Brand names: Advair HFA (combination), AirDuo RespiClick (combination), Serevent Diskus
Drug class: Selective beta-2-Adrenergic Agonists

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Bronchodilator; a relatively selective, long-acting β₂-adrenergic agonist.

Uses for Salmeterol Xinafoate (Systemic, Oral Inhalation)

Bronchospasm in Asthma

Salmeterol is used only concomitantly with long-term asthma controller therapy (e.g., inhaled corticosteroids) for treatment of asthma and prevention of bronchospasm in patients with reversible obstructive airway disease, including symptoms of nocturnal asthma.

Monotherapy with long-acting β₂-adrenergic agonists (e.g., salmeterol) increases the risk of asthma-related death and may increase risk of asthma-related hospitalization in children and adolescents. Use of salmeterol for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated. (See Boxed Warning and also Asthma-related Death and Life-threatening Events under Cautions.)

Salmeterol is used only as additional therapy in patients with asthma currently receiving long-term asthma controller therapy (e.g., inhaled corticosteroids) but whose disease is inadequately controlled with such therapy.

Salmeterol in fixed combination with fluticasone is used only in patients with asthma not responding adequately to long-term asthma controller therapy (e.g., inhaled corticosteroids) or whose disease severity warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist.

Once asthma control achieved and maintained, assess patient at regular intervals and step down therapy (e.g., discontinue salmeterol) if possible without loss of asthma control, and maintain patient on long-term asthma controller therapy (e.g., inhaled corticosteroids).

Salmeterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated. (See Concomitant Anti-inflammatory Therapy under Cautions.)

Do not use salmeterol alone or in fixed combination with fluticasone in patients with asthma adequately controlled on low or medium dosage of inhaled corticosteroids.

In children and adolescents with asthma requiring addition of a long-acting β₂-adrenergic agonist to an inhaled corticosteroid, generally use a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist to ensure compliance with both drugs.

When separate administration of long-term asthma controller therapy (e.g., inhaled corticosteroids) and a long-acting β₂-adrenergic agonist is clinically indicated, take appropriate steps to ensure compliance with both drugs. If compliance cannot be ensured, a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist is recommended.

Salmeterol alone or in fixed combination with fluticasone not indicated for relief of acute bronchospasm. (See Deterioration of Disease and Acute Episodes under Cautions.)

Exercise-induced Bronchospasm

Prevention of exercise-induced bronchospasm.

Use as a single agent for prevention of exercise-induced bronchospasm may be clinically indicated in patients without persistent asthma.

Use for prevention of exercise-induced bronchospasm may be clinically indicated in patients with persistent asthma; however, treatment of asthma should include long-term asthma controller therapy (e.g., inhaled corticosteroids).

Bronchospasm in COPD

Long-term symptomatic treatment of reversible bronchospasm associated with moderate to severe COPD (e.g., FEV₁ less than 80% of predicted), including chronic bronchitis and emphysema.

Fixed combination with fluticasone as the inhalation powder (Advair Diskus) is used for maintenance treatment of airflow obstruction in COPD, including chronic bronchitis and/or emphysema; also used to reduce COPD exacerbations in patients with a history of exacerbations.

Not indicated for relief of acute bronchospasm. Use a short-acting inhaled β₂-agonist intermittently (as needed) for acute symptoms of COPD. (See Deterioration of Disease and Acute Episodes under Cautions.)

Salmeterol Xinafoate (Systemic, Oral Inhalation) Dosage and Administration

General

• When initiating salmeterol alone or in fixed combination with fluticasone, discontinue regular use of short-acting, oral or inhaled β₂-agonists; use a short-acting, inhaled β₂-agonist, not salmeterol (alone or in fixed combination with fluticasone), to relieve acute symptoms such as shortness of breath.

• Increasing use of short-acting, inhaled β₂-agonists is a marker of deteriorating asthma and failure to respond to a previously effective dosage is often a sign of asthma destabilization. Extra/increased doses of salmeterol alone or in fixed combination with fluticasone are not recommended. (See Deterioration of Disease and Acute Episodes under Cautions.) Consult clinician.

