Salmeterol Xinafoate (Systemic, Oral Inhalation) (Monograph)

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.

Warning

Monotherapy with long-acting β₂-adrenergic agonists (e.g., salmeterol) increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in children and adolescents.²²⁶ ²²⁷ ²⁴¹ ²⁴² ²⁴⁸ ²⁶⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (See Asthma-related Death and Life-threatening Events under Cautions.)
Use of salmeterol for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated.²⁴⁸ ²⁷⁰ (See Contraindications under Cautions.)
Use salmeterol 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.²⁴⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (See Bronchospasm in Asthma under Uses.)
Use salmeterol 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.²⁶⁷ ²⁶⁸ ²⁶⁹ (See Bronchospasm in Asthma under Uses.)

Introduction

Bronchodilator; a relatively selective, long-acting β₂-adrenergic agonist.¹ ² ³ ⁵ ¹⁸⁸

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.¹⁵⁶ ²²² ²⁶³ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.²⁴⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ Use of salmeterol for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated.²⁴⁸ ²⁷⁰ (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.²²² ²⁶³ ²⁷⁰

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.²⁶⁷ ²⁶⁸ ²⁶⁹

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).²²¹ ²⁴⁸ ²⁵⁷ ²⁷⁰

Salmeterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated.¹ ²²⁶ ²⁷⁰ (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.²⁶⁷ ²⁶⁸ ²⁷⁰

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.¹⁸⁸

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.¹⁸⁸ If compliance cannot be ensured, a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β₂-adrenergic agonist is recommended.¹⁸⁸

Salmeterol alone or in fixed combination with fluticasone not indicated for relief of acute bronchospasm.¹⁵⁴ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (See Deterioration of Disease and Acute Episodes under Cautions.)

Exercise-induced Bronchospasm

Prevention of exercise-induced bronchospasm.¹ ¹² ²¹ ⁹¹ ¹⁰⁵ ¹⁷² ¹⁸⁸ ²¹⁴ ²²² ²⁶³

Use as a single agent for prevention of exercise-induced bronchospasm may be clinically indicated in patients without persistent asthma.¹⁸⁸

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).¹⁸⁸

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.¹ ¹⁸² ¹⁸³ ¹⁸⁸ ²²³ ²²⁴ ²²⁵ ²³⁸ ²³⁹

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.²⁶⁷

Not indicated for relief of acute bronchospasm.¹⁵⁴ ¹⁸⁸ ²⁶⁷ Use a short-acting inhaled β₂-agonist intermittently (as needed) for acute symptoms of COPD.²³⁸ ²³⁹ (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;⁹⁷ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ 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.⁹⁷ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.¹ ¹¹¹ ¹¹² ¹⁵⁴ ²²² ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ Extra/increased doses of salmeterol alone or in fixed combination with fluticasone are not recommended.¹ ¹¹¹ ¹¹² ¹⁵⁴ ²²² ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (See Deterioration of Disease and Acute Episodes under Cautions.) Consult clinician.¹ ¹¹³ ¹⁸⁸

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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

Administer twice daily, approximately every 12 hours.¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵

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.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵

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.¹⁸⁹ ²⁵³ ²⁵⁴ A dose counter will advance each time the lever is depressed.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵

Exhale completely, place the mouthpiece of the inhaler between the lips, and inhale deeply and rapidly through the inhaler with a steady, even breath.¹⁸⁹ ¹⁹⁰ ²⁵³ ²⁵⁴ ²⁵⁵ Remove the inhaler from the mouth and hold the breath for 10 seconds before slowly exhaling.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵

Do not exhale into the Diskus device.¹⁸⁹ ¹⁹⁰ ²⁵³ ²⁵⁴ ²⁵⁵ ²⁶⁷

Do not use another dose from the Diskus device if the patient does not feel or taste the drug.²⁵³ ²⁵⁴

