"The US Food and Drug Administration (FDA) has expanded the indication for the short-acting beta-agonist albuterol sulfate inhalation powder (ProAir RespiClick, Teva) to children aged 4 to 11 years, the company announced today.
LABA, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see WARNINGS AND PRECAUTIONS].
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]
- Reduction in bone mineral density [see WARNINGS AND PRECAUTIONS]
- Growth effects [see WARNINGS AND PRECAUTIONS]
- Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]
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.
Clinical Trials Experience In Asthma
Adult And Adolescent Subjects Aged 12 Years And Older
The incidence of adverse reactions associated with ADVAIR DISKUS in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (349 females and 356 males) previously treated with salmeterol or inhaled corticosteroids were treated twice daily with ADVAIR DISKUS (100/50-or 250/50-mcg doses), fluticasone propionate inhalation powder (100-or 250-mcg doses), salmeterol inhalation powder 50 mcg, or placebo. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group.
Table 2: Adverse Reactions with ADVAIR DISKUS with ≥ 3%
Incidence and More Common than Placebo in Adult and Adolescent Subjects with
|Adverse Event||ADVAIR DISKUS 100/50
(n = 92) %
|ADVAIR DISKUS 250/50
(n = 84) %
|Fluticasone Propionate 100 mcg
(n = 90) %
|Fluticasone Propionate 250 mcg
(n = 84) %
|Salmeterol 50 mcg
(n = 180) %
(n = 175) %
|Ear, nose, and throat|
|Upper respiratory tract infection||27||21||29||25||19||14|
|Upper respiratory inflammation||7||6||7||8||8||5|
|Hoarseness/dysphonia||5||2||2||4||< 1||< 1|
|Viral respiratory infections||4||4||4||10||6||3|
|Nausea and vomiting||4||6||3||4||1||1|
|Gastrointestinal discomfort and pain||4||1||0||2||1||1|
|Viral gastrointestinal infections||3||0||3||1||2||2|
|Candidiasis unspecified site||3||0||1||4||0||1|
The types of adverse reactions and events reported in Trial 3, a 28-week non-U.S. clinical trial in 503 subjects previously treated with inhaled corticosteroids who were treated twice daily with ADVAIR DISKUS 500/50, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg, were similar to those reported in Table 2.
Additional Adverse Reactions
Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with ADVAIR DISKUS compared with subjects treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum.
Pediatric Subjects Aged 4 To 11 Years
The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks' treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving inhaled corticosteroids at trial entry were randomized to either ADVAIR DISKUS 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (greater than or equal to 3% and greater than placebo) seen in the pediatric subjects but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections.
Laboratory Test Abnormalities
Elevation of hepatic enzymes was reported in greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.
Clinical Trials Experience In Chronic Obstructive Pulmonary Disease
Short-Term (6 Months to 1 Year) Trials
The short-term safety data are based on exposure to ADVAIR DISKUS 250/50 twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, a total of 723 adult subjects (266 females and 457 males) were treated twice daily with ADVAIR DISKUS 250/50, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder, or placebo. The mean age of the subjects was 64, and the majority (93%) was Caucasian. In this trial, 70% of the subjects treated with ADVAIR DISKUS reported an adverse reaction compared with 64% on placebo. The average duration of exposure to ADVAIR DISKUS 250/50 was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month trial is shown in Table 3.
Table 3: Overall Adverse Reactions with ADVAIR DISKUS
250/50 with ≥ 3% Incidence in Subjects with Chronic Obstructive
Pulmonary Disease Associated with Chronic Bronchitis
|Adverse Event||ADVAIR DISKUS 250/50
(n = 178) %
|Fluticasone Propionate 250 mcg
(n = 183) %
|Salmeterol 50 mcg
(n = 177) %
(n = 185) %
|Ear, nose, and throat|
|Viral respiratory infections||6||4||3||3|
|Malaise and fatigue||3||2||2||3|
|Muscle cramps and spasms||3||3||1||1|
In the two 1-year trials, ADVAIR DISKUS 250/50 was compared with salmeterol in 1,579 subjects (863 males and 716 females). The mean age of the subjects was 65 years, and the majority (94%) was Caucasian. To be enrolled, all of the subjects had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the subjects treated with ADVAIR DISKUS and 86% of the subjects treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of greater than 5% and more frequently in the subjects treated with ADVAIR DISKUS were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the subjects treated with ADVAIR DISKUS and 25 (3%) of the subjects treated with salmeterol developed pneumonia.
The incidence of pneumonia was higher in subjects older than 65 years, 9% in the subjects treated with ADVAIR DISKUS compared with 4% in the subjects treated with ADVAIR DISKUS younger than 65 years. In the subjects treated with salmeterol, the incidence of pneumonia was the same (3%) in both age-groups. [See WARNINGS AND PRECAUTIONS, Use In Specific Populations]
Long-Term (3 Years) Trial
The safety of ADVAIR DISKUS 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year trial in 6,184 adult subjects with COPD (4,684 males and 1,500 females). The mean age of the subjects was 65 years, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with ADVAIR DISKUS 250/50. In addition, pneumonia was reported in a significantly increased number of subjects treated with ADVAIR DISKUS 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with subjects treated with salmeterol 50 mcg or placebo (11% and 9%, respectively). When adjusted for time on treatment, the rates of pneumonia were 84 and 88 events per 1,000 treatment-years in the groups treated with fluticasone propionate 500 mcg and with ADVAIR DISKUS 500/50, respectively, compared with 52 events per 1,000 treatment-years in the salmeterol and placebo groups. Similar to what was seen in the 1-year trials with ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with ADVAIR DISKUS 500/50 versus 8% with placebo). [See WARNINGS AND PRECAUTIONS, Use In Specific Populations]
Additional Adverse Reactions
Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with COPD treated with ADVAIR DISKUS compared with subjects treated with placebo include the following: syncope; ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection; hypothyroidism; dry eyes; eye infections; gastrointestinal signs and symptoms; oral lesions; abnormal liver function tests; bacterial infections; edema and swelling; viral infections.
There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval 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 DISKUS, fluticasone propionate, and/or salmeterol or a combination of these factors.
Cushing's syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.
Immune System Disorders
Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.
Infections And Infestations
Metabolic and Nutrition Disorders
Hyperglycemia, weight gain.
Musculoskeletal, Connective Tissue, And Bone Disorders
Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.
Reproductive System And Breast Disorders
Respiratory, Thoracic, And Mediastinal Disorders
Chest congestion; chest tightness; dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Skin And Subcutaneous Tissue Disorders
Read the Advair Diskus (fluticasone propionate) Side Effects Center for a complete guide to possible side effects
ADVAIR DISKUS has been used concomitantly with other drugs, including short-acting beta2agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions [see CLINICAL PHARMACOLOGY]. No formal drug interaction trials have been performed with ADVAIR DISKUS.
Inhibitors Of Cytochrome P450 3A4
Fluticasone propionate and salmeterol, the individual components of ADVAIR DISKUS, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR DISKUS is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.
Fluticasone Propionate: A drug interaction trial 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.
Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.
Salmeterol: In a drug interaction trial 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 DISKUS 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 DISKUS, 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 DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD 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 non–potassiumsparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of ADVAIR DISKUS with non–potassium-sparing diuretics.
Read the Advair Diskus Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/23/2016
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