Administration

Oral Inhalation

Administer by oral inhalation using a special oral inhaler (Diskus device) that delivers powdered salmeterol xinafoate alone (Serevent Diskus) or in fixed combination with fluticasone (Advair Diskus, AirDuo RespiClick) or using an inhalation aerosol containing salmeterol in fixed combination with fluticasone (Advair HFA) via an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant.

Administer twice daily, approximately every 12 hours.

Inhalation Powder

Hold the Diskus device in one hand, put the thumb of the other hand on the thumbgrip, and push the thumbgrip until the mouthpiece appears and snaps into position.

To release powdered drug into the exit port, hold the inhaler in a level, horizontal position and depress the lever on the Diskus in a direction away from the patient.

To avoid releasing and wasting additional doses of the drug, do not close the Diskus device, play with the lever, or advance the lever more than once. A dose counter will advance each time the lever is depressed.

Exhale completely, place the mouthpiece of the inhaler between the lips, and inhale deeply and rapidly through the inhaler with a steady, even breath. Remove the inhaler from the mouth and hold the breath for 10 seconds before slowly exhaling.

Do not exhale into the Diskus device.

Do not use another dose from the Diskus device if the patient does not feel or taste the drug.

Close the inhalation device and reset for the next dose by sliding the thumbgrip toward the patient as far as it will go. Do not wash the inhaler. Do not take inhaler apart.

Discard the inhaler when every blister of salmeterol alone or in fixed combination with fluticasone has been used. Alternatively, discard the inhaler 6 or 4 weeks after removal of salmeterol alone or in fixed combination with fluticasone, respectively, from its foil overwrap pouch.

Consult manufacturer’s labeling for instructions on use of the AirDuo RespiClick oral inhaler.

Spacer devices not recommended with the Serevent or Advair Diskus inhaler. Spacer devices or volume holding chambers not recommended with the AirDuo RespiClick inhaler.

Rinse the mouth without swallowing after inhalation of salmeterol in fixed combination with fluticasone propionate.

Salmeterol/Fluticasone Inhalation Aerosol

Use the inhalation aerosol only with the actuator supplied with the product.

Shake the oral aerosol inhaler well for 5 seconds before each inhalation. Test spray inhaler 4 times into the air (away from face) before initial use, and shake well for 5 seconds before each spray. If inhaler not used for >4 weeks or if inhaler was dropped, test spray inhaler twice into the air (away from face) and shake well for 5 seconds before each spray.

Remove cap covering mouthpiece of the aerosol inhaler. Look for foreign objects inside inhaler prior to use and check to see that canister is fully seated within actuator.

After exhaling as completely as possible, place mouthpiece of inhaler well into mouth and close lips firmly around it. Inhale deeply through mouth while actuating inhaler. Remove mouthpiece from mouth and hold breath for as long as possible (up to 10 seconds) and exhale slowly. It is recommended that 30 seconds elapse between inhalations. After inhalation, rinse mouth and spit out water.

Clean the aerosol inhaler by wiping the opening where medicine sprays out of metal canister and mouthpiece with a dry cotton swab and dampened tissue, respectively, at least once a week after evening dose. Allow actuator to air-dry overnight.

When dose counter on the aerosol inhaler reads “020,” recommend that the patient contact the pharmacy for a refill or consult clinician to determine need for a refill. Discard inhaler when the dose counter reads “000.” Never alter or remove dose counter from canister.

Dosage

Available as salmeterol xinafoate; dosage expressed in terms of salmeterol.

Each blister in the Serevent Diskus device contains 50 mcg of salmeterol inhalation powder; however, precise amount of drug delivered to lungs with each activation of the device depends on factors such as patient’s inspiratory flow.

Each blister in the Advair Diskus device contains 50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate; however, precise amount of each drug delivered to lungs with each activation of device depends on factors such as patient’s inspiratory flow.

Each actuation of the AirDuo RespiClick device contains 14 mcg of salmeterol and 55, 113, or 232 mcg of fluticasone propionate; however, precise amount of each drug delivered to the lungs with each actuation of the device depends on factors such as the patient’s inspiratory flow.

