PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

NDC 66993-586-97

Fluticasone Propionate/Salmeterol DISKUS Inhalation Powder

500 mcg /50 mcg

PRASCO

Rx Only

FOR ORAL INHALATION ONLY

Each blister contains 500 mcg of fluticasone propionate and 72.5 mcg of salmeterol xinafoate, equivalent to 50 mcg of salmeterol base, with lactose.

1 DISKUS Inhalation Device

Containing 1 Foil Strip of 60 Blisters

62000000089843 Rev. 9/23

DESCRIPTION SECTION

11 DESCRIPTION

Fluticasone Propionate/Salmeterol DISKUS inhalation powder 100/50 mcg, Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg, and Fluticasone Propionate/Salmeterol DISKUS inhalation powder 500/50 mcg are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Fluticasone Propionate/Salmeterol DISKUS is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure:


Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of Fluticasone Propionate/Salmeterol DISKUS is salmeterol xinafoate, a beta2-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure:


Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Fluticasone Propionate/Salmeterol DISKUS is a purple plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone propionate (100, 250, or 500 mcg) and micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, Fluticasone Propionate/Salmeterol DISKUS delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from Fluticasone Propionate/Salmeterol DISKUS inhalation powder 100/50 mcg, Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg, and Fluticasone Propionate/Salmeterol DISKUS inhalation powder 500/50 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) subjects with asthma inhaling maximally through the DISKUS inhaler show mean PIF of 122.2 L/min (range: 81.6 to 152.1 L/min). Inhalation profiles for pediatric subjects with asthma inhaling maximally through the DISKUS inhaler show a mean PIF of 75.5 L/min (range: 49.0 to 104.8 L/min) for the 4-year-old subject set (N = 20) and 107.3 L/min (range: 82.8 to 125.6 L/min) for the 8-year-old subject set (N = 20).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

WARNINGS AND PRECAUTIONS SECTION

Highlight: •

LABA monotherapy increases the risk of serious asthma-related events. (5.1)

•

Do not initiate in acutely deteriorating asthma or COPD. Do not use to treat acute symptoms. (5.2)

•

Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3)

•

 Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4)

•

Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (5.5)

•

Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.6)

•

Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Fluticasone Propionate/Salmeterol DISKUS. (5.7)

•

Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Fluticasone Propionate/Salmeterol DISKUS slowly. (5.8)

•

If paradoxical bronchospasm occurs, discontinue Fluticasone Propionate/Salmeterol DISKUS and institute alternative therapy. (5.10)

•

Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. (5.12)

•

Assess for decrease in bone mineral density initially and periodically thereafter. (5.13)

•

Monitor growth of pediatric patients. (5.14)

•

Glaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Propionate/Salmeterol DISKUS long term. (5.15)

•

Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18)

•

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17)

5 WARNINGS AND PRECAUTIONS

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)]. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed- dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma‑related events (hospitalizations, intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists

Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies (14.1)], 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies (14.1)]. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.

The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non- inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

 Asthma-related death

 Asthma-related intubation (endotracheal)

 Asthma-related hospitalization (≥24-hour stay)

The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

5.2 Deterioration of Disease and Acute Episodes

Fluticasone Propionate/Salmeterol DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Fluticasone Propionate/Salmeterol DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of Fluticasone Propionate/Salmeterol DISKUS in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of Fluticasone Propionate/Salmeterol DISKUS, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life‑threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short‑acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Fluticasone Propionate/Salmeterol DISKUS with a higher strength, adding additional ICS, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of Fluticasone Propionate/Salmeterol DISKUS.

