ADVERSE REACTIONS
Long-acting beta 2 -adrenergic agonists, such as salmeterol, may 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). Salmeterol is a component of ADVAIR DISKUS. However, the data from this study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other component of ADVAIR DISKUS, or other asthma controller therapy modifies the risk of asthma-related death.
Asthma
Adult and Adolescent Patients 12 Years of Age and Older
The incidence of common adverse events in Table 4 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 2). A total of 705 adolescent and adult patients (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.
Table 4. Overall Adverse Events With ≥3% Incidence in US Controlled Clinical Trials With ADVAIR DISKUS in Patients With Asthma |
ADVAIR
|
ADVAIR
|
Fluticasone
|
Fluticasone
| | |
|
DISKUS
|
DISKUS
|
Propionate
|
Propionate
|
Salmeterol
|
Placebo
|
|
100/50
|
250/50
|
100 mcg
|
250 mcg
|
50 mcg
|
(N =
|
|
(N = 92)
|
(N = 84)
|
(N = 90)
|
(N = 84)
|
(N = 180)
|
175)
|
|
Adverse Event
|
%
|
%
|
%
|
%
|
%
|
%
|
|
Ear, nose, & throat
| | | | | | |
|
Upper respiratory tract
|
27
|
21
|
29
|
25
|
19
|
14
|
|
infection
| | | | | | |
|
Pharyngitis
|
13
|
10
|
7
|
12
|
8
|
6
|
|
Upper respiratory
|
7
|
6
|
7
|
8
|
8
|
5
|
|
inflammation
| | | | | | |
|
Sinusitis
|
4
|
5
|
6
|
1
|
3
|
4
|
|
Hoarseness/dysphonia
|
5
|
2
|
2
|
4
|
<1
|
<1
|
|
Oral candidiasis
|
1
|
4
|
2
|
2
|
0
|
0
|
|
Lower respiratory
| | | | | | |
|
Viral respiratory infections
|
4
|
4
|
4
|
10
|
6
|
3
|
|
Bronchitis
|
2
|
8
|
1
|
2
|
2
|
2
|
|
Cough
|
3
|
6
|
0
|
0
|
3
|
2
|
|
Neurology
| | | | | | |
|
Headaches
|
12
|
13
|
14
|
8
|
10
|
7
|
|
Gastrointestinal
| | | | | | |
|
Nausea & vomiting
|
4
|
6
|
3
|
4
|
1
|
1
|
|
Gastrointestinal discomfort
|
4
|
1
|
0
|
2
|
1
|
1
|
|
& pain
| | | | | | |
|
Diarrhea
|
4
|
2
|
2
|
2
|
1
|
1
|
|
Viral gastrointestinal
|
3
|
0
|
3
|
1
|
2
|
2
|
|
infections
| | | | | | |
|
Non-site specific
| | | | | | |
|
Candidiasis unspecified site
|
3
|
0
|
1
|
4
|
0
|
1
|
|
Musculoskeletal
| | | | | | |
|
Musculoskeletal pain
|
4
|
2
|
1
|
5
|
3
|
3
|
|
Average duration of exposure (days)
|
77.3
|
78.7
|
72.4
|
70.1
|
60.1
|
42.3
|
Table 4 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in either of the groups receiving ADVAIR DISKUS and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account. Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.
These adverse reactions were mostly mild to moderate in severity.
Other adverse events that occurred in the groups receiving ADVAIR DISKUS in these studies with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:
Blood and Lymphatic
Lymphatic signs and symptoms.
Cardiovascular
Palpitations.
Drug Interaction, Overdose, and Trauma
Muscle injuries, fractures, wounds and lacerations, contusions and hematomas, burns.
Ear, Nose, and Throat
Rhinorrhea/postnasal drip; ear, nose, and throat infections; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; rhinitis; sneezing; nasal irritation; blood in nasal mucosa.
Eye
Keratitis and conjunctivitis, viral eye infections, eye redness.
Gastrointestinal
Dental discomfort and pain, gastrointestinal signs and symptoms, gastrointestinal infections, gastroenteritis, gastrointestinal disorders, oral ulcerations, oral erythema and rashes, constipation, appendicitis, oral discomfort and pain.
Hepatobiliary Tract and Pancreas
Abnormal liver function tests.
Lower Respiratory
Lower respiratory signs and symptoms, pneumonia, lower respiratory infections.
Musculoskeletal
Arthralgia and articular rheumatism; muscle stiffness, tightness, and rigidity; bone and cartilage disorders.
Neurology
Sleep disorders, tremors, hypnagogic effects, compressed nerve syndromes.
Non-Site Specific
Allergies and allergic reactions, congestion, viral infections, pain, chest symptoms, fluid retention, bacterial infections, wheeze and hives, unusual taste.
Skin
Viral skin infections, urticaria, skin flakiness and acquired ichthyosis, disorders of sweat and sebum, sweating.
The incidence of common adverse events reported in Study 3, a 28-week, non-US clinical study of 503 patients 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 was similar to the incidences reported in Table 4.
Pediatric Patients
Pediatric Study
ADVAIR DISKUS 100/50 was well tolerated in clinical trials conducted in children with asthma aged 4 to 11 years. The incidence of common adverse events in Table 5 is based upon a 12-week US study in 203 patients with asthma aged 4 to 11 years (74 females and 129 males) who were receiving inhaled corticosteroids at study entry and were randomized to either ADVAIR DISKUS 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily.