Commercially available AirDuo RespiClick oral inhaler delivers 60 actuations.

Each actuation of the Advair HFA oral aerosol inhaler delivers 25 mcg of salmeterol and 50, 125, or 250 mcg of fluticasone propionate from the valve. Dosages in the fixed-combination inhalation aerosol are expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 21 mcg of salmeterol and 45, 115, or 230 mcg of fluticasone propionate from the mouthpiece.

Commercially available Advair HFA inhalation aerosol delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.

Pediatric Patients

Asthma

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

Children ≥12 years of age: 42 mcg of salmeterol and 90, 230, or 460 mcg of fluticasone propionate (2 inhalations of Advair HFA) twice daily; recommended initial dosage is based on patient’s asthma severity and current asthma therapy, including dosage of inhaled corticosteroids, as well as patient’s current control of asthma symptoms and risk of future exacerbations.

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength of the fixed combination with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.

Oral Inhalation Powder

Children 4–11 years of age: 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily in those inadequately controlled on an inhaled corticosteroid.

Children ≥12 years of age: 50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily; recommended initial dosage is based on patient’s asthma severity and current asthma therapy, including dosage of inhaled corticosteroids, as well as patient’s current control of asthma symptoms and risk of future exacerbations.

Children ≥12 years of age: 14 mcg of salmeterol and 55, 113, or 232 mcg of fluticasone propionate (1 inhalation of AirDuo RespiClick) twice daily at approximately the same time every day; recommended initial dosage is based on patient’s current asthma therapy and asthma severity. Usual recommended initial dosage is 14 mcg of salmeterol and 55 mcg of fluticasone propionate (1 inhalation) twice daily in patients not previously receiving inhaled corticosteroid therapy.

Administration of the inhalation powder of salmeterol in fixed combination with fluticasone more frequently than twice daily or exceeding 1 inhalation twice daily is not recommended.

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength of the fixed combination with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) administered at least 30 minutes before exercise.

Adults

Asthma

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

42 mcg of salmeterol and 90, 230, or 460 mcg of fluticasone propionate (2 inhalations) twice daily; recommended initial dosage is based on patient’s asthma severity and current asthma therapy, including dosage of inhaled corticosteroids, as well as patient’s current control of asthma symptoms and risk of future exacerbations.

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength of the fixed combination with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.

Oral Inhalation Powder

50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily; recommended initial dosage is based on patient’s asthma severity and current asthma therapy, including dosage of inhaled corticosteroids, as well as patient’s current control of asthma symptoms and risk of future exacerbations.

14 mcg of salmeterol and 55, 113, or 232 mcg of fluticasone propionate (1 inhalation of AirDuo RespiClick) twice daily at approximately the same time every day; recommended initial dosage is based on patient’s current asthma therapy and asthma severity. Usual recommended initial dosage is 14 mcg of salmeterol and 55 mcg of fluticasone propionate (1 inhalation) twice daily in patients not previously receiving inhaled corticosteroid therapy.

Administration of the inhalation powder of salmeterol in fixed combination with fluticasone more frequently than twice daily or exceeding 1 inhalation twice daily is not recommended.

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength of the fixed combination with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) administered at least 30 minutes before exercise.

COPD

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Powder

50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.

Use of higher dosages or administration more frequently than twice daily not recommended.

Prescribing Limits

Pediatric Patients

Asthma

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

Children or adolescents ≥12 years of age: Maximum 42 mcg of salmeterol and 460 mcg of fluticasone propionate (2 inhalations of Advair HFA) twice daily.

Oral Inhalation Powder

Children 4–11 years of age: Maximum 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.

Children or adolescents ≥12 years of age: Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.

Children or adolescents ≥12 years of age: Maximum 14 mcg of salmeterol and 232 mcg of fluticasone propionate (1 inhalation of AirDuo RespiClick) twice daily.

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).

Adults

Asthma

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

Maximum 42 mcg of salmeterol and 460 mcg of fluticasone propionate (2 inhalations) twice daily.

Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.

