Fluticasone Propionate and Salmeterol DISKUS (Page 4 of 13)

5.15 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of ICS, including fluticasone propionate, a component of Fluticasone Propionate/Salmeterol DISKUS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Propionate/Salmeterol DISKUS long term.

Effects of treatment with fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 subjects with COPD in the 3-year survival trial. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this trial because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of subjects treated with fluticasone propionate/salmeterol DISKUS 500/50 mcg who were eligible and available for evaluation of cataracts at the end of the trial (n = 53). The incidence of newly diagnosed glaucoma was 2% with fluticasone propionate/salmeterol DISKUS 500/50 mcg, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo.

5.16 Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled fluticasone propionate, a component of Fluticasone Propionate/Salmeterol DISKUS, may present with systemic eosinophilic conditions. Some of these patients have 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 ICS in this clinical setting. 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.

5.17 Coexisting Conditions

Fluticasone Propionate/Salmeterol DISKUS, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.18 Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with fluticasone propionate/salmeterol DISKUS at recommended doses.

6 ADVERSE REACTIONS

Use of LABA may result in the following:

Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1)]
Cardiovascular and central nervous system effects [see Warnings and Precautions (5.12)]

Systemic and local corticosteroid use may result in the following:

Candida albicans infection [see Warnings and Precautions (5.4)]
Pneumonia in patients with COPD [see Warnings and Precautions (5.5)]
Immunosuppression [see Warnings and Precautions (5.6)]
Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
Reduction in bone mineral density [see Warnings and Precautions (5.13)]
Growth effects [see Warnings and Precautions (5.14)]
Glaucoma and cataracts [see Warnings and Precautions (5.15)]

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.

6.1 Clinical Trials Experience in Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

The incidence of adverse reactions associated with fluticasone propionate/salmeterol 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 ICS were treated twice daily with fluticasone propionate/salmeterol 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 Fluticasone Propionate/Salmeterol DISKUS with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma

Adverse Event

Fluticasone Propionate/ Salmeterol DISKUS

100/50 mcg

(n = 92)

%

Fluticasone Propionate/ Salmeterol DISKUS

250/50 mcg

(n = 84)

%

Fluticasone Propionate

100 mcg

(n = 90)

%

Fluticasone Propionate

250 mcg

(n = 84)

%

Salmeterol

50 mcg

(n = 180)

%

Placebo

(n = 175)

%

Ear, nose, and 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 and vomiting

4

6

3

4

1

1

Gastrointestinal discomfort and 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 Trial 3, a 28-week, non-U.S. clinical trial in 503 subjects previously treated with ICS who were treated twice daily with fluticasone propionate/salmeterol DISKUS 500/50 mcg, 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 fluticasone propionate/salmeterol 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 ICS at trial entry were randomized to either fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (≥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 ≥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.

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