Close the inhalation device and reset for the next dose by sliding the thumbgrip toward the patient as far as it will go.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵ Do not wash the inhaler.¹⁸⁹ ²⁵³ ²⁵⁴ ²⁵⁵ Do not take inhaler apart.¹⁹⁰ ²⁵³ ²⁵⁴ ²⁵⁵ ²⁶⁷ ²⁷⁰

Discard the inhaler when every blister of salmeterol alone or in fixed combination with fluticasone has been used.¹⁹⁰ ²⁵³ ²⁵⁴ ²⁶⁷ ²⁷⁰ 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.¹⁹⁰ ²⁵³ ²⁵⁴ ²⁶⁷ ²⁷⁰

Consult manufacturer’s labeling for instructions on use of the AirDuo RespiClick oral inhaler.²⁶⁹

Spacer devices not recommended with the Serevent or Advair Diskus inhaler.²⁵³ ²⁵⁴ ²⁶⁷ ²⁷⁰ Spacer devices or volume holding chambers not recommended with the AirDuo RespiClick inhaler.²⁶⁹

Rinse the mouth without swallowing after inhalation of salmeterol in fixed combination with fluticasone propionate.²⁵⁴ ²⁵⁵ ²⁶⁷ ²⁶⁹

Salmeterol/Fluticasone Inhalation Aerosol

Use the inhalation aerosol only with the actuator supplied with the product.²⁵⁸

Shake the oral aerosol inhaler well for 5 seconds before each inhalation.²⁵⁷ ²⁵⁸ Test spray inhaler 4 times into the air (away from face) before initial use, and shake well for 5 seconds before each spray.²⁵⁷ ²⁵⁸ 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.²⁵⁷ ²⁵⁸

Remove cap covering mouthpiece of the aerosol inhaler.²⁵⁸ Look for foreign objects inside inhaler prior to use and check to see that canister is fully seated within actuator.²⁵⁸

After exhaling as completely as possible, place mouthpiece of inhaler well into mouth and close lips firmly around it.²⁵⁸ Inhale deeply through mouth while actuating inhaler.²⁵⁸ Remove mouthpiece from mouth and hold breath for as long as possible (up to 10 seconds) and exhale slowly.²⁵⁸ It is recommended that 30 seconds elapse between inhalations.²⁵⁸ After inhalation, rinse mouth and spit out water.²⁵⁷ ²⁵⁸

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.²⁵⁷ ²⁵⁸ Allow actuator to air-dry overnight.²⁵⁸

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.²⁵⁷ Discard inhaler when the dose counter reads “000.”²⁵⁷ Never alter or remove dose counter from canister.²⁵⁷

Dosage

Available as salmeterol xinafoate; dosage expressed in terms of salmeterol.¹

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.²⁷⁰

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.²⁶⁷

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.²⁶⁹

Commercially available AirDuo RespiClick oral inhaler delivers 60 actuations.²⁶⁹

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.²⁶⁸ 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.²⁶⁸

Commercially available Advair HFA inhalation aerosol delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.²⁶⁸

Pediatric Patients

Asthma

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) twice daily.²⁷⁰

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;²⁵⁸ ²⁶⁵ ²⁶⁸ 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.²⁶⁸

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.²⁶⁸

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.²⁶⁷

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;²²¹ ²⁶⁵ ²⁶⁷ 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.²⁶⁷

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;²⁶⁹ recommended initial dosage is based on patient’s current asthma therapy and asthma severity.²⁶⁹ 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.²⁶⁹

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.²⁶⁷ ²⁶⁹

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) administered at least 30 minutes before exercise.²⁷⁰

Adults

Asthma

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.²⁷⁰

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

42 mcg of salmeterol and 90, 230, or 460 mcg of fluticasone propionate (2 inhalations) twice daily;²⁵⁷ ²⁵⁸ ²⁶⁵ ²⁶⁸ 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.²⁶⁸

Oral Inhalation Powder

50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily;²⁶⁵ ²⁶⁷ 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.²⁶⁷