Fluticasone Propionate/Salmeterol DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Fluticasone Propionate/Salmeterol DISKUS has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with Fluticasone Propionate/Salmeterol DISKUS, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

5.3 Excessive Use of Fluticasone Propionate/Salmeterol DISKUS and Use with

Other Long-acting Beta2-agonists

Fluticasone Propionate/Salmeterol DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Fluticasone Propionate/Salmeterol DISKUS should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with fluticasone propionate/salmeterol DISKUS. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Fluticasone Propionate/Salmeterol DISKUS continues, but at times therapy with Fluticasone Propionate/Salmeterol DISKUS may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the inhaled administration of corticosteroids, including fluticasone propionate and fluticasone propionate/salmeterol DISKUS. In 2 replicate 1-year trials in 1,579 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the subjects treated with fluticasone propionate/salmeterol DISKUS was higher in subjects older than 65 years (9%) compared with the incidence in subjects younger than 65 years (4%). [See Adverse Reactions (6.2), Use in Specific Populations (8.5).]

In a 3-year trial in 6,184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving fluticasone propionate/salmeterol DISKUS 500/50 mcg compared with placebo (16% with fluticasone propionate/salmeterol DISKUS 500/50 mcg, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). 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 Adverse Reactions (6.2), Use in Specific Populations (8.5).]

5.6 Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although Fluticasone Propionate/Salmeterol DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Fluticasone Propionate/Salmeterol DISKUS. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with Fluticasone Propionate/Salmeterol DISKUS. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to Fluticasone Propionate/Salmeterol DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression

Fluticasone propionate, a component of Fluticasone Propionate/Salmeterol DISKUS, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Fluticasone Propionate/Salmeterol DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Fluticasone Propionate/Salmeterol DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with Fluticasone Propionate/Salmeterol DISKUS should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, Fluticasone Propionate/Salmeterol DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Fluticasone Propionate/Salmeterol DISKUS is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.10 Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medicines, Fluticasone Propionate/Salmeterol DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Fluticasone Propionate/Salmeterol DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; Fluticasone Propionate/Salmeterol DISKUS should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate/salmeterol DISKUS.

5.11 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Fluticasone Propionate/Salmeterol DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use Fluticasone Propionate/Salmeterol DISKUS [see Contraindications (4)].

5.12 Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10.2)]. Therefore, Fluticasone Propionate/Salmeterol DISKUS, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol, a component of Fluticasone Propionate/Salmeterol DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.13 Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating Fluticasone Propionate/Salmeterol DISKUS and periodically thereafter. If significant reductions in BMD are seen and Fluticasone Propionate/Salmeterol DISKUS is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.

2-Year Fluticasone Propionate Trial

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

3-Year Bone Mineral Density Trial

Effects of treatment with fluticasone propionate/salmeterol DISKUS 250/50 mcg or salmeterol 50 mcg on BMD at the L1-L4 lumbar spine and total hip were evaluated in 186 subjects with COPD (aged 43 to 87 years) in a 3-year double- blind trial. Of those enrolled, 108 subjects (72 males and 36 females) were followed for the entire 3 years. BMD evaluations were conducted at baseline and at 6-month intervals. Conclusions cannot be drawn from this trial regarding BMD decline in subjects treated with fluticasone propionate/salmeterol DISKUS versus salmeterol due to the inconsistency of treatment differences across gender and between lumbar spine and total hip.

In this trial there were 7 non-traumatic fractures reported in 5 subjects treated with fluticasone propionate/salmeterol DISKUS and 1 non-traumatic fracture in 1 subject treated with salmeterol. None of the non-traumatic fractures occurred in the vertebrae, hip, or long bones.

3-Year Survival Trial

Effects of treatment with fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on BMD was evaluated in a subset of 658 subjects (females and males aged 40 to 80 years) with COPD in the 3-year survival trial. BMD evaluations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions cannot be drawn from this trial because of the large number of dropouts (>50%) before the end of the follow-up and the maldistribution of covariates among the treatment groups that can affect BMD.

Fracture risk was estimated for the entire population of subjects with COPD in the survival trial (N = 6,184). The probability of a fracture over 3 years was 6.3% for fluticasone propionate/salmeterol DISKUS, 5.4% for fluticasone propionate, 5.1% for salmeterol, and 5.1% for placebo.