Maximum 14 mcg of salmeterol and 232 mcg of fluticasone propionate (1 inhalation of AirDuo RespiClick) twice daily.

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).

COPD

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation) twice daily.

Special Populations

The following information addresses dosage of salmeterol in special populations. When salmeterol is used in fixed combination with fluticasone propionate, dosage requirements for fluticasone propionate should be considered.

Hepatic Impairment

No specific dosage recommendations at this time. Monitor patients receiving salmeterol alone or in fixed combination with fluticasone for increased drug exposure and systemic corticosteroid effects. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

Dosage adjustments not recommended solely because of age in geriatric patients.

Cautions for Salmeterol Xinafoate (Systemic, Oral Inhalation)

Contraindications

• Contraindicated for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) because of increased risk of asthma-related death and hospitalization. (See Boxed Warning and also Asthma-related Death and Life-threatening Events under Cautions.)

• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD when required.

• Alone or in fixed combination with fluticasone as inhalation powder: Patients with severe hypersensitivity to milk proteins.

Warnings/Precautions

Warnings

Use of Fixed Combinations

When used in fixed combination with fluticasone, consider cautions, precautions, contraindications, and interactions associated with fluticasone.

Asthma-related Death and Life-threatening Events

Increased risk of asthma-related death reported with long-acting β₂-adrenergic agonists (e.g., salmeterol) when used as monotherapy. Data from clinical trials suggest that use of long-acting β₂-adrenergic agonists as monotherapy also increases the risk of asthma-related hospitalization in children and adolescents. (See Boxed Warning.)

Use of long-acting β₂-adrenergic agonists, including salmeterol, alone for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated because of increased risk of asthma-related death and hospitalization.

Use only as additional therapy in patients with asthma currently receiving long-term asthma controller therapy (e.g., inhaled corticosteroids) but whose disease is inadequately controlled with such therapy.

Use in fixed combination with fluticasone only in patients with asthma not responding adequately to long-term asthma controller therapy (e.g., inhaled corticosteroids) or whose disease severity warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist. (See Bronchospasm in Asthma under Uses.)

Large safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed an increase in asthma-related deaths in patients receiving salmeterol. Because of similar mechanisms of action among long-acting β₂-adrenergic agonists, these study findings are considered a class effect of these drugs.

Based on review of 4 clinical trials (3 in adults and adolescents and 1 in children), FDA concluded that there is no clinically important increased risk of serious asthma-related events (i.e., asthma-related hospitalization, intubation, death) associated with use of fixed-combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids compared with use of inhaled corticosteroids alone for the treatment of asthma. These studies also showed that fixed-combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids was more effective in reducing the incidence of asthma exacerbations compared with use of inhaled corticosteroids alone.

No adequate studies conducted to determine whether the rate of death is increased in patients with COPD receiving long-acting β₂-adrenergic agonists.

Deterioration of Disease and Acute Episodes

Do not initiate therapy in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Salmeterol alone or in fixed combination with fluticasone not studied in patients with acutely deteriorating asthma or COPD; initiation of salmeterol in this setting not appropriate.

Serious acute respiratory events, including fatalities, reported when salmeterol initiated in patients with substantially worsening or acutely deteriorating asthma. These adverse events mostly occurred in patients with severe asthma and in some patients with acutely deteriorating asthma. However, such events also have occurred in patients with less severe asthma; not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of short-acting, inhaled β₂-agonists is a marker of deteriorating asthma and failure to respond to a previously effective dosage of salmeterol alone or in fixed combination with fluticasone is often a sign of asthma destabilization. Immediate reevaluation with reassessment of the treatment regimen is required in this situation, giving special consideration to the possible need for adding additional inhaled corticosteroids or initiating systemic corticosteroids.

If asthma deteriorates in patients receiving salmeterol in fixed combination with fluticasone, immediate reevaluation with reassessment of the treatment regimen is required, giving special consideration to the possible need for increasing the strength of the fixed combination (higher strengths contain higher dosages of fluticasone only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids. Do not use extra/increased doses of salmeterol alone or in fixed combination with fluticasone in such situations.

