Advair HFA (combination), Serevent Diskus

Pronunciation

Generic Name: Salmeterol Xinafoate
Class: Selective beta-2-Adrenergic Agonists
VA Class: RE102
Chemical Name: ±-4-Hydroxy-α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol compd. with 1-hydroxy-2-naphthalenecarboxylic acid (1:1)
Molecular Formula: C25H37NO4•C11 H8O3
CAS Number: 94749-08-3

Warning(s)

  • Long-acting β2-adrenergic agonists (e.g., salmeterol) increase the risk of asthma-related death and may increase the risk of asthma-related hospitalization in children and adolescents.188 221 226 227 241 242 248 257 (See Asthma-related Death and Life-threatening Events under Cautions.)

  • Data currently inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma controller therapy mitigates the increased risk of asthma-related death from long-acting β2-adrenergic agonists.188 221 257

  • Use of salmeterol for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated.188 248 (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.188 221 248 257 (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 clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.221 257 (See Bronchospasm in Asthma under Uses.)

REMS:

FDA approved a REMS for salmeterol to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of salmeterol and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Advair HFA (combination), Serevent Diskus

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.156 188 221 222 263

Long-acting β2-adrenergic agonists (e.g., salmeterol) increase the risk of asthma-related death and may increase risk of asthma-related hospitalization in children and adolescents.188 221 248 257 Use of salmeterol for treatment of asthma without concomitant use of long-term asthma controller therapy (e.g., inhaled corticosteroids) is contraindicated.188 248 (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.188 222 263

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 clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.221 257

Slideshow: Flashback: FDA Drug Approvals 2013

Once asthma control achieved and maintained, assess patient at regular intervals and step down therapy (e.g., discontinue salmeterol or salmeterol in fixed combination with fluticasone) if possible without loss of asthma control, and maintain patient on long-term asthma controller therapy (e.g., inhaled corticosteroids).188 221 248 257

Salmeterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated.1 188 226 (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.188 221 257

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.154 188 221 257 (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.221

Not indicated for relief of acute bronchospasm.154 188 221 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.)

Advair HFA (combination), Serevent Diskus 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;97 188 221 257 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.97 188 221 257

  • 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.1 111 112 154 188 221 222 257 Extra/increased doses of salmeterol alone or in fixed combination with fluticasone are not recommended.1 111 112 154 188 221 222 257 (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) from foil-wrapped blisters or using an inhalation aerosol containing salmeterol in fixed combination with fluticasone (Advair HFA) via an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant.188 221 257

Administer twice daily, approximately every 12 hours (morning and evening).1 188 221 257

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.189 190 221 253 254 255

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

Spacer devices are not recommended with the Serevent or Advair Diskus inhaler.188 221 253 254

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.188 190 221 253 254 255

Discard the inhaler when every blister of salmeterol alone or in fixed combination with fluticasone has been used.188 190 221 253 254 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.188 190 221 253 254

Rinse the mouth without swallowing after inhalation of salmeterol in fixed combination with fluticasone propionate.221 254 255

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.188

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.221

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.257 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.257

Commercially available Advair HFA inhalation aerosol delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.257

Pediatric Patients

Asthma
Salmeterol
Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) twice daily.188

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) twice daily;257 258 265 recommended initial dosage is based on patient’s current asthma therapy.257

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.257

Oral Inhalation Powder

Children 4–11 years of age: 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation) twice daily in those inadequately controlled on an inhaled corticosteroid.221

Children ≥12 years of age: 50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation) twice daily;221 265 recommended initial dosage is based on patient’s asthma severity.221

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.221

Exercise-induced Bronchospasm
Salmeterol
Oral Inhalation Powder

Children ≥4 years of age: 50 mcg (1 inhalation) administered at least 30 minutes before exercise.188

Adults

Asthma
Salmeterol
Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.188

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 recommended initial dosage is based on patient’s current asthma therapy.257

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.257

Oral Inhalation Powder

50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation) twice daily;221 265 recommended initial dosage is based on patient’s asthma severity.221

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength with a higher strength (higher strengths contain higher dosages of fluticasone only) may provide additional asthma control.221