5.14 Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving Fluticasone Propionate/Salmeterol DISKUS routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Fluticasone Propionate/Salmeterol DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.1), Use in Specific Populations (8.4)].

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.

ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (incidence ≥3%) include:

•

Asthma: Upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting. (6.1)

•

COPD: Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain. (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or [www.fda.gov/medwatch](https://www.fda.gov/safety/medwatch-fda-safety- information-and-adverse-event-reporting-program).

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.

 Upper respiratory tract infection

 Pharyngitis

 Upper respiratory inflammation

 Sinusitis

 Hoarseness/dysphonia

 Oral candidiasis

 Viral respiratory infections

 Bronchitis

 Cough

 Headaches

 Nausea and vomiting

 Gastrointestinal discomfort and pain

 Diarrhea

 Viral gastrointestinal infections

 Candidiasis unspecified site

 Musculoskeletal pain

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.

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.

 Candidiasis mouth/throat

 Throat irritation

 Hoarseness/dysphonia

 Sinusitis

 Viral respiratory infections

 Headaches

 Dizziness

 Fever

 Malaise and fatigue

 Musculoskeletal pain

 Muscle cramps and spasms

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.

6.3 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of fluticasone propionate/salmeterol, 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 fluticasone propionate/salmeterol 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’s 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.

Infections and Infestations

Esophageal candidiasis.

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.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

In clinical trials comparing fluticasone propionate/salmeterol DISKUS with its individual components, improvements in most efficacy endpoints were greater with fluticasone propionate/salmeterol DISKUS than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed similar results between fluticasone propionate/salmeterol DISKUS and the concurrent use of fluticasone propionate plus salmeterol at corresponding doses from separate inhalers.

Trials Comparing Fluticasone Propionate/Salmeterol DISKUS with Fluticasone Propionate Alone or Salmeterol Alone: Three (3) double-blind, parallel-group clinical trials were conducted with fluticasone propionate/salmeterol DISKUS in 1,208 adult and adolescent subjects (aged 12 years and older, baseline FEV1 63% to 72% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were inhalation powders given as 1 inhalation from the DISKUS inhaler twice daily, and other maintenance therapies were discontinued.

Trial 1: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 100/50 mcg: This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate/salmeterol DISKUS 100/50 mcg with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The trial was stratified according to baseline asthma maintenance therapy; subjects were using either ICS (n = 250) (daily doses of beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000 mcg) or salmeterol (n = 106). Baseline FEV1 measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 100/50 mcg, 2.17 L; fluticasone propionate 100 mcg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial. Worsening asthma was defined as a clinically important decrease in FEV1 or PEF, increase in use of VENTOLIN (albuterol, USP) Inhalation Aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in Table 4, statistically significantly fewer subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

The FEV1 results are displayed in Figure 1. Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. Subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with fluticasone propionate/salmeterol DISKUS were achieved regardless of baseline asthma maintenance therapy (ICS or salmeterol).

Figure 1. Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

The effect of fluticasone propionate/salmeterol DISKUS 100/50 mcg on morning and evening PEF endpoints is shown in Table 5.

 Baseline

 Change from baseline

 Baseline

 Change from baseline

The subjective impact of asthma on subjects’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point scale where 1 = maximum impairment and 7 = none). Subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of ≥0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

Trial 2: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 250/50 mcg: This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate/salmeterol DISKUS 250/50 mcg with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 462 to 672 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 mcg; or triamcinolone acetonide 1,100 to 1,600 mcg). Baseline FEV1 measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 250/50 mcg, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg were withdrawn from this trial for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, fluticasone propionate/salmeterol DISKUS 250/50 mcg was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg also had clinically meaningful improvements in overall asthma- specific quality of life as described in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

Trial 3: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 500/50 mcg: This 28-week, non-U.S. trial compared fluticasone propionate/salmeterol DISKUS 500/50 mcg with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50 mcg plus fluticasone propionate 500 mcg administered from separate inhalers) twice daily in 503 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]). The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the trial. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 500/50 mcg, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with fluticasone propionate/salmeterol DISKUS 500/50 mcg compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with fluticasone propionate/salmeterol DISKUS 500/50 mcg were similar to improvements observed with concurrent therapy.