Do not use salmeterol alone or in fixed combination with fluticasone for relief of acute symptoms (i.e., as rescue therapy for treatment of acute episodes of bronchospasm). Use a short-acting, inhaled β₂-agonist, not salmeterol (alone or in fixed combination with fluticasone), to relieve acute symptoms such as shortness of breath.

When initiating salmeterol alone or in fixed combination with fluticasone, discontinue regular use (e.g., 4 times daily) of short-acting, oral or inhaled β₂-agonists.

Concomitant Corticosteroid Therapy

Not a substitute for inhaled or oral corticosteroids. No data available demonstrating clinical anti-inflammatory effects of salmeterol such as that associated with corticosteroids. Possible worsening of asthma if corticosteroid dosage is altered or discontinued when salmeterol therapy is initiated.

In patients receiving oral or inhaled corticosteroids for treatment of asthma, continue a suitable dosage of corticosteroid therapy to maintain clinical stability even if the patient feels better as a result of initiating salmeterol. Changes in corticosteroid dosage recommended only after clinical evaluation.

Particular care is needed during and after transfer of patients from systemic to inhaled corticosteroid therapy since death resulting from adrenal insufficiency has occurred during and after such transfer. Do not use salmeterol in fixed combination with fluticasone inhalation aerosol to transfer patients from systemic corticosteroid therapy. Transfer of patients from systemic to inhaled corticosteroid therapy may unmask conditions previously suppressed by systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

Excessive Use and Use With Other Long-acting β2-Adrenergic Agonists

Do not use salmeterol alone or in fixed combination with fluticasone more frequently or at higher dosages than recommended, or in conjunction with other preparations containing long-acting β₂-adrenergic agonists, since an overdose may result.

Clinically important cardiovascular effects and fatalities associated with excessive use of inhaled sympathomimetic drugs reported. (See Cardiovascular Effects under Cautions.)

Patients receiving salmeterol alone or in fixed combination with fluticasone should not use additional salmeterol or other long-acting β₂-adrenergic agonists for any reason.

Paradoxical Bronchospasm and Upper Airway Symptoms

Possible acute bronchospasm or paradoxical bronchospasm reported; may be life-threatening and represent a hypersensitivity reaction. (See Sensitivity Reactions under Cautions.)

If paradoxical bronchospasm occurs, immediately treat patient with a short-acting, inhaled bronchodilator, discontinue salmeterol alone or in fixed combination with fluticasone, and institute alternative therapy.

Upper airway symptoms, including laryngeal spasm, irritation, or swelling (e.g., stridor, choking), and oropharyngeal irritation reported.

Cardiovascular Effects

Possible clinically important changes in pulse rate, BP, and/or cardiovascular symptoms; may require discontinuance of drug.

ECG changes (e.g., flattening of T wave, prolongation of QT_c interval, ST-segment depression) reported with β-agonists; clinical importance unknown. (See Coexisting Conditions under Cautions.)

Clinically important prolongation of the QT_c interval, potentially causing ventricular arrhythmias, associated with administration of large dosages of oral or inhaled (about 12–20 times the recommended dose) of salmeterol or other β₂-agonists. Fatalities also reported in association with excessive use of inhaled sympathomimetic drugs. (See Excessive Use and Use With Other Long-acting β₂-Adrenergic Agonists under Cautions.)

Angina, hypertension or hypotension, tachycardia (rates up to 200 beats/minute), arrhythmias, and palpitations associated with excessive β-adrenergic stimulation.

Sensitivity Reactions

Immediate hypersensitivity reactions may occur; urticaria, angioedema, rash, bronchospasm, and anaphylaxis reported.

Anaphylactic reactions reported very rarely in patients with severe milk protein allergy. (See Contraindications under Cautions.)

Possible acute bronchospasm; frequently occurs with the first use of a new oral inhalation aerosol canister. (See Paradoxical Bronchospasm and Upper Airway Symptoms under Cautions.)

General Precautions

CNS Effects

Possible CNS stimulation and adverse nervous system effects including headache, tremor, nervousness, dizziness/giddiness, migraine, sleep disturbances, paresthesia, anxiety, or excitement.