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;²⁶⁹ recommended initial dosage is based on patient’s current asthma therapy and asthma severity.²⁶⁹ 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.²⁶⁹

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.²⁶⁷ ²⁶⁹

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) administered at least 30 minutes before exercise.²⁷⁰

COPD

Salmeterol

Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.²⁷⁰

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Powder

50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.²⁶⁷

Use of higher dosages or administration more frequently than twice daily not recommended.²⁶⁷

Prescribing Limits

Pediatric Patients

Asthma

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily.²⁷⁰

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.²⁶⁸

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.²⁶⁷

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.²⁶⁷

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.²⁶⁹

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).²⁷⁰

Adults

Asthma

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.²⁷⁰

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Aerosol

Maximum 42 mcg of salmeterol and 460 mcg of fluticasone propionate (2 inhalations) twice daily.²⁶⁸

Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation of Advair Diskus) twice daily.²⁶⁷

Maximum 14 mcg of salmeterol and 232 mcg of fluticasone propionate (1 inhalation of AirDuo RespiClick) twice daily.²⁶⁹

Exercise-induced Bronchospasm

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).²⁷⁰

COPD

Salmeterol

Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.²⁷⁰

Salmeterol/Fluticasone Fixed Combination

Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation) twice daily.²⁶⁷

Special Populations

The following information addresses dosage of salmeterol in special populations.¹⁸⁸ When salmeterol is used in fixed combination with fluticasone propionate, dosage requirements for fluticasone propionate should be considered.²⁶⁷ ²⁶⁸ ²⁶⁹

Hepatic Impairment

No specific dosage recommendations at this time.²⁷⁰ Monitor patients receiving salmeterol alone or in fixed combination with fluticasone for increased drug exposure and systemic corticosteroid effects.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

Geriatric Patients

Dosage adjustments not recommended solely because of age in geriatric patients.²⁵⁷ ²⁶⁷ ²⁷⁰

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.²⁷⁰ (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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Alone or in fixed combination with fluticasone as inhalation powder: Patients with severe hypersensitivity to milk proteins.²⁶⁷ ²⁶⁹ ²⁷⁰

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.¹⁸⁸ ²⁴⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ 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.²⁴⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (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.¹⁸⁸ ²⁴⁸

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.²⁴⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.²⁶⁷ ²⁶⁸ ²⁶⁹ (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.¹ ¹⁸⁸ ²²¹ ²²⁶ ²²⁷ Because of similar mechanisms of action among long-acting β₂-adrenergic agonists, these study findings are considered a class effect of these drugs.²⁴⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.²⁶⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷¹ ²⁷² 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.²⁶⁶ ²⁷¹ ²⁷²

No adequate studies conducted to determine whether the rate of death is increased in patients with COPD receiving long-acting β₂-adrenergic agonists.¹⁸⁸

Deterioration of Disease and Acute Episodes

Do not initiate therapy in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ 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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Serious acute respiratory events, including fatalities, reported when salmeterol initiated in patients with substantially worsening or acutely deteriorating asthma.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ These adverse events mostly occurred in patients with severe asthma and in some patients with acutely deteriorating asthma.⁶¹ ⁶³ ⁸⁹ ¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ However, such events also have occurred in patients with less severe asthma;¹ ¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ not possible from these reports to determine whether salmeterol contributed to these events.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

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.¹⁵⁴ ²²² ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ 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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.²⁶⁷ ²⁶⁸ ²⁶⁹ Do not use extra/increased doses of salmeterol alone or in fixed combination with fluticasone in such situations.¹ ⁸ ¹¹³ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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).¹ ² ⁴² ⁶¹ ¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ 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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Concomitant Corticosteroid Therapy

