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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 longterm 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 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]. Given the similar basic mechanisms of action of beta2-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. No trials have been conducted that were primarily designed 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 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 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 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 healthcare provider should also prescribe 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
SEREVENT DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines 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 another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
Paradoxical Bronchospasm And Upper Airway Symptoms
As with other inhaled medicines, 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]. 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 electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. 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 (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. 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 [see CONTRAINDICATIONS]
Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
The use of strong cytochrome P450 3A4 (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 [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
SEREVENT DISKUS, like all medicines 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 medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY]. 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 trials with SEREVENT DISKUS at recommended doses.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients that salmeterol 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 long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other longterm asthma control drugs mitigates the increased risk of asthma-related death from LABA. Inform patients that when SEREVENT DISKUS is added to their treatment regimen they must continue to use their long-term asthma control medication.
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 beta2-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 beta2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta2-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 inhaled corticosteroid 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 Beta2-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 beta2-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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).
In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHDID for adults and children, respectively, on a mg/m basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, on a mg/m basis). These findings in rodents are similar to those reported previously for other betaadrenergic agonist drugs. The relevance of these findings to human use is unknown.
Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m basis).
Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled trials with SEREVENT DISKUS in pregnant women. Beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproductive studies are not always predictive of human response, SEREVENT DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking SEREVENT DISKUS.
No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the maximum recommended daily inhalation dose (MRHDID) (on a mg/m² basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg/day).
New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHDID (on a mg/m basis at a maternal oral dose of 10 mg/kg/day).
Salmeterol crossed the placenta following oral administration to mice and rats.
Labor And Delivery
There are no well-controlled human trials that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of SEREVENT DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. Since there are no data from controlled trials on the use of SEREVENT DISKUS by nursing mothers, caution should be exercised when SEREVENT DISKUS is administered to a nursing woman.
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, WARNINGS AND PRECAUTIONS].
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]. A large 28-week placebo-controlled US trial 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]. 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 (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 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 corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1). SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population.
In 2 randomized studies 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 patients.
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 beta2-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 betaagonists. Data from the trials in subjects with COPD suggested a greater effect on FEV1 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.
Formal pharmacokinetic studies using SEREVENT DISKUS have not been conducted in patients with hepatic impairment. Since salmeterol is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/25/2017
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