Exercise-induced Bronchospasm
Salmeterol
Oral Inhalation Powder

50 mcg (1 inhalation) administered at least 30 minutes before exercise.188

COPD
Salmeterol
Oral Inhalation Powder

50 mcg (1 inhalation) twice daily.188

Salmeterol/Fluticasone Fixed-combination
Oral Inhalation Powder

50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation) twice daily.221

Use of higher dosages produces no additional improvement in lung function.221

Prescribing Limits

Pediatric Patients

Asthma
Salmeterol
Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily.188

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) twice daily.257

Oral Inhalation Powder

Children 4–11 years of age: Maximum 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation) twice daily.221

Children or adolescents ≥12 years of age: Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation) twice daily.221

Exercise-induced Bronchospasm
Salmeterol
Oral Inhalation Powder

Children ≥4 years of age: Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).188

Adults

Asthma
Salmeterol
Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.188

Salmeterol/Fluticasone Fixed-combination
Oral Inhalation Aerosol

Maximum 42 mcg of salmeterol and 460 mcg of fluticasone propionate (2 inhalations) twice daily.257

Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation) twice daily.221

Exercise-induced Bronchospasm
Salmeterol
Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily (every 12 hours).188

COPD
Salmeterol
Oral Inhalation Powder

Maximum 50 mcg (1 inhalation) twice daily.188

Salmeterol/Fluticasone Fixed-combination
Oral Inhalation Powder

Maximum 50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation) twice daily.221

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.221 257

Hepatic Impairment

No specific dosage recommendations at this time.188 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.188 221

Geriatric Patients

Dosage adjustments not recommended solely because of age in geriatric patients.188 221 257

Cautions for Advair HFA (combination), Serevent Diskus

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.188 (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.188 221 257

  • Alone or in fixed combination with fluticasone as inhalation powder: Patients with severe hypersensitivity to milk proteins.188 221

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).188 221 248 257 Data from clinical trials suggest that long-acting β2-adrenergic agonists also increase the risk of asthma-related hospitalization in children and adolescents.188 221 248 257 (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 Data currently inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma controller therapy mitigates the increased risk of asthma-related death from long-acting β2-adrenergic agonists.188 221 257

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.188 221 248 257

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 clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.221 257 (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.188 221 246 257 Data inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma controller therapy mitigates the risk of asthma-related death.188 221 257

No adequate studies conducted to determine whether the rate of death is increased in patients with COPD receiving long-acting β2-adrenergic agonists.188 221

Deterioration of Disease and Acute Episodes

Do not initiate therapy in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.188 221 257 Salmeterol not studied in patients with acutely deteriorating asthma or COPD; initiation of salmeterol in this setting not appropriate.188

Serious acute respiratory events, including fatalities, reported when salmeterol initiated in patients with substantially worsening or acutely deteriorating asthma.188 These adverse events mostly occurred in patients with severe asthma and in some patients with acutely deteriorating asthma.61 63 89 188 221 257 However, such events also have occurred in patients with less severe asthma;1 188 not possible from these reports to determine whether salmeterol contributed to these events.188

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.154 188 221 222 257 Immediate reevaluation with reassessment of the treatment regimen is required in this situation, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids.188

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.221 257 Do not use extra/increased doses of salmeterol alone or in fixed combination with fluticasone in such situations.1 8 113 188 221 257

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 61 188 221 257 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.188 221 257

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.188 221 257

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.221 257 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).221

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.188 221 257

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.188 221 257

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.1 153 156 188 221 257

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 QTc interval, ST-segment depression) reported with β-agonists; clinical importance unknown.188 (See Coexisting Conditions under Cautions.)

Clinically important prolongation of the QTc 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.188 221 (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.188 221 257

Lactation

Distributed into milk in rats;38 188 not known whether distributed into human milk.253 Discontinue nursing or the drug.188

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 long-acting β2-adrenergic agonists may increase the risk of asthma-related death and hospitalization in children and adolescents.188 221 257 (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 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.221 243 Safety and efficacy of such a combination in children <4 years of age not established.221

Safety and efficacy of salmeterol in fixed combination with fluticasone inhalation aerosol in children <12 years of age not established.257 Data from a limited number of adolescents 12–17 years of age receiving salmeterol-fluticasone inhalation aerosol fixed combination suggest that safety and efficacy are similar to that in adults.257

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 in patients ≥65 years of age with asthma to determine whether geriatric patients respond differently than younger adults.221

Increased incidence of serious adverse effects reported in patients ≥65 years of age with COPD receiving salmeterol in fixed combination with fluticasone inhalation powder compared with younger adults; however, distribution of adverse effects similar in the two groups.221

Use with caution in geriatric patients who have concomitant cardiovascular disease.1 188 221 257 (See Cardiovascular Effects under Cautions.)