Not a substitute for inhaled or oral corticosteroids.¹⁸⁸ No data available demonstrating clinical anti-inflammatory effects of salmeterol such as that associated with corticosteroids.¹⁸⁸ Possible worsening of asthma if corticosteroid dosage is altered or discontinued when salmeterol therapy is initiated.² ⁵ ¹⁶ ²⁰ ⁴⁰ ⁴² ⁴³ ⁴⁵ ⁶¹ ⁶² ⁶³ ⁷² ⁸⁵ ⁹⁷ ¹⁸⁸

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.¹⁸⁸ Changes in corticosteroid dosage recommended only after clinical evaluation.¹⁸⁸

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.²⁶⁷ ²⁶⁸ ²⁶⁹ Do not use salmeterol in fixed combination with fluticasone inhalation aerosol to transfer patients from systemic corticosteroid therapy.²⁵⁷ 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).²⁶⁷ ²⁶⁸ ²⁶⁹

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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Clinically important cardiovascular effects and fatalities associated with excessive use of inhaled sympathomimetic drugs reported.⁶⁴ ⁸¹ ¹¹⁰ ¹¹¹ ¹¹² ¹¹⁵ ¹¹⁹ ¹⁸⁸ (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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Paradoxical Bronchospasm and Upper Airway Symptoms

Possible acute bronchospasm¹ ⁵⁶ ⁵⁹ ¹¹¹ ¹¹² ¹¹⁶ ¹⁵³ ¹⁵⁴ ¹⁵⁶ or paradoxical bronchospasm reported; may be life-threatening¹⁸⁸ and represent a hypersensitivity reaction.¹⁷ ²⁰ ⁵⁶ ⁵⁷ ⁵⁹ ¹¹⁴ (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.¹ ¹⁵³ ¹⁵⁶ ¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Upper airway symptoms, including laryngeal spasm, irritation, or swelling (e.g., stridor, choking), and oropharyngeal irritation reported.¹⁸⁸

Cardiovascular Effects

Possible clinically important changes in pulse rate, BP, and/or cardiovascular symptoms;¹⁸⁸ may require discontinuance of drug.¹³ ¹⁸⁸ ²¹⁰

ECG changes (e.g., flattening of T wave, prolongation of QT_c interval, ST-segment depression) reported with β-agonists; clinical importance unknown.¹⁸⁸ (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.¹⁹ ³³ ³⁷ ¹⁸⁸ Fatalities also reported in association with excessive use of inhaled sympathomimetic drugs.¹⁸⁸ (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.¹⁸⁸

Sensitivity Reactions

Immediate hypersensitivity reactions may occur; urticaria, angioedema, rash, bronchospasm, and anaphylaxis reported.¹⁸⁸

Anaphylactic reactions reported very rarely in patients with severe milk protein allergy.¹⁸⁸ ²⁶⁷ ²⁶⁹ (See Contraindications under Cautions.)

Possible acute bronchospasm; frequently occurs with the first use of a new oral inhalation aerosol canister.¹ ⁵⁶ ⁵⁹ ¹¹¹ ¹¹² ¹¹⁶ ¹⁵³ ¹⁵⁴ ¹⁵⁶ (See Paradoxical Bronchospasm and Upper Airway Symptoms under Cautions.)

General Precautions

CNS Effects

Possible CNS stimulation and adverse nervous system effects¹ ² ¹³ ¹⁵ ¹⁹ ¹⁸⁸ including headache,¹ ¹⁶ ¹⁷ ¹⁹ ²³ ⁵² ¹⁸⁸ tremor,¹ ¹⁶ ¹⁷ ¹⁰² ¹⁰⁷ ¹⁸² ¹⁸⁸ nervousness,¹ ¹⁵⁴ ¹⁵⁶ ¹⁸⁸ dizziness/giddiness,¹⁴⁷ ¹⁵² ¹⁸⁸ migraine,¹⁸⁸ sleep disturbances,¹⁸⁸ paresthesia,¹⁸⁸ anxiety,¹⁸⁸ or excitement.¹ ¹⁰⁶

