Version May 2024
Long-acting beta-2 adrenergic agonists (LABAs), such as salmeterol, as monotherapy (without inhaled corticosteroids) increase the risk of asthma-related death. Data from a large, placebo-controlled, US study that compared the safety of salmeterol 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). Use of background inhaled corticosteroids (ICS) was not required in this study. When LABAs 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 to ICS alone.
Use of salmeterol for the treatment of asthma as monotherapy without a concomitant ICS is contraindicated. Use salmeterol only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS. Do not use salmeterol for patients whose asthma is adequately controlled on low- or medium-dose ICS.
Available data from controlled clinical trials suggest that LABAs 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 an ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be ensured, a fixed-dose combination product containing both an ICS and a LABA is recommended.
Note: Do not use for the relief of acute bronchospasm.
Asthma/Bronchospasm: Dry powder inhaler (50 mcg/actuation): Oral inhalation: One inhalation twice daily (~12 hours apart); maximum: 1 inhalation twice daily. Note: For asthma control, long-acting beta-2 agonists (LABAs) should be used in combination with inhaled corticosteroids and not as monotherapy.
Chronic obstructive pulmonary disease, maintenance:
Note: Depending on symptoms and exacerbation risk, use in combination with long-acting bronchodilators (long-acting beta agonist and long-acting muscarinic antagonist). In addition, a short-acting bronchodilator is used for symptom relief (Ref).
Dry powder inhaler (50 mcg/actuation): Oral inhalation: One inhalation twice daily.
Exercise-induced bronchospasm: Note: Alternatively, may consider a combination ICS-formoterol (preferred) for either an as-needed basis or for maintenance of symptoms (Ref)
Dry powder inhaler (50 mcg/actuation): Oral inhalation: One inhalation at least 30 minutes prior to exercise; additional doses should not be used for 12 hours or used in individuals already receiving salmeterol twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, salmeterol is primarily cleared in the liver and plasma levels may be increased. Use with caution and monitor closely.
Refer to adult dosing.
(For additional information see "Salmeterol: Pediatric drug information")
Asthma: Note: Not indicated for relief of acute bronchospasm. For asthma treatment, long-acting beta2-agonists (LABAs), such as salmeterol should always be used in combination with inhaled corticosteroids (ICS); use without ICS is contraindicated.
Children ≥4 years and Adolescents: Dry powder inhaler: 50 mcg/inhalation: Oral inhalation: One inhalation twice daily, ~12 hours apart.
Exercise-induced bronchospasm, prevention: Note: Because LABAs may disguise poorly controlled persistent asthma, frequent or chronic use of LABAs for exercise-induced bronchospasm is discouraged by asthma guidelines (Ref). Tolerance to the protective effects of LABAs against exercise-induced bronchospasm may develop with greater than once-daily use (Ref).
Children ≥4 years and Adolescents: Dry powder inhaler: 50 mcg/inhalation: Oral inhalation: 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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, salmeterol is primarily cleared in the liver and plasma levels may be increased. Use with caution and monitor closely.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Central nervous system: Headache (13% to 17%), pain (1% to 12%)
1% to 10%:
Cardiovascular: Hypertension (4%), edema (1% to 3%)
Central nervous system: Dizziness (4%), sleep disorder (1% to 3%), anxiety (1% to 3%), migraine (1% to 3%), paresthesia (1% to 3%)
Dermatologic: Skin rash (1% to 4%), contact dermatitis (1% to 3%), eczema (1% to 3%), urticaria (3%), photodermatitis (1% to 2%), pallor
Endocrine & metabolic: Hyperglycemia (1% to 3%)
Gastrointestinal: Dyspepsia (1% to 3%), gastrointestinal infection (1% to 3%), nausea (1% to 3%), oropharyngeal candidiasis (1% to 3%), toothache (1% to 3%), xerostomia (1% to 3%)
Hepatic: Increased liver enzymes
Infection: Influenza (5%)
Neuromuscular & skeletal: Muscle cramps (≤3%), muscle spasm (≤3%), arthritis (1% to 3%), arthralgia (1% to 3%), muscle rigidity (1% to 3%)
Ophthalmic: Conjunctivitis (≤3%), keratitis (≤3%)
Respiratory: Nasal congestion (4% to 9%), bronchitis (≤7%), throat irritation (7%), tracheitis (≤7%; may be paradoxical), pharyngitis (≤6%), cough (5%), viral respiratory tract infection (5%), sinusitis (4% to 5%), rhinitis (4% to 5%), asthma (3% to 4%)
Miscellaneous: Fever (1% to 3%)