Onset of Action and Progression of Improvement in Asthma Control: The onset of action and progression of improvement in asthma control were evaluated in the 2 placebo-controlled U.S. trials. Following the first dose, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1) in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours (Figure 2). Following the initial dose, predose FEV1 relative to Day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both trials. No diminution in the 12-hour bronchodilator effect was observed with either fluticasone propionate/salmeterol DISKUS 100/50 mcg (Figures 2 and 3) or fluticasone propionate/salmeterol DISKUS 250/50 mcg as assessed by FEV1 following 12 weeks of therapy.

Figure 2. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

First Treatment Day

Figure 3. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Last Treatment Day (Week 12)

Reduction in asthma symptoms and use of rescue VENTOLIN Inhalation Aerosol and improvement in morning and evening PEF also occurred within the first day of treatment with fluticasone propionate/salmeterol DISKUS, and continued to improve over the 12 weeks of therapy in both trials.

Pediatric Subjects

In a 12-week U.S. trial, fluticasone propionate/salmeterol DISKUS 100/50 mcg twice daily was compared with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At trial entry, the children were symptomatic on low doses of ICS (beclomethasone dipropionate 252 to 336 mcg/day; budesonide 200 to 400 mcg/day; flunisolide 1,000 mcg/day; triamcinolone acetonide 600 to 1,000 mcg/day; or fluticasone propionate 88 to 250 mcg/day). The primary objective of this trial was to determine the safety of fluticasone propionate/salmeterol DISKUS 100/50 mcg compared with fluticasone propionate inhalation powder 100 mcg in this age group; however, the trial also included secondary efficacy measures of pulmonary function. Morning predose FEV1 was obtained at baseline and Endpoint (last available FEV1 result) in children aged 6 to 11 years. In subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg, FEV1 increased from 1.70 L at baseline (n = 79) to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at baseline (n = 83) to 1.77 L at Endpoint (n = 75) in subjects receiving fluticasone propionate 100 mcg.

The findings of this trial, along with extrapolation of efficacy data from subjects aged 12 years and older, support the overall conclusion that fluticasone propionate/salmeterol DISKUS 100/50 mcg is efficacious in the treatment of asthma in subjects aged 4 to 11 years.

Safety and Efficacy Trials Comparing Fluticasone Propionate/Salmeterol DISKUS with Fluticasone Propionate

Serious Asthma-Related Events: Two 26-week, randomized, double-blind, parallel-group, active comparator trials were conducted to compare the safety and efficacy of fluticasone propionate/salmeterol DISKUS with fluticasone propionate inhalation powder in adult and adolescent subjects (Trial 4, NCT01475721) and in pediatric subjects aged 4 to 11 years (Trial 5, NCT01462344). The primary safety objective of both trials was to evaluate whether the addition of salmeterol xinafoate to fluticasone propionate therapy (fluticasone propionate/salmeterol DISKUS) was non-inferior to ICS fluticasone propionate in terms of the risk of a serious asthma-related event (hospitalization, endotracheal intubation, and death). The trials were designed to rule out pre-defined risk margins for serious asthma‑related events of 2.0 for Trial 4 and 2.7 for Trial 5. A blinded adjudication committee determined whether events were asthma related.