Seizures, nervousness, headache, tremor, nausea, dizziness, fatigue, malaise, and insomnia associated with excessive β-adrenergic stimulation.¹⁸⁸

Use with caution in patients with seizure disorders.¹ ¹⁸⁷ ¹⁸⁸ ²¹⁰

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.¹ ¹⁸⁷ ¹⁸⁸ ²¹⁰ (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.¹¹¹ ¹¹⁹ ¹⁸⁸

Hypokalemia and Hyperglycemia

Clinically important hypokalemia (usually transient and not requiring supplementation) may occur in some patients receiving β-adrenergic agonists;² ¹⁵ ¹⁹ ²⁵ ³³ ³⁷ ⁴² ⁴³ may result in adverse cardiovascular effects (e.g., arrhythmias).¹¹¹ ¹¹⁹ ¹⁸⁷ ¹⁸⁸ (See Cardiovascular Effects under Cautions.)

Specific Populations

Pregnancy

Category C.¹⁸⁸ ²⁶⁸ ²⁷⁰ No adequate and well-controlled studies of salmeterol or salmeterol in fixed combination with fluticasone in pregnant women.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ Use during pregnancy only if potential benefit justifies potential risk to the fetus.²⁶⁸ ²⁷⁰

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.²⁶⁷ ²⁶⁹ Closely monitor pregnant women with asthma and adjust dosage of medications as needed to maintain optimal asthma control.²⁶⁷ ²⁶⁹

Lactation

Salmeterol distributed into milk in rats;³⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ not known whether salmeterol or fluticasone distributed into human milk.²⁵³ ²⁶⁷ ²⁶⁸ ²⁶⁹ Corticosteroids, other than fluticasone, distributed into human milk.²⁶⁷ ²⁶⁸ ²⁶⁹ Effects of salmeterol or fluticasone on breast-fed infants or milk production also not known.²⁶⁷ ²⁶⁹

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.²⁶⁷ ²⁶⁹ Use caution in nursing women.²⁶⁸ ²⁷⁰

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.¹⁸⁸ (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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (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.¹⁸⁸ Current data suggest that such children may receive the same dosage as adults for the treatment of asthma or exercise-induced bronchospasm.¹⁸⁸

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.²⁴³ ²⁶⁷ Safety and efficacy of such a combination in children <4 years of age not established.²⁶⁷

Safety and efficacy of salmeterol in fixed combination with fluticasone inhalation powder (AirDuo RespiClick) in children <12 years of age not established.²⁶⁹

Safety and efficacy of salmeterol in fixed combination with fluticasone inhalation aerosol (Advair HFA) in children <12 years of age not established.²⁶⁸ 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.²⁶⁸

Geriatric Use

Adverse effect profile of salmeterol alone or in fixed combination with fluticasone inhalation aerosol similar to that in younger adults.¹ ⁷⁷ ⁸² ⁹² ¹⁸⁸ ²⁵⁷

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.²⁶⁷ ²⁶⁸

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.²⁶⁹

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.²⁶⁷

Use with caution in geriatric patients who have concomitant cardiovascular disease.¹ ¹⁸⁸ ²⁶⁷ ²⁶⁸ (See Cardiovascular Effects under Cautions.)

Hepatic Impairment

Plasma concentrations may be increased.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ (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.¹⁸⁸

Closely monitor patients with hepatic impairment.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹

Common Adverse Effects

Patients with asthma (Serevent Diskus): Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis.²⁷⁰

Patients with asthma (Advair Diskus): Upper respiratory tract infection/inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headache, nausea, vomiting.²⁶⁷

Patients with asthma (AirDuo RespiClick): Nasopharyngitis, oral candidiasis, back pain, headache, cough.²⁶⁹

Patients with asthma (Advair HFA): Upper respiratory tract infection/inflammation, throat irritation, dysphonia, headache, dizziness, nausea, vomiting.²⁶⁸