Seizures, nervousness, headache, tremor, nausea, dizziness, fatigue, malaise, and insomnia associated with excessive β-adrenergic stimulation.

Use with caution in patients with seizure disorders.

Coexisting Conditions

Use with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, or hypertension; in patients with seizure disorders or thyrotoxicosis; and in those unusually responsive to sympathomimetic amines. (See Cardiovascular Effects under Cautions and also CNS Effects under Cautions.)

Large IV doses of β₂-adrenergic agonist albuterol (IV preparation not commercially available in the US) reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Clinically important hypokalemia (usually transient and not requiring supplementation) may occur in some patients receiving β-adrenergic agonists; may result in adverse cardiovascular effects (e.g., arrhythmias). (See Cardiovascular Effects under Cautions.)

Specific Populations

Pregnancy

Category C. No adequate and well-controlled studies of salmeterol or salmeterol in fixed combination with fluticasone in pregnant women. Use during pregnancy only if potential benefit justifies potential risk to the fetus.

Increased risk of adverse perinatal events (e.g., preeclampsia, prematurity, low birth weight, small size for gestational age) in pregnant women with poorly or moderately controlled asthma. Closely monitor pregnant women with asthma and adjust dosage of medications as needed to maintain optimal asthma control.

Lactation

Salmeterol distributed into milk in rats; not known whether salmeterol or fluticasone distributed into human milk. Corticosteroids, other than fluticasone, distributed into human milk. Effects of salmeterol or fluticasone on breast-fed infants or milk production also not known.

Consider benefits of breast-feeding and the woman’s clinical need for salmeterol or fluticasone along with any potential adverse effects on the breast-fed infant from the drugs or from the underlying maternal condition. Use caution in nursing women.

Pediatric Use

Safety and efficacy of salmeterol oral inhalation powder in adolescents ≥12 years of age established based on trials conducted in adults and adolescents. (See Bronchospasm in Asthma under Uses.) However, data suggest that monotherapy with long-acting β₂-adrenergic agonists may increase the risk of asthma-related death and hospitalization in children and adolescents. (See Boxed Warning and also Asthma-related Death and Life-threatening Events under Cautions.)

Safety and efficacy of salmeterol oral inhalation powder in children 4–11 years of age with asthma evaluated for periods up to 1 year. Current data suggest that such children may receive the same dosage as adults for the treatment of asthma or exercise-induced bronchospasm.

Use of salmeterol in fixed combination with fluticasone inhalation powder (Advair Diskus) in children 4–11 years of age with asthma is supported by data from one clinical trial and from extrapolation of efficacy data from older patients. Safety and efficacy of such a combination in children <4 years of age not established.

Safety and efficacy of salmeterol in fixed combination with fluticasone inhalation powder (AirDuo RespiClick) in children <12 years of age not established.

Safety and efficacy of salmeterol in fixed combination with fluticasone inhalation aerosol (Advair HFA) in children <12 years of age not established. Data from a limited number of adolescents 12–17 years of age receiving salmeterol and fluticasone inhalation aerosol in fixed combination suggest that safety and efficacy are similar to that in adults.

Geriatric Use

Adverse effect profile of salmeterol alone or in fixed combination with fluticasone inhalation aerosol similar to that in younger adults.

Insufficient experience with salmeterol in fixed combination with fluticasone inhalation powder (Advair Diskus) or inhalation aerosol (Advair HFA) in patients ≥65 years of age with asthma to determine whether geriatric patients respond differently than younger adults.

No overall differences in safety or efficacy observed in geriatric patients receiving salmeterol in fixed combination with fluticasone inhalation powder (AirDuo RespiClick) compared with younger adults.

Increased incidence of serious adverse effects reported in patients ≥65 years of age with COPD receiving salmeterol in fixed combination with fluticasone inhalation powder (Advair Diskus) compared with younger adults; however, distribution of adverse effects similar in the two groups.

Use with caution in geriatric patients who have concomitant cardiovascular disease. (See Cardiovascular Effects under Cautions.)

Hepatic Impairment

Plasma concentrations may be increased. (See Special Populations under Pharmacokinetics.)

