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Long-acting beta2-adrenergic agonists, such as salmeterol one of the active ingredients in ADVAIR DISKUS (fluticasone propionate) , 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 LABA. Available data from controlled clinical trials suggest that LABA 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]

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 Patients Aged 12 Years and Older

The incidence of adverse reactions associated with ADVAIR DISKUS (fluticasone propionate) in Table 2 is based upon 2 placebo-controlled, 12­week, 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. 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 ≥ 3% Incidence With ADVAIR DISKUS (fluticasone propionate) in Adult and Adolescent Patients With Asthma

Adverse Event ADVAIR DISKUS (fluticasone propionate)
100/50
(N = 92)
%
ADVAIR DISKUS (fluticasone propionate)
250/50
(N = 84) %
Fluticasone Propionate
100 mcg
(N = 90) %
Fluticasone Propionate
250 mcg
(N = 84)
%
Salmeterol
50 mcg
(N = 180)
%
Placebo
(N = 175)
%
Ear, nose, & throat
  Upper respiratory tract infection 27 21 29 25 19 14
  Pharyngitis 13 10 7 12 8 6
  Upper respiratory inflammation 7 6 7 8 8 5
  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 & pain 4 1 0 2 1 1
  Diarrhea 4 2 2 2 1 1
  Viral gastrointestinal infections 3 0 3 1 2 2
Non-site specific
  Candidiasis unspecified site 3 0 1 4 0 1
Musculoskeletal
  Musculoskeletal pain 4 2 1 5 3 3

The types of adverse reactions and 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, 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 patients with asthma treated with ADVAIR DISKUS (fluticasone propionate) compared with patients 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 Patients Aged 4 to 11 Years

The safety data for pediatric patients aged 4 to 11 years is based upon 1 US trial of 12 weeks' treatment duration. A total of 203 patients (74 females and 129 males) who were receiving inhaled corticosteroids at study entry were randomized to either ADVAIR DISKUS 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions ( ≥ 3% and greater than placebo) seen in the pediatric patients 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 ≥ 1% of patients in clinical trials. The elevations were transient and did not lead to discontinuation from the studies. 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 (fluticasone propionate) 250/50 twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, 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, or placebo. The mean age of the patients was 64, and the majority (93%) was Caucasian. In this trial, 70% of the patients treated with ADVAIR DISKUS (fluticasone propionate) reported an adverse reaction compared with 64% on placebo. The average duration of exposure to ADVAIR DISKUS (fluticasone propionate) 250/50 was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month study is shown in Table 3.

Table 3: Overall Adverse Reactions  With ≥ 3% Incidence With ADVAIR DISKUS (fluticasone propionate) 250/50 in Patients With Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis

Adverse Event ADVAIR
DISK US
250/50
(N = 178)
%
Fluticasone
Propionate
250 mcg
(N = 183)
%
Salmeterol
50 mcg
(N = 177)
%
Placebo
(N = 185)
%
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

In the two 1-year studies, ADVAIR DISKUS (fluticasone propionate) 250/50 was compared with salmeterol in 1,579 patients (863 males and 716 females). The mean age of the patients was 65, and the majority (94%) was Caucasian. To be enrolled, all of the patients had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the patients treated with ADVAIR DISKUS (fluticasone propionate) and 86% of the patients treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of > 5% and more frequently in the patients treated with ADVAIR DISKUS (fluticasone propionate) were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the patients treated with ADVAIR DISKUS (fluticasone propionate) and 25 (3%) of the patients treated with salmeterol developed pneumonia.

The incidence of pneumonia was higher in patients over 65 years of age, 9% in the patients treated with ADVAIR DISKUS (fluticasone propionate) compared with 4% in the patients treated with ADVAIR DISKUS (fluticasone propionate) less than 65 years of age. In the patients 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-Year) Trial

The safety of ADVAIR DISKUS (fluticasone propionate) 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year study in 6,184 adult patients with COPD (4,684 males and 1,500 females). The mean age of the patients was 65, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with ADVAIR DISKUS (fluticasone propionate) 250/50. In addition, pneumonia was reported in a significantly increased number of patients treated with ADVAIR DISKUS 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with patients 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 (fluticasone propionate) 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 studies with ADVAIR DISKUS (fluticasone propionate) 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with ADVAIR DISKUS (fluticasone propionate) 500/50 vs. 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS (fluticasone propionate) 500/50 vs. 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 patients with COPD treated with ADVAIR DISKUS (fluticasone propionate) compared with patients 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.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.

Postmarketing Experience

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.

Cardiac Disorders

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders

Cushing syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders

Glaucoma.

Gastrointestinal Disorders

Abdominal pain, dyspepsia, xerostomia.

Immune System Disorders

Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.

Metabolic and Nutrition Disorders

Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, and Bone Disorders

Arthralgia, cramps, myositis, osteoporosis.

Nervous System Disorders

Paresthesia, restlessness.

Psychiatric Disorders

Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Reproductive System and Breast Disorders

Dysmenorrhea.

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

Ecchymoses, photodermatitis.

Vascular Disorders

Pallor.