<1%, postmarketing, and/or case reports: Abdominal pain, agitation, aggressive behavior, anaphylaxis (some in patients with severe milk allergy), angioedema, aphonia, atrial fibrillation, bruise, cardiac arrhythmia, cataract, chest congestion, chest tightness, choking sensation, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss), Cushing's syndrome, Cushingoid appearance, decreased linear skeletal growth rate (children and adolescents), depression, dysmenorrhea, dyspnea, ecchymoses, edema (facial, oropharyngeal), eosinophilia, glaucoma, hypercorticoidism, hypersensitivity reaction (immediate and delayed), hypokalemia, hypothyroidism, increased intraocular pressure, irregular menses, laryngospasm, local irritation (larynx), myositis, oropharyngeal irritation, osteoporosis, otalgia, paradoxical bronchospasm, pelvic inflammatory disease, prolonged QT interval on ECG, restlessness, sinus pain (paranasal), stridor, supraventricular tachycardia, syncope, tremor, vaginitis, vulvovaginal candidiasis, vulvovaginitis, ventricular tachycardia, weight gain
Hypersensitivity to salmeterol or any component of the formulation; severe hypersensitivity to milk proteins; monotherapy in the treatment of asthma (ie, use without concomitant inhaled corticosteroid); treatment of status asthmaticus or other acute episodes of asthma or COPD
Canadian labeling: Additional contraindications (not in US labeling): Presence of tachyarrhythmias
Concerns related to adverse effects:
• Asthma-related deaths: [US Boxed Warning]: Monotherapy with a long-acting beta-2 agonist (LABA) is contraindicated in the treatment of asthma. LABAs as monotherapy (without inhaled corticosteroids) increase the risk of asthma-related death. Data from a large, placebo-controlled clinical trial demonstrated an increase in asthma-related deaths in patients treated with salmeterol (when added to usual asthma therapy); use of background inhaled corticosteroids was not required. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone. Salmeterol should only be used in asthma patients as adjuvant therapy in patients who are currently receiving but are not adequately controlled on an inhaled corticosteroid. Monotherapy with a LABA without concomitant use of an inhaled corticosteroid is contraindicated in the treatment of asthma. Do not use salmeterol for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
• Bronchospasm: Paradoxical bronchospasm that may be life threatening may occur with use of inhaled agents; this should be distinguished from inadequate response. If paradoxical bronchospasm occurs, discontinue use and institute alternative therapy.
• Hypersensitivity: Immediate hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, have been reported; discontinue immediately if signs/symptoms of a hypersensitivity reaction occur.
• Serious effects/fatalities: Do not exceed recommended dose or frequency or use with other medications containing LABAs; 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:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease (eg, arrhythmia, coronary insufficiency, hypertension); beta agonists may cause elevation in blood pressure and heart rate. Beta-2 agonists may also produce changes in ECG (eg, T wave, prolongation of the QTc interval, ST segment depression).
• Diabetes: Use with caution in patients with diabetes mellitus; beta-2 agonists may increase serum glucose and aggravate ketoacidosis; the effect is usually transient.
• 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; accumulation of salmeterol in plasma may occur in hepatic dysfunction.
• Hyperthyroidism: Use with caution in hyperthyroidism; beta-2 agonists may stimulate thyroid activity.
• Hypokalemia: Use with caution in patients with hypokalemia; beta-2 agonists may decrease serum potassium; the effect is usually transient.
• Seizures: Use with caution in patients with seizure disorders; beta agonists may result in CNS stimulation/excitation.
Special populations:
• Pediatric: [US Boxed Warning]: LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. A fixed-dose combination product containing both an inhaled corticosteroid (ICS) and a LABA is preferred in pediatric patients who require addition of a LABA to an ICS to ensure adherence with both drugs. In cases where use of a separate ICS and LABA is indicated, appropriate steps must be taken to ensure adherence with both treatment components; if adherence cannot be ensured, patient should be switched to a fixed-dose combination product.
Dosage form specific issues:
• Lactose: Powder for oral inhalation may contain lactose; use is contraindicated in patients with severe milk protein allergy.
Other warnings/precautions:
• Appropriate use: Asthma: Not indicated for the initial (rescue) treatment of acute episodes of bronchospasm. 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.