Patients with COPD (Serevent Diskus): Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection.²⁷⁰

Patients with COPD (Advair Diskus): Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain.²⁶⁷

Drug Interactions

The following information addresses potential interactions with salmeterol.¹⁸⁸ When used in fixed combination with fluticasone, consider interactions associated with fluticasone.²⁶⁷ ²⁶⁸ ²⁶⁹ No formal drug interaction studies have been performed to date with the fixed combinations.²⁶⁷ ²⁶⁸ ²⁶⁹

Salmeterol and fluticasone are substrates for CYP3A4.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ Concomitant use of potent CYP3A4 inhibitors with salmeterol alone or in fixed combination with fluticasone not recommended.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

Specific Drugs

Drug	Interaction	Comments
Atazanavir	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
β₂-Adrenergic agonists, short-acting	Potential for increased adverse cardiovascular effects, but such effects less likely with a selective β₂-adrenergic agonist like salmeterol¹¹⁰ ¹¹⁵ ¹¹⁶ ¹¹⁷ ¹¹⁸ ¹²⁰	Safety of concomitant use of >8 inhalations of supplemental, short-acting β₂-agonist therapy with salmeterol inhalation therapy not established¹ ¹⁸⁸
β-Adrenergic blocking agents	Potential for antagonism of pulmonary effects and production of severe bronchospasm in patients with asthma or COPD¹⁵⁴ ¹⁵⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	If concomitant therapy required, consider cautious use of cardioselective β-adrenergic blocking agents²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Clarithromycin	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Cromolyn sodium	No apparent alteration in safety profile of salmeterol oral inhalation when administered concurrently¹⁶ ¹⁷ ²⁵ ⁴⁵ ⁵² ¹⁰² ¹⁸⁸
Diuretics, non-potassium-sparing	Potential for additive hypokalemia and/or ECG changes, especially when recommended β-agonist dose is exceeded¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Clinical importance unknown; however, use concomitantly with caution¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Indinavir	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Itraconazole	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Ketoconazole	Increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
MAO inhibitors	Potential for increased effect of salmeterol on the vascular system¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Extreme caution recommended with concomitant therapy or within 2 weeks following discontinuance of an MAO inhibitor¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Nefazodone	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Nelfinavir	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Ritonavir	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Saquinavir	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Telithromycin	Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects²²¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Concomitant use not recommended²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Tricyclic antidepressants	Potential for increased effect of salmeterol on the vascular system¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰	Extreme caution recommended with concomitant therapy or in patients receiving salmeterol within 2 weeks of discontinuance of these agents¹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Xanthine derivatives	Potential for increased cardiotoxic effects with concomitant administration of sympathomimetic agents and aminophylline but not theophylline¹ ¹²³ ¹²⁴ ¹⁵⁴ No apparent alteration in safety profile of salmeterol oral inhalation observed when administered concurrently with theophylline in patients with asthma or COPD in clinical studies¹⁸⁸

Salmeterol Xinafoate (Systemic, Oral Inhalation) Pharmacokinetics

Absorption

Bioavailability

Most of an orally inhaled drug actually is swallowed.¹ ² ³⁸ ³⁹ ¹⁸⁸ 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.¹ ² ³⁸ ³⁹ ¹⁸⁸

Low or undetectable systemic concentrations occur after inhalation of the recommended dosage and are not predictive of therapeutic effects.¹ ³⁹ ¹⁸⁸

Onset

Time to onset of effective bronchodilation 60 minutes with salmeterol oral inhalation powder.¹⁸⁸ 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.²²¹ ²⁵⁷

Maximum improvement in FEV₁ generally occurs within 3 hours after administration of salmeterol oral inhalation powder.¹⁸⁸

Duration

Clinically important improvements are maintained for up to 12 hours in most patients receiving salmeterol oral inhalation powder.¹⁸⁸ 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.¹⁸⁸

