Fluticasone Propionate and Salmeterol DISKUS (Page 5 of 13)

6.2 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 fluticasone propionate/salmeterol DISKUS 250/50 mcg 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 fluticasone propionate/salmeterol DISKUS 250/50 mcg, 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 fluticasone propionate/salmeterol DISKUS reported an adverse reaction compared with 64% on placebo. The average duration of exposure to fluticasone propionate/salmeterol DISKUS 250/50 mcg 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 Fluticasone Propionate/Salmeterol DISKUS 250/50 mcg with ≥3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis

Adverse Event

Fluticasone Propionate/ Salmeterol DISKUS 250/50 mcg

(n = 178)

%

Fluticasone Propionate 250 mcg

(n = 183)

%

Salmeterol 50 mcg

(n = 177)

%

Placebo

(n = 185)

%

Ear, nose, and 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 and fatigue

3

2

2

3

Musculoskeletal

Musculoskeletal pain

9

8

12

9

Muscle cramps and spasms

3

3

1

1

In the two 1-year trials, fluticasone propionate/salmeterol DISKUS 250/50 mcg 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 fluticasone propionate/salmeterol DISKUS and 86% of the subjects treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of >5% and more frequently in the subjects treated with fluticasone propionate/salmeterol 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 fluticasone propionate/salmeterol 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 fluticasone propionate/salmeterol DISKUS compared with 4% in the subjects treated with fluticasone propionate/salmeterol 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 (5.5), Use in Specific Populations (8.5).]

Long-term (3 Years) Trial

The safety of fluticasone propionate/salmeterol DISKUS 500/50 mcg 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 fluticasone propionate/salmeterol DISKUS 250/50 mcg. In addition, pneumonia was reported in a significantly increased number of subjects treated with fluticasone propionate/salmeterol DISKUS 500/50 mcg 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 fluticasone propionate/salmeterol DISKUS 500/50 mcg, 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 fluticasone propionate/salmeterol DISKUS 250/50 mcg, the incidence of pneumonia was higher in subjects older than 65 years (18% with fluticasone propionate/salmeterol DISKUS 500/50 mcg versus 10% with placebo) compared with subjects younger than 65 years (14% with fluticasone propionate/salmeterol DISKUS 500/50 mcg versus 8% with placebo). [See Warnings and Precautions (5.5), Use in Specific Populations (8.5).]

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 fluticasone propionate/salmeterol 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.

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.

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