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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(sal ME te role)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089125.pdf, must be dispensed with this medication.
REMS Components
Communication Plan; Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Maintenance treatment of asthma and prevention of bronchospasm (as concomitant therapy) in patients with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma; prevention of exercise-induced bronchospasm (monotherapy may be indicated in patients without persistent asthma); maintenance treatment of bronchospasm associated with COPD
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal studies have demonstrated (dose-dependent) teratogenicity. There are no adequate and well-controlled studies in pregnant women. Beta-agonists may interfere with uterine contractility if administered during labor. Use only if clearly needed.
Lactation
Enters breast milk/use caution
Contraindications
Hypersensitivity to salmeterol or any component of the formulation (milk proteins); monotherapy in the treatment of asthma (ie, use without a concomitant long-term asthma control medication, such as an inhaled corticosteroid); status asthmaticus or other acute episodes of asthma or COPD
Warnings/Precautions
Boxed warnings:
• Asthma-related deaths: See “Concerns related to adverse effects” below.
• Asthma-related hospitalization: Pediatrics: See “Concerns related to special populations” below.
Concerns related to adverse effects:
• Asthma-related deaths: [U.S. Boxed Warning]: Long-acting beta2-agonists (LABAs) increase the risk of asthma-related deaths. Salmeterol should only be used in asthma patients as adjuvant therapy in patients who are currently receiving but are not adequately controlled on a long-term asthma control medication (ie, an inhaled corticosteroid). Monotherapy with an LABA is contraindicated in the treatment of asthma. In a large, randomized, placebo-controlled U.S. clinical trial (SMART, 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use. Assess patients at regular intervals once asthma control is maintained on combination therapy to determine if step-down therapy is appropriate and the LABA can be discontinued (without loss of asthma control), and the patient can be maintained on an inhaled corticosteroid. LABAs are not appropriate in patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
• Bronchospasm: Rarely, paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response.
• Hypersensitivity reactions: Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm) have been reported.
• Serious effects/fatalities: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.
• Upper airway symptoms: There have been reports of laryngeal spasm, irritation, swelling (stridor, choking) with use.
Disease-related concerns:
• Asthma: Appropriate use: Do not use for acute bronchospasm. Short-acting beta2-agonist (eg, albuterol) should be used for acute symptoms and symptoms occurring between treatments. Do not initiate in patients with significantly worsening or acutely deteriorating asthma; reports of severe (sometimes fatal) respiratory events have been reported when salmeterol has been initiated in this situation. Corticosteroids should not be stopped or reduced when salmeterol is initiated. During initiation, watch for signs of worsening asthma.
• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, hypertension or HF); beta-agonists may cause elevation in blood pressure, heart rate and result in CNS stimulation/excitation. Beta2-agonists may also increase risk of arrhythmias.
• COPD: Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Data are not available to determine if LABA use increases the risk of death in patients with COPD.
• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may increase serum glucose.
• Exercise-induced bronchospasm: Because LABAs may disguise poorly controlled persistent asthma, frequent or chronic use of LABAs for exercise-induced bronchospasm is discouraged by the NIH Asthma Guidelines (NIH, 2007).
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Hyperthyroidism: Use with caution in hyperthyroidism; may stimulate thyroid activity.
• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.
• Seizures: Use with caution in patients with seizure disorders; beta-agonists may result in CNS stimulation/excitation.
Concurrent drug therapy issues:
• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
Special populations:
• Pediatrics: [U.S. Boxed Warning]: LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. In general, a combination product containing a LABA and an inhaled corticosteroid is preferred in patients <18 years of age to ensure compliance.
Dosage form specific issues:
• Lactose: Powder for oral inhalation contains lactose; very rare anaphylactic reactions have been reported in patients with severe milk protein allergy.
Other warnings/precautions:
• Patient information: Patients must be instructed to use inhaled short-acting beta2-agonists (eg, albuterol) for acute asthmatic or COPD symptoms and to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use of inhaled short-acting beta2-agonist may indicate deterioration of asthma, and medical evaluation must not be delayed. Salmeterol should not be used more than twice daily; do not use with other long-acting beta2-agonists.
