Salmeterol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol Powder Breath Activated, Inhalation:

Serevent Diskus: 50 mcg/dose (28 ea, 60 ea) [contains lactose]

Pharmacology

Mechanism of Action

Relaxes bronchial smooth muscle by selective action on beta-2 receptors with little effect on heart rate; salmeterol acts locally in the lung.

Pharmacokinetics/Pharmacodynamics

Absorption

Systemic: Inhalation: Undetectable to poor

Metabolism

Hepatic; hydroxylated via CYP3A4

Excretion

Feces (60%); urine (25%)

Onset of Action

Asthma: 30 to 48 minutes, COPD: 2 hours; Peak effect: Asthma: 3 hours, COPD: 2 to 5 hours

Time to Peak

Serum: ~20 minutes

Duration of Action

12 hours

Half-Life Elimination

5.5 hours

Protein Binding

96%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

May lead to accumulation of salmeterol in plasma.

Use: Labeled Indications

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 treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (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.

Contraindications

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

Documentation of allergenic cross-reactivity for sympathomimetics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: Do not use for the relief of acute bronchospasm.

Asthma/Bronchospasm: Oral inhalation: Dry powder inhaler: One inhalation (50 mcg) 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: Oral inhalation: Dry powder inhaler: One inhalation (50 mcg) twice daily (~12 hours apart); maximum: 1 inhalation twice daily

Exercise-induced bronchospasm: Oral inhalation: Dry powder inhaler: One inhalation (50 mcg) 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. Note: Because LABAs may disguise poorly controlled persistent asthma, frequent or chronic use of LABAs for exercise-induced bronchospasm is discouraged by the Asthma Guidelines (NAEPP 2007).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Do not use for the relief of acute bronchospasm.

Asthma, maintenance treatment and prevention: Children ≥4 years and Adolescents: Oral inhalation (50 mcg/inhalation): One inhalation twice daily, ~12 hours apart. Note: For long-term asthma control, long-acting beta₂-agonists (LABAs) should be used in combination with inhaled corticosteroids and not as monotherapy.

Exercise-induced bronchospasm, prevention: Children ≥4 years and Adolescents: Oral inhalation (50 mcg/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. Note: Because long-acting beta₂-agonists (LABAs) may disguise poorly controlled persistent asthma, frequent or chronic use of LABAs for exercise-induced bronchospasm is discouraged by the NAEPP Asthma Guidelines (NAEPP 2007).

Administration

Oral inhalation: 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.

Storage

Store at 20°C and 25°C (68°F and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from direct heat or sunlight. Store Diskus in the unopened foil pouch and only open when ready for use. Discard device 6 weeks after removal from foil pouch or when the dose counter reads "0" (whichever comes first).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. 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. Monitor therapy

Beta2-Agonists (Long-Acting): May enhance the adverse/toxic effect of other Beta2-Agonists (Long-Acting). 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. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Salmeterol. Exceptions: Grapefruit Juice. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Salmeterol. Avoid combination

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. 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. 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. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tipranavir: May increase the serum concentration of Salmeterol. Avoid combination

Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Adverse Reactions

>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 Q-T interval on ECG, restlessness, sinus pain (paranasal), stridor, supraventricular tachycardia, syncope, tremor, vaginitis, vulvovaginal candidiasis, vulvovaginitis, ventricular tachycardia, weight gain

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta-2 adrenergic agonists (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. Current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2018; NIH/NHLBI 2007). No data exist associating LABA use with an increased risk of death in patients with COPD.
• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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. Short-acting beta-2 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.
• 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.

Monitoring Parameters

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).

Pregnancy

Pregnancy Considerations

Beta-agonists have the potential to affect uterine contractility if administered during labor.

Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, pre-eclampsia, preterm birth, low birth weight infants). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Salmeterol may be used when a long-acting beta agonist is needed to treat moderate persistent or severe persistent asthma in pregnant women (ACOG 2008; GINA 2018; NAEPP 2007).

Patient Education

What is this drug used for?

• It is used to treat asthma.
• It is used to treat COPD (chronic obstructive pulmonary disease).
• It is used to prevent exercise-induced breathing problems.
• This drug is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor.

Frequently reported side effects of this drug

• Nose irritation
• Sore throat
• Flu-like symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Severe anxiety
• Severe headache
• Seizures
• Passing out
• Vision changes
• Severe nausea
• Vomiting
• Severe loss of strength and energy
• Trouble sleeping
• Severe dizziness
• Tremors
• Trouble breathing
• Wheezing
• Severe cough
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.