Distribution

Extent

Crosses the blood-brain barrier in trace amounts.¹³ ³⁸

Not known whether the drug and/or its metabolites cross the placenta.¹⁵⁴

Distributed into milk in rats;³⁸ ¹⁸⁸ not known whether is distributed into human milk.²⁵³

Plasma Protein Binding

94–98%.²⁵ ¹⁵⁴

Elimination

Metabolism

Extensively metabolized in the liver by hydroxylation.¹ ² ²⁵ ³⁸

Elimination Route

Eliminated in feces (60%) and urine (25%), ¹ ² ²⁵ ³⁸ ¹⁸⁸ principally as metabolites.¹ ² ³⁸ ¹⁵⁴ ¹⁸⁸

Half-life

About 5.5 hours (oral administration).¹ ²⁵ ¹⁸⁸

Special Populations

Pharmacokinetics not studied in patients with hepatic impairment; however, increased plasma concentrations may occur since drug is predominantly cleared by hepatic metabolism.¹⁸⁸ (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.²⁵³ ²⁶⁷ ²⁷⁰

Salmeterol in fixed combination with fluticasone (AirDuo RespiClick): 15–25°C in a dry place away from extreme heat, cold, and humidity.²⁶⁹

Discard Serevent Diskus 6 weeks after removal from foil pouch or when every blister used (when the dose counter reads “0”), whichever comes first.²⁷⁰

Discard Advair Diskus 1 month after removal from foil pouch or when every blister used (when the dose counter reads “0”), whichever comes first.²⁵⁴ ²⁵⁵ ²⁶⁷

Discard AirDuo RespiClick 30 days after opening the foil pouch or when the dose counter reads “0,” whichever comes first.²⁶⁹

Aerosol

Fixed combination with fluticasone (Advair HFA): 20–25°C (may be exposed to 15–30°C) with mouthpiece down.²⁵⁸ ²⁶⁸

Contents under pressure; do not puncture, use or store near heat or open flame, or place into fire or incinerator.²⁵⁸ ²⁶⁸ Exposure to temperatures >49°C may cause canister to burst.²⁶⁸ Discard when dose counter reads “000.”²⁶⁸

Actions

Long-acting, synthetic, sympathomimetic amine bronchodilator.¹ ² ³ ⁵ ¹⁸⁸
Stimulates β₂-adrenergic receptors, with little or no effect on α- , β₁- , or β₃-adrenergic receptors.¹ ⁵ ²⁴ ⁴⁵ ⁸⁴ ⁸⁶ ¹⁸⁸
Increases concentrations of cyclic adenosine-3′, 5′-monophosphate (cAMP),¹ ² ³ ⁴⁴ ⁹³ ¹²⁹ ¹³⁰ ¹³¹ ¹⁸⁸ resulting in relaxation of bronchial smooth muscle, suppression of some aspects of inflammation, and stimulating airway epithelial ciliary function.² ⁵ ²⁶ ⁹³ ¹¹¹ ¹²⁹ ¹³⁰ ¹³¹ ¹³³ ¹⁵⁴
Decreases airway resistance and airway reactivity to histamine.⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² Inhibits the release of proinflammatory mediators (e.g., histamine, leukotrienes C₄and D₄, prostaglandin D₂) in human lung tissue.¹ ² ⁴ ⁵ ⁷⁹ ⁸⁷ ⁹¹ ⁹³ ¹⁸⁸
Prolonged therapy not associated with development of tolerance to the bronchodilatory effects.¹ ¹⁰ ¹⁶ ¹⁷ ²⁰ ⁴³ ⁵⁸ ¹⁰² ¹⁵⁴ ¹⁸⁸ ²¹³ ²¹⁴ ²¹⁶

Advice to Patients

When used in fixed combination with fluticasone, importance of informing patients of important cautionary information about fluticasone.²⁶⁷ ²⁶⁸ ²⁶⁹
Provide a copy of the manufacturer’s patient information (medication guide) for salmeterol alone or in fixed combination with fluticasone with each prescription.²⁴⁹ ²⁵⁰ ²⁵² ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ 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.²⁵³ ²⁵⁴ ²⁵⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰

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.¹⁸⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ Importance of informing patients that long-term asthma controller drugs must be continued when salmeterol is added to the treatment regimen.¹⁸⁸
Importance of children receiving therapy under adult supervision.²⁵³
Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system.¹ ²⁵ ¹⁸⁹ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Importance of adherence to dosing schedules, including not altering the dose or frequency of use unless otherwise instructed by a clinician.¹ ¹⁵⁶ ²⁵³ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.²⁵³ ²⁵⁴ ²⁵⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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).⁹⁷ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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).²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Importance of contacting a clinician if asthma symptoms do not improve after 1 week of therapy.²⁵³ ²⁵⁴ ²⁵⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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).²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.² ⁵ ¹⁶ ²⁰ ⁴⁰ ⁴² ⁴³ ⁴⁵ ⁶¹ ⁶² ⁶³ ⁷² ⁸⁵ ⁹⁷ ²⁷⁰ Importance of informing patients that salmeterol should not be used as a substitute for oral or inhaled corticosteroids.²⁷⁰
Importance of informing all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are receiving salmeterol.²⁷⁰
Importance of patients not discontinuing therapy with salmeterol without medical supervision, since symptoms may recur after discontinuance.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Importance of administering salmeterol inhalation powder at least 30 minutes prior to exercise for prevention of exercise-induced bronchospasm.²⁷⁰ Importance of not using additional doses of salmeterol for exercise-induced bronchospasm for 12 hours.²⁷⁰ Importance of not using additional salmeterol for exercise-induced bronchospasm while receiving therapy (twice daily) with salmeterol.²⁷⁰
Importance of informing patients of adverse effects associated with β₂-adrenergic agonists, such as palpitations, rapid heart rate, tremor, nervousness, or chest pain.¹⁵⁴ ¹⁵⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
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.¹⁸⁸ ²⁵³ ²⁵⁴ ²⁵⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.²⁵³ ²⁵⁴ ²⁵⁷ ²⁵⁸ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements.²⁵³ ²⁵⁴ ²⁵⁸
Importance of informing patients of other important precautionary information.²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ (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.

Salmeterol Xinafoate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Powder	50 mcg (of salmeterol) per inhalation	Serevent Diskus	GlaxoSmithKline

Salmeterol Xinafoate Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Aerosol	21 mcg (of salmeterol) with Fluticasone Propionate 45 mcg per metered spray (from the actuator)	Advair HFA (with hydrofluoroalkane propellant)	GlaxoSmithKline
		21 mcg (of salmeterol) with Fluticasone Propionate 115 mcg per metered spray (from the actuator)	Advair HFA (with hydrofluoroalkane propellant)	GlaxoSmithKline
		21 mcg (of salmeterol) with Fluticasone Propionate 230 mcg per metered spray (from the actuator)	Advair HFA (with hydrofluoroalkane propellant)	GlaxoSmithKline
	Powder	14 mcg (of salmeterol) with Fluticasone Propionate 55 mcg per inhalation	AirDuo RespiClick (combination)	Teva
		14 mcg (of salmeterol) with Fluticasone Propionate 113 mcg per inhalation	AirDuo RespiClick (combination)	Teva
		14 mcg (of salmeterol) with Fluticasone Propionate 232 mcg per inhalation	AirDuo RespiClick (combination)	Teva
		50 mcg (of salmeterol) with Fluticasone Propionate 100 mcg per inhalation	Advair Diskus	GlaxoSmithKline
		50 mcg (of salmeterol) with Fluticasone Propionate 250 mcg per inhalation	Advair Diskus	GlaxoSmithKline
		50 mcg (of salmeterol) with Fluticasone Propionate 500 mcg per inhalation	Advair Diskus	GlaxoSmithKline

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