Adverse Reactions
>10%:
Central nervous system: Headache (13% to 17%)
Neuromuscular & skeletal: Pain (1% to 12%)
1% to 10%:
Cardiovascular: Hypertension (4%), edema (1% to 3%), pallor
Central nervous system: Dizziness (4%), sleep disturbance (1% to 3%), fever (1% to 3%), anxiety (1% to 3%), migraine (1% to 3%)
Dermatologic: Rash (1% to 4%), contact dermatitis (1% to 3%), eczema (1% to 3%), urticaria (3%), photodermatitis (1% to 2%)
Endocrine & metabolic: Hyperglycemia (1% to 3%)
Gastrointestinal: Throat irritation (7%), nausea (1% to 3%), dyspepsia (1% to 3%), dental pain (1% to 3%), gastrointestinal infection (1% to 3%), oropharyngeal candidiasis (1% to 3%), xerostomia (1% to 3%)
Hepatic: Liver enzymes increased
Neuromuscular & skeletal: Muscular cramps/spasm (3%), articular rheumatism (1% to 3%), arthralgia (1% to 3%), joint pain (1% to 3%), muscular stiffness (1% to 3%), paresthesia (1% to 3%), rigidity (1% to 3%)
Ocular: Keratitis/conjunctivitis (1% to 3%)
Respiratory: Nasal congestion (4% to 9%), tracheitis/bronchitis (7%), pharyngitis (≤6%), cough (5%), influenza (5%), viral respiratory tract infection (5%), sinusitis (4% to 5%), rhinitis (4% to 5%), asthma (3% to 4%)
<1%, postmarketing, and/or case reports: Abdominal pain, agitation, aggression, anaphylactic reaction (some in patients with severe milk allergy [Diskus®]), angioedema, aphonia, arrhythmia, atrial fibrillation, bronchospasm and immediate bronchospasm, cataracts, chest congestion, chest tightness, choking, contusions, Cushing syndrome, Cushingoid features, depression, dysmenorrhea, dyspnea, earache, ecchymoses, edema (facial, oropharyngeal), eosinophilic conditions, glaucoma, growth velocity reduction in children/adolescents, hypercorticism, hypersensitivity reaction (immediate and delayed), hypokalemia, hypothyroidism, intraocular pressure increased, laryngeal spasm/irritation, irregular menstruation, myositis, oropharyngeal irritation, osteoporosis, pallor, paradoxical tracheitis, paranasal sinus pain, PID, restlessness, stridor, supraventricular tachycardia, syncope, tremor, vaginal candidiasis, vaginitis, vulvovaginitis, rare cases of vasculitis (Churg-Strauss syndrome), ventricular tachycardia, weight gain
Metabolism/Transport Effects
Substrate of CYP3A4 (major)
Drug Interactions
Alpha-/Beta-Blockers: May diminish the therapeutic effect of Beta2-Agonists. Risk D: Consider therapy modification
Atomoxetine: May enhance the tachycardic effect of Beta2-Agonists. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Risk D: Consider therapy modification
Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Risk C: Monitor therapy
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Salmeterol. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Salmeterol. Risk X: Avoid combination
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Storage
Inhalation powder (Serevent® Diskus®): Store at controlled room temperature 20°C to 25°C (68°F to 77°F) in a dry place away from direct heat or sunlight. Stable for 6 weeks after removal from foil pouch.
Mechanism of Action
Relaxes bronchial smooth muscle by selective action on beta2-receptors with little effect on heart rate; salmeterol acts locally in the lung.
Pharmacodynamics/Kinetics
Onset of action: Asthma: 30-48 minutes, COPD: 2 hours
Peak effect: Asthma: 3 hours, COPD: 2-5 hours
Duration: 12 hours
Absorption: Systemic: Inhalation: Undetectable to poor
Protein binding: 96%
Metabolism: Hepatic; hydroxylated via CYP3A4
Half-life elimination: 5.5 hours
Time to peak, serum: ~20 minutes
Excretion: Feces (60%); urine (25%)
Dosage
Inhalation, powder (50 mcg/inhalation):
Asthma, maintenance and prevention: Children ≥4 years and Adults: One inhalation twice daily (~12 hours apart); maximum: 1 inhalation twice daily. Note: For asthma control, long acting beta2-agonists (LABAs) should be used in combination with inhaled corticosteroids and not as monotherapy.
Exercise-induced asthma, prevention: Children ≥4 years and Adults: One inhalation at least 30 minutes prior to exercise; additional doses should not be used for 12 hours; should not be used in individuals already receiving salmeterol twice daily. Note: Because LABAs may disguise poorly controlled persistent asthma, frequent or chronic use of LABAs for exercise-induced bronchospasm is discouraged by the NIH Asthma Guidelines (NIH, 2007).
COPD maintenance: Adults: One inhalation twice daily (~12 hours apart); maximum: 1 inhalation twice daily
Dosage adjustment in hepatic impairment: No dosage adjustment required; manufacturer suggests close monitoring of patients with hepatic impairment.