Trial 4 enrolled subjects with moderate to severe persistent asthma with a history of asthma‑related hospitalization or at least 1 asthma exacerbation in the previous year treated with systemic corticosteroids. A total of 11,679 adult and adolescent subjects [5,834 receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg, fluticasone propionate/salmeterol DISKUS 250/50 mcg, or fluticasone propionate/salmeterol DISKUS 500/50 mcg and 5,845 receiving fluticasone propionate inhalation powder (100, 250, or 500 mcg)] were included. Trial 5 enrolled subjects with a diagnosis of asthma and a history of at least 1 asthma exacerbation in the previous year treated with systemic corticosteroid. A total of 6,208 subjects aged 4 to 11 years [3,107 receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate/salmeterol DISKUS 250/50 mcg and 3,101 receiving fluticasone propionate inhalation powder (100 or 250 mcg)] were included. In both trials, subjects with life-threatening asthma were excluded. In Trials 4 and 5, fluticasone propionate/salmeterol DISKUS was non-inferior to fluticasone propionate in terms of time to first serious asthma‑related events based on the pre-specified risk margins, with estimated hazard ratios of 1.03 (95% CI: 0.64, 1.66) and 1.29 (95% CI: 0.73, 2.27), respectively (Table 6).

Effect on Exacerbation: Trials 4 and 5 included time to first exacerbation as a secondary endpoint, where exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. In Trials 4 and 5, the hazard ratio for the time to first asthma exacerbation for fluticasone propionate/salmeterol DISKUS relative to fluticasone propionate inhalation powder was 0.79 (95% CI: 0.70, 0.89) and 0.86 (95% CI: 0.73, 1.01), respectively. The difference in exacerbations was primarily driven by a reduction in those requiring systemic corticosteroids only.

14.2 Chronic Obstructive Pulmonary Disease

The efficacy of fluticasone propionate/salmeterol DISKUS 250/50 mcg and fluticasone propionate/salmeterol DISKUS 500/50 mcg in the treatment of subjects with COPD was evaluated in 6 randomized, double-blind, parallel-group clinical trials in adult subjects aged 40 years and older. These trials were primarily designed to evaluate the efficacy of fluticasone propionate/salmeterol DISKUS on lung function (3 trials), exacerbations (2 trials), and survival (1 trial).

Lung Function

Two (2) of the 3 clinical trials primarily designed to evaluate the efficacy of fluticasone propionate/salmeterol DISKUS on lung function were conducted in 1,414 subjects with COPD associated with chronic bronchitis. In these 2 trials, all the subjects had a history of cough productive of sputum that was not attributable to another disease process on most days for at least 3 months of the year for at least 2 years. The trials were randomized, double-blind, parallel-group, 24-week treatment duration. One (1) trial evaluated the efficacy of fluticasone propionate/salmeterol DISKUS 250/50 mcg compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the efficacy of fluticasone propionate/salmeterol DISKUS 500/50 mcg compared with its components fluticasone propionate 500 mcg and salmeterol 50 mcg and with placebo. Trial treatments were inhalation powders given as 1 inhalation from the DISKUS inhaler twice daily. Maintenance COPD therapies were discontinued, with the exception of theophylline. The subjects had a mean pre-bronchodilator FEV1 of 41% and 20% reversibility at trial entry. Percent reversibility was calculated as 100 times (FEV1 post-albuterol minus FEV1 pre-albuterol)/FEV1 pre- albuterol.

Improvements in lung function (as defined by predose and postdose FEV1) were significantly greater with fluticasone propionate/salmeterol DISKUS than with fluticasone propionate, salmeterol, or placebo. The improvement in lung function with fluticasone propionate/salmeterol DISKUS 500/50 mcg was similar to the improvement seen with fluticasone propionate/salmeterol DISKUS 250/50 mcg.