Table 5. Overall Adverse Events With ≥3% Incidence With ADVAIR DISKUS 100/50 in Patients 4 to 11 Years of Age With Asthma |
ADVAIR DISKUS
|
Fluticasone Propionate
|
|
100/50
|
100 mcg
|
|
(N = 101)
|
(N = 102)
|
|
Adverse Event
|
%
|
%
|
|
Ear, nose, & throat
| | |
|
Upper respiratory tract infection
|
10
|
17
|
|
Throat irritation
|
8
|
7
|
|
Ear, nose, & throat infections
|
4
|
<1
|
|
Epistaxis
|
4
|
<1
|
|
Pharyngitis/throat infection
|
3
|
2
|
|
Ear signs & symptoms
|
3
|
<1
|
|
Sinusitis
|
3
|
0
|
|
Neurology
| | |
|
Headache
|
20
|
20
|
|
Gastrointestinal
| | |
|
Gastrointestinal discomfort &
|
7
|
5
|
|
pain
| | |
|
Nausea & vomiting
|
5
|
3
|
|
Candidiasis mouth/throat
|
4
|
<1
|
|
Non-site specific
| | |
|
Fever
|
5
|
13
|
|
Chest symptoms
|
3
|
<1
|
|
Average duration of exposure (days)
|
74.8
|
78.8
|
Table 5 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving ADVAIR DISKUS 100/50.
Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis
The incidence of common adverse events in Table 6 is based upon 1 placebo-controlled, 24-week, US clinical trial in patients with COPD associated with chronic bronchitis. A total of 723 adult patients (266 females and 457 males) were treated twice daily with ADVAIR DISKUS 250/50, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder 50 mcg, or placebo.
Table 6. Overall Adverse Events With ≥3% Incidence With ADVAIR DISKUS 250/50 in Patients With Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis |
ADVAIR
|
Fluticasone
| | |
|
DISKUS
|
Propionate
|
Salmeterol
| |
|
250/50
|
250 mcg
|
50 mcg
|
Placebo
|
|
(N = 178)
|
(N = 183)
|
(N = 177)
|
(N = 185)
|
|
Adverse Event
|
%
|
%
|
%
|
%
|
|
Ear, nose, & throat
| | | | |
|
Candidiasis mouth/throat
|
10
|
6
|
3
|
1
|
|
Throat irritation
|
8
|
5
|
4
|
7
|
|
Hoarseness/dysphonia
|
5
|
3
|
<1
|
0
|
|
Sinusitis
|
3
|
8
|
5
|
3
|
|
Lower respiratory
| | | | |
|
Viral respiratory infections
|
6
|
4
|
3
|
3
|
|
Neurology
| | | | |
|
Headaches
|
16
|
11
|
10
|
12
|
|
Dizziness
|
4
|
<1
|
3
|
2
|
|
Non-site specific
| | | | |
|
Fever
|
4
|
3
|
0
|
3
|
|
Malaise & fatigue
|
3
|
2
|
2
|
3
|
|
Musculoskeletal
| | | | |
|
Musculoskeletal pain
|
9
|
8
|
12
|
9
|
|
Muscle cramps & spasms
|
3
|
3
|
1
|
1
|
|
Average duration of exposure (days)
|
141.3
|
138.5
|
136.1
|
131.6
|
Table 6 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving ADVAIR DISKUS 250/50 and were more common than in the placebo group.
These adverse reactions were mostly mild to moderate in severity.
Other adverse events that occurred in the groups receiving ADVAIR DISKUS 250/50 with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:
Cardiovascular
Syncope.
Drug Interaction, Overdose, and Trauma
Postoperative complications.
Ear, Nose, and Throat
Ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection.
Endocrine and Metabolic
Hypothyroidism.
Eye
Dry eyes, eye infections.
Gastrointestinal
Constipation, gastrointestinal signs and symptoms, oral lesions.
Hepatobiliary Tract and Pancreas
Abnormal liver function tests.
Lower Respiratory
Breathing disorders, lower respiratory signs and symptoms.
Non-Site Specific
Bacterial infections, candidiasis unspecified site, edema and swelling, nonspecific conditions, viral infections.
Psychiatry
Situational disorders.
Observed During Clinical Practice
In addition to adverse events reported from clinical trials, the following events have been identified during worldwide use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. 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.
In extensive US and worldwide postmarketing experience with salmeterol, a component of ADVAIR DISKUS, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS), but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.
Cardiovascular
Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.
Ear, Nose, and Throat
Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, throat soreness.
Endocrine and Metabolic
Cushing syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, hyperglycemia, weight gain, osteoporosis.
Eye
Cataracts, glaucoma.
Gastrointestinal
Abdominal pain, dyspepsia, xerostomia.
Musculoskeletal
Back pain, cramps, muscle spasm, myositis.
Neurology
Paresthesia, restlessness.
Non-Site Specific
Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction), pallor. Very rare anaphylactic reaction in patients with severe milk protein allergy.
Psychiatry
Agitation, aggression, depression.
Respiratory
Chest congestion; chest tightness; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Skin
Contact dermatitis, contusions, ecchymoses, photodermatitis.
Urogenital
Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.
Eosinophilic Conditions
In rare cases, patients on inhaled fluticasone propionate, a component of ADVAIR DISKUS, may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. While ADVAIR DISKUS should not be used for transferring patients from systemic corticosteroid therapy, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see PRECAUTIONS: General: Eosinophilic Conditions).
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