Administration: Inhalation
Not to be used for the relief of acute attacks. Not for use with a spacer device. Administer with Diskus® in a level, horizontal position. Do not wash mouthpiece; Diskus® should be kept dry. Discard device 6 weeks after removal from foil pouch or when the dose counter reads "0" (whichever comes first).
Monitoring Parameters
FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation. Monitor for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating asthma condition.
Dietary Considerations
Some products may contain lactose; very rare anaphylactic reactions have been reported in patients with severe milk protein allergy.
Patient Education
This medication is not to be used as a rescue treatment for acute asthmatic symptoms. You may experience headache, nervousness, dizziness, fatigue, dry mouth, or stomach upset. Report immediately any swelling of face, tongue, or throat; rash; or difficulty swallowing or choking. Report unresolved GI upset; dizziness or fatigue; vision changes; chest pain, rapid heartbeat, or palpitations; insomnia; nervousness or hyperactivity; or muscle cramping or tremors.
Geriatric Considerations
Geriatric patients were included in four clinical studies of salmeterol; no apparent differences in efficacy and safety were noted in geriatric patients compared to younger adults. Because salmeterol is only to be used for prevention of bronchospasm, patients also need a short-acting beta-agonist to treat acute attacks. Elderly patients should be carefully counseled about which inhaler to use and the proper scheduling of doses.
Cardiovascular Considerations
Inhaled beta-agonists may increase heart rate. This should be considered in patients with disease states that may require heart rate control (eg, atrial fibrillation) since frequent use may counteract pharmacologic interventions directed at rate control.
Because of the frequent coexistence of chronic obstructive lung disease and coronary artery disease, many patients may require concurrent therapy with beta-agonists and beta-blockade. Selectivity for the beta-1 receptor varies among the available beta blockers. Cardioselective beta blockade (eg, atenolol, esmolol, metoprolol) with careful titration is preferred when this situation exists (Anderson, 2007). When an inhaled beta-agonist becomes necessary, monitor heart rate closely.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), dental pain, and oropharyngeal candidiasis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause nervousness, dizziness, hyperactivity, or insomnia
Mental Health: Effects on Psychiatric Treatment
Salmeterol is a sympathomimetic; use MAO inhibitors and TCAs with caution
Nursing: Physical Assessment/Monitoring
Not for use to relieve acute asthmatic attacks. Evaluate for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating asthma condition. For inpatient care, monitor vital signs and lung sounds prior to and periodically during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Powder, for oral inhalation:
Serevent® Diskus®: 50 mcg (28s, 60s) [contains lactose]
Pricing: U.S. (www.drugstore.com)
Aerosol powder (Serevent Diskus)
50 mcg/dose (60): $177.99
References
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, The Society of Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons,” J Am Coll Cardiol, 2007, 50(7):1-157.
Bateman ED, Boushey HA, Bousquet J, et al, “Can Guideline-Defined Asthma Control Be Achieved? The Gaining Optimal Asthma ControL study,” Am J Respir Crit Care Med, 2004, 170(8):836-44.
Bone RC, “Another Word of Caution Regarding a new Long-Acting Bronchodilator,” JAMA, 1995, 273(12):967-8.
Brogden RN and Faulds D, “Salmeterol Xinafoate: A Review of Its Pharmacological Properties and Therapeutic Potential in Reversible Obstructive Airways Disease,” Drugs, 1991, 42(5):895-912.
Castle W, Fuller R, Hall J, et al, “Serevent Nationwide Surveillance Study: Comparison of Salmeterol With Salbutamol in Asthmatic Patients Who Require Regular Bronchodilator Treatment,” BMJ, 1993, 306(6884):1034-7.
Clark CE, Ferguson AD, and Siddorn JA, “Respiratory Arrests in Young Asthmatics on Salmeterol,” Respir Med, 1993, 87(3):227-8.
Devoy MA, Fuller RW, and Palmer JB, “Are There any Detrimental Effects of the Use of Inhaled Long-Acting Beta2-Agonists in the Treatment of Asthma?” Chest, 1995, 107(4):1116-24.
Expert Panel Report 3, “Guidelines for the Diagnosis and Management of Asthma,” Clinical Practice Guidelines, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No. 08-4051, prepublication 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
Hatton MQ, Allen MB, Mellor EJ, et al, “Salmeterol Rash,” Lancet, 1991, 337(8750):1169-70.
International Brand Names
Lexi-Comp.com
Last full review/revision June 2011
Content last modified June 2011
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