• Appropriate use: COPD: 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Aerosol Powder Breath Activated, Inhalation:
Serevent Diskus: 50 mcg/actuation (28 ea [DSC], 60 ea) [contains lactose]
No
Aerosol powder (Serevent Diskus Inhalation)
50 mcg/ACT (per each): $8.47
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Aerosol Powder Breath Activated, Inhalation:
Serevent Diskus: 50 mcg/actuation (1 ea) [contains lactose, milk protein]
Oral inhalation: Dry power inhaler: For oral inhalation only. Remove from sealed pouch immediately prior to first use. Before inhaling the dose, breathe out fully; do not exhale into the Diskus device; activate and use only in a level, flat position. Inhale quickly and deeply through the Diskus; hold breath for about 10 seconds or for as long as comfortable and exhale slowly. Do not use with a spacer device or wash mouthpiece; Diskus should be kept dry.
Oral inhalation: For oral inhalation route only. Remove from foil pouch immediately prior to first use and write the "Pouch opened" and "Use by" dates on the label on the device. The "Use by" date is 6 weeks after removal from foil pouch. After opening the Diskus, hold in a level, horizontal position and activate by sliding the lever until it clicks. Before inhaling the dose, breathe out fully; do not exhale into the Diskus device. Place inhaler in mouth, close lips around mouthpiece, and inhale quickly and deeply through the Diskus; hold breath for about 10 seconds or for as long as comfortable and exhale slowly. Do not use with a spacer device or wash mouthpiece; Diskus should be kept dry. The dose indicator tells how many doses are left. When the numbers 5 to 0 appear in red, only a few doses remain. Discard device 6 weeks after removal from foil pouch or when the dose counter reads "0" (whichever comes first).
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.
Asthma/Bronchospasm: Treatment of asthma and the prevention of bronchospasm (as concomitant therapy with an inhaled corticosteroid [ICS]) in patients ≥4 years of age with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma.
Chronic obstructive pulmonary disease, maintenance: Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (including emphysema and chronic bronchitis).
Exercise-induced bronchospasm: Prevention of exercise-induced bronchospasm (EIB) in patients ≥4 years of age (use in combination with an ICS in patients with persistent asthma).
Note: Not indicated for the relief of acute bronchospasm.
Salmeterol may be confused with Salbutamol, SOLU-Medrol
Serevent may be confused with Atrovent, Combivent, sertraline, Sinemet, Spiriva, Zoloft
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Atomoxetine: May enhance the tachycardic effect of Beta2-Agonists. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Risk C: Monitor therapy
Beta2-Agonists (Long-Acting): May enhance the adverse/toxic effect of other Beta2-Agonists (Long-Acting). Risk X: Avoid combination
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 X: Avoid combination
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Cobicistat: May increase the serum concentration of Salmeterol. Risk X: Avoid combination
Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification
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
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
Levothyroxine: May enhance the adverse/toxic effect of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Levothyroxine may enhance the therapeutic effect of Sympathomimetics. Sympathomimetics may enhance the therapeutic effect of Levothyroxine. Risk C: Monitor therapy
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider therapy modification
Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combination
Methacholine: Beta2-Agonists (Long-Acting) may diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta2 agonists for 36 hours before methacholine use. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May increase the serum concentration of Salmeterol. Risk X: Avoid combination
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Theophylline Derivatives: Beta2-Agonists may enhance the adverse/toxic effect of Theophylline Derivatives. Specifically, sympathomimetic effects may be increased. Theophylline Derivatives may enhance the hypokalemic effect of Beta2-Agonists. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Tipranavir: May increase the serum concentration of Salmeterol. Risk X: Avoid combination
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Maternal use of beta-2 agonists are not associated with an increased risk of fetal malformations (GINA 2023).
Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low-birth-weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes) (ERS/TSANZ [Middleton 2020]; GINA 2023).
Salmeterol is the preferred long-acting beta-2 agonist (LABA) for the management of asthma in pregnant patients (ERS/TSANZ [Middleton 2020]). Stepping down controller treatment is not recommended during pregnancy (GINA 2023). Maternal asthma symptoms should be monitored monthly (ERS/TSANZ [Middleton 2020]; GINA 2023).
Beta-agonists have the potential to affect uterine contractility if administered during labor.
Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant patients in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.
It is not known if salmeterol is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Salmeterol oral inhalation is considered likely compatible with breastfeeding (ERS/TSANZ [Middleton 2020]).
FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation; serum potassium; signs/symptoms of glaucoma; hypersensitivity reactions; decreased bronchodilator response (tachyphylaxis).
Relaxes bronchial smooth muscle by selective action on beta-2 receptors with little effect on heart rate; salmeterol acts locally in the lung.
Onset of action: Asthma: 30 to 48 minutes, COPD: 2 hours
Peak effect: Asthma: 3 hours, COPD: 2 to 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%)
Hepatic function impairment: May lead to accumulation of salmeterol in plasma.
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