.
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.
Diuretics
The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of Serevent Diskus with nonpotassium-sparing diuretics.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies with Serevent Diskus in pregnant women. Serevent Diskus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
No teratogenic effects occurred in rats at oral doses approximately 160 times the maximum recommended daily inhalation dose (MRHD) on an mg/m2 basis. In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHD based on comparison of the AUCs, salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at an oral dose approximately 20 times the MRHD based on comparison of the AUCs.
New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHD on an mg/m2 basis. Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans.
Labor and Delivery
There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Serevent Diskus during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Nursing Mothers
Plasma levels of salmeterol, a component of Serevent Diskus, 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 salmeterol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Serevent Diskus, taking into account the importance of Serevent Diskus to the mother. Caution should be exercised when Serevent Diskus is administered to a nursing woman.
Pediatric Use
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) has 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 US study comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol [see Clinical Studies (14.1)]. Post-hoc analyses in pediatric patients aged 12 to 18 years were also performed. Pediatric patients accounted for approximately 12% of patients 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 (<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 patients aged 4 to 11 years with asthma, 346 of whom were administered Serevent Diskus for 1 year. Based on available data, no adjustment of dosage of Serevent Diskus in pediatric patients is warranted for either asthma or EIB.
In 2 randomized, double-blind, controlled clinical trials of 12 weeks’ duration, Serevent Diskus 50 mcg was administered to 211 pediatric patients with asthma who did and who did not receive concurrent inhaled c
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