LABAs, such as salmeterol, one of the active ingredients in ADVAIR HFA, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see WARNINGS AND PRECAUTIONS]. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients.
Systemic and local corticosteroid use may result in the following:
- Candida albicans infection [see WARNINGS AND PRECAUTIONS]
- Pneumonia in patients with COPD [see WARNINGS AND PRECAUTIONS]
- Immunosuppression [see WARNINGS AND PRECAUTIONS]
- Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
- Growth effects [see WARNINGS AND PRECAUTIONS]
- Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult and Adolescent Patients Aged 12 Years and Older
The incidence of adverse reactions associated with ADVAIR HFA in Table 2 is based upon 2 placebo-controlled 12-week US clinical studies (Studies 1 and 3) and 1 active-controlled 12-week US clinical study (Study 2). A total of 1,008 adult and adolescent patients with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or inhaled corticosteroids were treated twice daily with 2 inhalations of ADVAIR HFA 45/21 or ADVAIR HFA 115/21, fluticasone propionate chlorofluorocarbon (CFC) inhalation aerosol (44- or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol. The average duration of exposure was 71 to 81 days in the active treatment groups compared with 51 days in the placebo group.
Table 2: Adverse Reactions With ≥ 3% Incidence
With ADVAIR HFA Inhalation Aerosol in Adult and Adolescent Patients With Asthma
|Adverse Event||ADVAIR HFA Inhalation Aerosol||Fluticasone Propionate CFC Inhalation Aerosol||Salmeterol CFC Inhalation Aerosol||Placebo HFA Inhalation Aerosol|
(n = 187) %
(n = 94) %
(n = 186) %
(n = 91) %
(n = 274) %
|(n = 176) %|
|Ear, nose, & throat|
|Upper respiratory tract infection||16||24||13||15||17||13|
|Upper respiratory inflammation||4||4||3||7||5||3|
|Viral respiratory infection||3||5||4||5||3||4|
|Nausea & vomiting||5||3||4||2||2||3|
|Viral gastrointestinal infection||4||2||2||0||1||2|
|Gastrointestinal signs & symptoms||3||2||2||1||1||1|
|Muscle pain||4||1||1||1||3||< 1|
The incidence of common adverse reactions reported in Study 4, a 12-week non-US clinical study of 509 patients previously treated with inhaled corticosteroids who were treated twice daily with 2 inhalations of ADVAIR HFA 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 2.
Additional Adverse Reactions
Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that occurred in the groups receiving ADVAIR HFA with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo include the following: tachycardia, arrhythmias, myocardial infarction, postoperative complications, wounds and lacerations, soft tissue injuries, ear signs and symptoms, rhinorrhea/postnasal drip, epistaxis, nasal congestion/blockage, laryngitis, unspecified oropharyngeal plaques, dryness of nose, weight gain, allergic eye disorders, eye edema and swelling, gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, abdominal discomfort and pain, oral abnormalities, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain, muscle injuries, sleep disorders, migraines, allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation, bacterial reproductive infections, lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage, eczema, dermatitis and dermatosis, urinary infections.
Laboratory Test Abnormalities
In Study 3, there were more reports of hyperglycemia among adults and adolescents receiving ADVAIR HFA, but this was not seen in Studies 1 and 2.
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR, fluticasone propionate, and/or salmeterol or a combination of these factors.
Endocrine and Metabolic: Cushing's syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis.
Eye: Cataracts, glaucoma.
Hepatobiliary Tract and Pancreas: Abnormal liver function tests.
Musculoskeletal: Back pain, myositis.
Neurology: Paresthesia, restlessness.
Non-Site Specific: Fever, pallor.
Psychiatry: Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.
Respiratory: Asthma; asthma exacerbation; chest congestion; chest tightness; cough; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; pneumonia; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Read the Advair HFA (fluticasone propionate and salmeterol) Side Effects Center for a complete guide to possible side effects »
ADVAIR HFA has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma, without adverse drug reactions [see CLINICAL PHARMACOLOGY]. No formal drug interaction studies have been performed with ADVAIR HFA.
Inhibitors of Cytochrome P450 3A4
Fluticasone propionate and salmeterol, the individual components of ADVAIR HFA, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR HFA is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.
Ritonavir: Fluticasone Propionate: A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see CLINICAL PHARMACOLOGY]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.
Ketoconazole: Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.
Salmeterol: In a drug interaction study in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
ADVAIR HFA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR HFA, on the vascular system may be potentiated by these agents.
Beta-Adrenergic Receptor Blocking Agents
Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR HFA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.
The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists such as salmeterol, a component of ADVAIR HFA, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of ADVAIR HFA with nonpotassium-sparing diuretics.
Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
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