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

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

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

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

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

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

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

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

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

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

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

Category C.188 221 257

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

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

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.)

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

• 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

Applies to salmeterol: inhalation aerosol, inhalation aerosol with adapter, inhalation powder

Musculoskeletal

Very common (10% or more): Musculoskeletal pain (12%)
Common (1% to 10%): Arthralgia, articular rheumatism, muscle cramps and spasm, bone and skeletal pain, muscle pain, muscle stiffness, muscle tightness, muscle rigidity, musculoskeletal inflammation
Frequency not reported: Join pain[Ref]

Nervous system

Very common (10% or more): Headache (up to 14%)
Common (1% to 10%): Dizziness, migraines, tremor
Frequency not reported: Sinus headache, paresthesia[Ref]

Cardiovascular

Common (1% to 10%): Pallor, hypertension, palpitations
Uncommon (0.1% to 1%): Tachycardia
Very rare (less than 0.01%): Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles)
Frequency not reported: Peripheral vasodilation and a compensatory small increase in heart rate[Ref]

Dermatologic

Common (1% to 10%): Skin rashes, urticaria, photodermatitis
Frequency not reported: Contact dermatitis, eczema[Ref]

Gastrointestinal

Common (1% to 10%): Gastrointestinal signs and symptoms, nausea, vomiting, candidiasis mouth/throat, dental discomfort and pain, dyspeptic symptoms, gastrointestinal infections, hyposalivation
Frequency not reported: Oral mucosal abnormality[Ref]

Hepatic

Common (1% to 10%): Transient elevation of hepatic enzymes[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia
Rare (less than 0.1%): Hypokalemia[Ref]

Ocular

Common (1% to 10%): Conjunctivitis, keratitis[Ref]

Other

Common (1% to 10%): Influenza, ear signs and symptoms, edema and swelling
Frequency not reported: Localized aches and pains, pyrexia of unknown origin[Ref]

Psychiatric

Common (1% to 10%): Anxiety
Uncommon (0.1% to 1%): Nervousness
Rare (less than 0.1%): Insomnia
Frequency not reported: Sleep disturbances[Ref]

Respiratory

Common (1% to 10%): Nasal/sinus congestion, rhinitis, asthma, tracheitis/bronchitis, pharyngitis, sinusitis, upper respiratory tract infection, cough, throat irritation, lower respiratory signs and symptoms
Very rare (less than 0.01%): Paradoxical bronchospasm, non specific chest pain, oropharyngeal irritation
Frequency not reported: Bronchospasm
Postmarketing reports: Upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking[Ref]

Hypersensitivity

Very rare (less than 0.01%): Anaphylactic reactions including edema and angioedema, bronchospasm and anaphylactic shock
Frequency not reported: Immediate hypersensitivity reactions
Postmarketing reports: Anaphylaxis[Ref]

Some side effects of salmeterol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Prevention of Exercise Induced Bronchospasm:
-Less than 4 years: Not approved.
-4 years or older: 50 mcg (1 inhalation) orally at least 30 minutes before exercise

Comments:
-Protection may last up to 9 hours in adolescents and up to 12 hours in pediatrics aged 4 to 11 years, when used intermittently as needed for prevention.
-Additional doses should not be used for 12 hours.
-Patients receiving twice daily doses for the treatment of asthma should not use additional doses for the prevention of EIB.

Uses:
-For the prevention of EIB, as a single agent in patients with no persistent asthma
-In patients with persistent asthma use of this drug for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.

Data not available

Use with caution.

Data not available

LactMed Record Number

243

Last Revision Date

20151210

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