Transient elevation of hepatic enzymes reported in at least 1% of patients with asthma receiving salmeterol in clinical studies; however, did not lead to discontinuance from the studies.

Closely monitor patients with hepatic impairment.

Common Adverse Effects

Patients with asthma (Serevent Diskus): Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis.

Patients with asthma (Advair Diskus): Upper respiratory tract infection/inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headache, nausea, vomiting.

Patients with asthma (AirDuo RespiClick): Nasopharyngitis, oral candidiasis, back pain, headache, cough.

Patients with asthma (Advair HFA): Upper respiratory tract infection/inflammation, throat irritation, dysphonia, headache, dizziness, nausea, vomiting.

Patients with COPD (Serevent Diskus): Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection.

Patients with COPD (Advair Diskus): Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain.

Drug Interactions

The following information addresses potential interactions with salmeterol. When used in fixed combination with fluticasone, consider interactions associated with fluticasone. No formal drug interaction studies have been performed to date with the fixed combinations.

Salmeterol and fluticasone are substrates for CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic (increased peak plasma concentrations and AUC of salmeterol) and pharmacologic interactions (increased risk of adverse cardiovascular effects [e.g., QT_c prolongation, palpitations, sinus tachycardia]) with concomitant use of potent CYP3A4 inhibitors. Concomitant use of potent CYP3A4 inhibitors with salmeterol alone or in fixed combination with fluticasone not recommended.

Specific Drugs

Salmeterol Xinafoate (Systemic, Oral Inhalation) Pharmacokinetics

Absorption

Bioavailability

Most of an orally inhaled drug actually is swallowed. Bronchodilating action of orally inhaled sympathomimetic agents is believed to result from a local action of the portion of dose that reaches the bronchial tree.

Low or undetectable systemic concentrations occur after inhalation of the recommended dosage and are not predictive of therapeutic effects.

Onset

Time to onset of effective bronchodilation 60 minutes with salmeterol oral inhalation powder. Initial improvement in asthma control may occur within 30 minutes following oral inhalation of salmeterol in fixed combination with fluticasone propionate. Maximum benefit may not be achieved for 1 week or longer after initiating treatment with salmeterol in fixed combination with fluticasone propionate.

Maximum improvement in FEV₁ generally occurs within 3 hours after administration of salmeterol oral inhalation powder.

Duration

Clinically important improvements are maintained for up to 12 hours in most patients receiving salmeterol oral inhalation powder. In the prevention of exercise-induced bronchospasm in adolescents and adults, salmeterol oral inhalation powder provides protection for up to 9 hours and up to 12 hours in children 4–11 years of age.

Distribution

Extent

Crosses the blood-brain barrier in trace amounts.

Not known whether the drug and/or its metabolites cross the placenta.

Distributed into milk in rats; not known whether is distributed into human milk.

Plasma Protein Binding

94–98%.

Elimination

Metabolism

Extensively metabolized in the liver by hydroxylation.

Elimination Route

Eliminated in feces (60%) and urine (25%), principally as metabolites.

Half-life

About 5.5 hours (oral administration).

Special Populations

Pharmacokinetics not studied in patients with hepatic impairment; however, increased plasma concentrations may occur since drug is predominantly cleared by hepatic metabolism. (See Hepatic Impairment under Cautions.)

Stability

Storage

Oral Inhalation

Powder

Salmeterol (Serevent Diskus) alone or in fixed combination with fluticasone (Advair Diskus): 20–25°C in a dry place away from direct heat and sunlight.

Salmeterol in fixed combination with fluticasone (AirDuo RespiClick): 15–25°C in a dry place away from extreme heat, cold, and humidity.

Discard Serevent Diskus 6 weeks after removal from foil pouch or when every blister used (when the dose counter reads “0”), whichever comes first.

Discard Advair Diskus 1 month after removal from foil pouch or when every blister used (when the dose counter reads “0”), whichever comes first.

Discard AirDuo RespiClick 30 days after opening the foil pouch or when the dose counter reads “0,” whichever comes first.