Hepatic Impairment

Plasma concentrations may be increased.188 (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

Common Adverse Effects

Patients with asthma: Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis.188

Patients with COPD: Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection.188

Interactions for Advair HFA (combination), Serevent Diskus

The following information addresses potential interactions with salmeterol.188 When used in fixed combination with fluticasone, consider interactions associated with fluticasone.221 257 No formal drug interaction studies have been performed to date with the fixed-combination.221 257

Salmeterol is a substrate for CYP3A4.221 257

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., QTc prolongation, palpitations, sinus tachycardia]) with concomitant use of CYP3A4 inhibitors.188 221 257 Concomitant use of potent CYP3A4 inhibitors with salmeterol alone or in fixed combination with fluticasone not recommended.188 221 257

Specific Drugs

Drug

Interaction

Comments

Atazanavir

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

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 resulting in severe bronchospasm in patients with asthma or COPD154 156 188

If concomitant therapy required, consider cautious use of cardioselective β-adrenergic blocking agents188

Clarithromycin

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

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

Clinical importance unknown; however, use concomitantly with caution1 188

Indinavir

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Itraconazole

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Ketoconazole

Increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects 188 221 257

Concomitant use not recommended188 221 257

MAO inhibitors

Potential for increased effect of salmeterol on the vascular system1

Extreme caution recommended with concomitant therapy or within 2 weeks following discontinuance of an MAO inhibitor1

Nefazodone

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Nelfinavir

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Ritonavir

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Saquinavir

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Telithromycin

Possible increased peak concentrations and AUC of salmeterol; possible increased risk of adverse cardiovascular effects188 221 257

Concomitant use not recommended188 221 257

Tricyclic antidepressants

Potential for increased effect of salmeterol on the vascular system1

Extreme caution recommended with concomitant therapy or in patients receiving salmeterol within 2 weeks of discontinuance of these agents1

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

Advair HFA (combination), Serevent Diskus 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.188 221 253

Discard Serevent Diskus 6 weeks after removal from foil pouch or when every blister used (when the dose counter reads “0”), whichever comes first.188

Discard Advair Diskus 1 month after removal from foil pouch or when every blister used, whichever comes first.254 255

Aerosol

Fixed combination with fluticasone: 25°C (may be exposed to 15–30°C) with mouthpiece down.257 258

Contents under pressure; do not puncture, use or store near heat or open flame, or place into fire or incinerator.257 258 Exposure to temperatures >49°C may cause canister to burst.257 Discard when dose counter reads “000.”257

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.221 257

  • 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 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time prescription is refilled.253 254 258

  • Importance of informing patients that long-acting β2-adrenergic agonists, including salmeterol, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalization in children and adolescents.188 221 257

    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 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 25 188 189 221 257

  • Importance of adherence to dosing schedules, including not altering the dose or frequency of use unless otherwise instructed by a clinician.1 156 188 221 253 257

  • 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

  • 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).97 188 221 257

  • 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).188 221 257

  • Importance of contacting a clinician if asthma symptoms do not improve after 1 week of therapy.253 254 258

  • 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).188 221 257

  • 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.188 221 257

  • 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 97 188 Importance of informing patients that salmeterol should not be used as a substitute for oral or inhaled corticosteroids.188

  • Importance of informing all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are receiving salmeterol.188

  • Importance of patients not discontinuing therapy with salmeterol without medical supervision, since symptoms may recur after discontinuance.188 221 257

  • Importance of administering salmeterol inhalation powder at least 30 minutes prior to exercise for prevention of exercise-induced bronchospasm.188 Importance of not using additional doses of salmeterol for exercise-induced bronchospasm for 12 hours.188 Importance of not using additional salmeterol for exercise-induced bronchospasm while receiving therapy (twice daily) with salmeterol.188

  • Importance of informing patients of adverse effects associated with β2-adrenergic agonists, such as palpitations, rapid heart rate, tremor, nervousness, or chest pain.154 156 188 221 257

  • 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.188 221 253 254 258

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.253 254 257 258

  • 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.188 221 257 (See Cautions.)

Preparations

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

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

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Serevent Diskus 50MCG/DOSE Aerosol (GLAXO SMITH KLINE): 60/$180.99 or 120/$355.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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