Aerosol

Fixed combination with fluticasone (Advair HFA): 20–25°C (may be exposed to 15–30°C) with mouthpiece down.

Contents under pressure; do not puncture, use or store near heat or open flame, or place into fire or incinerator. Exposure to temperatures >49°C may cause canister to burst. Discard when dose counter reads “000.”

Actions

• Long-acting, synthetic, sympathomimetic amine bronchodilator.

• Stimulates β₂-adrenergic receptors, with little or no effect on α- , β₁- , or β₃-adrenergic receptors.

• Increases concentrations of cyclic adenosine-3′, 5′-monophosphate (cAMP), resulting in relaxation of bronchial smooth muscle, suppression of some aspects of inflammation, and stimulating airway epithelial ciliary function.

• Decreases airway resistance and airway reactivity to histamine. Inhibits the release of proinflammatory mediators (e.g., histamine, leukotrienes C₄and D₄, prostaglandin D₂) in human lung tissue.

• Prolonged therapy not associated with development of tolerance to the bronchodilatory effects.

Advice to Patients

• When used in fixed combination with fluticasone, importance of informing patients of important cautionary information about fluticasone.

• Provide a copy of the manufacturer’s patient information (medication guide) for salmeterol alone or in fixed combination with fluticasone with each prescription. Importance of instructing patients to read the patient information, instructions for use, and/or medication guide prior to initiation of therapy and each time prescription is refilled.

• Importance of informing patients that monotherapy with long-acting β₂-adrenergic agonists, including salmeterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in children and adolescents.

  Importance of informing patients that salmeterol should not be the only therapy used for asthma treatment and must only be used as additional therapy when long-term asthma controller therapy (e.g., inhaled corticosteroids) does not adequately control symptoms. Importance of informing patients that long-term asthma controller drugs must be continued when salmeterol is added to the treatment regimen.

• Importance of children receiving therapy under adult supervision.

• Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system.

• Importance of adherence to dosing schedules, including not altering the dose or frequency of use unless otherwise instructed by a clinician.

• Importance of advising patient that if a dose of salmeterol alone or in fixed combination with fluticasone is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.

• Importance of all patients being provided with and instructed in the use of a short-acting, inhaled β₂-agonist (e.g., albuterol) as treatment for acute symptoms (e.g., shortness of breath).

• Importance of discontinuing regular use of short-acting, oral or inhaled β-agonists when initiating salmeterol and using short-acting, inhaled β-agonists to relieve acute symptoms (e.g., shortness of breath).

• Importance of contacting a clinician if asthma symptoms do not improve after 1 week of therapy.

• Importance of contacting a clinician immediately if patient experiences decreasing effectiveness of short-acting inhaled β₂-agonists, need for more inhalations than usual of short-acting inhaled β₂-agonists, or clinically important decrease in lung function (as outlined by clinician).

• Importance of patients who are receiving salmeterol-containing preparations not to use additional salmeterol or other long-acting β₂-adrenergic agonists for any reason, including prevention of exercise-induced bronchospasm or treatment of asthma or COPD.

• Importance of patients receiving corticosteroid therapy not to discontinue or alter dosage of corticosteroids without consulting a clinician, even if the patient feels better after initiating salmeterol. Importance of informing patients that salmeterol should not be used as a substitute for oral or inhaled corticosteroids.

• Importance of informing all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are receiving salmeterol.

• Importance of patients not discontinuing therapy with salmeterol without medical supervision, since symptoms may recur after discontinuance.

• Importance of administering salmeterol inhalation powder at least 30 minutes prior to exercise for prevention of exercise-induced bronchospasm. Importance of not using additional doses of salmeterol for exercise-induced bronchospasm for 12 hours. Importance of not using additional salmeterol for exercise-induced bronchospasm while receiving therapy (twice daily) with salmeterol.

• Importance of informing patients of adverse effects associated with β₂-adrenergic agonists, such as palpitations, rapid heart rate, tremor, nervousness, or chest pain.

• Importance of informing a clinician of heart problems, high BP, seizures, thyroid disorders, diabetes mellitus, allergies to drugs or food (including milk proteins), or liver disorders prior to initiation of therapy.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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