Figures 4 and 5 display predose and 2-hour postdose, respectively, FEV1 results for the trial with fluticasone propionate/salmeterol DISKUS 250/50 mcg. To account for subject withdrawals during the trial, FEV1 at Endpoint (last evaluable FEV1) was evaluated. Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg had significantly greater improvements in predose FEV1 at Endpoint (165 mL, 17%) compared with salmeterol 50 mcg (91 mL, 9%) and placebo (1 mL, 1%), demonstrating the contribution of fluticasone propionate to the improvement in lung function with fluticasone propionate/salmeterol DISKUS (Figure 4). Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg had significantly greater improvements in postdose FEV1 at Endpoint (281 mL, 27%) compared with fluticasone propionate 250 mcg (147 mL, 14%) and placebo (58 mL, 6%), demonstrating the contribution of salmeterol to the improvement in lung function with fluticasone propionate/salmeterol DISKUS (Figure 5).

Figure 4. Predose FEV1: Mean Percent Change from Baseline in Subjects with Chronic Obstructive Pulmonary Disease


Figure 5. Two-Hour Postdose FEV1: Mean Percent Changes from Baseline over Time in Subjects with Chronic Obstructive Pulmonary Disease

The third trial was a 1-year trial that evaluated fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo in 1,465 subjects. The subjects had an established history of COPD and exacerbations, a pre-bronchodilator FEV1 <70% of predicted at trial entry, and 8.3% reversibility. The primary endpoint was the comparison of pre-bronchodilator FEV1 in the groups receiving fluticasone propionate/salmeterol DISKUS 500/50 mcg or placebo. Subjects treated with fluticasone propionate/salmeterol DISKUS 500/50 mcg had greater improvements in FEV1 (113 mL, 10%) compared with fluticasone propionate 500 mcg (7 mL, 2%), salmeterol (15 mL, 2%), and placebo (-60 mL, -3%).

Exacerbations

Two (2) trials were primarily designed to evaluate the effect of fluticasone propionate/salmeterol DISKUS 250/50 mcg on exacerbations. In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered severe if hospitalization was required.

Exacerbations were also evaluated as a secondary outcome in the 1- and 3-year trials with fluticasone propionate/salmeterol DISKUS 500/50 mcg. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with antibiotics and/or systemic corticosteroids (moderately severe) or requiring hospitalization (severe).

The 2 exacerbation trials with fluticasone propionate/salmeterol DISKUS 250/50 mcg were identical trials designed to evaluate the effect of fluticasone propionate/salmeterol DISKUS 250/50 mcg and salmeterol 50 mcg, each given twice daily, on exacerbations of COPD over a 12-month period. A total of 1,579 subjects had an established history of COPD (but no other significant respiratory disorders). Subjects had a pre-bronchodilator FEV1 of 33% of predicted, a mean reversibility of 23% at baseline, and a history of ≥1 COPD exacerbation in the previous year that was moderate or severe. All subjects were treated with fluticasone propionate/salmeterol DISKUS 250/50 mcg twice daily during a 4-week run-in period prior to being assigned trial treatment with twice-daily fluticasone propionate/salmeterol DISKUS 250/50 mcg or salmeterol 50 mcg. In both trials, treatment with fluticasone propionate/salmeterol DISKUS 250/50 mcg resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (30.5% reduction [95% CI: 17.0, 41.8], P<0.001) in the first trial and (30.4% reduction [95% CI: 16.9, 41.7], P<0.001) in the second trial. Subjects treated with fluticasone propionate/salmeterol DISKUS 250/50 mcg also had a significantly lower annual rate of exacerbations requiring treatment with oral corticosteroids compared with subjects treated with salmeterol (39.7% reduction [95% CI: 22.8, 52.9], P<0.001) in the first trial and (34.3% reduction [95% CI: 18.6, 47.0], P<0.001) in the second trial. Secondary endpoints including pulmonary function and symptom scores improved more in subjects treated with fluticasone propionate/salmeterol DISKUS 250/50 mcg than with salmeterol 50 mcg in both trials.

Exacerbations were evaluated in the 1- and the 3-year trials with fluticasone propionate/salmeterol DISKUS 500/50 mcg as 1 of the secondary efficacy endpoints. In the 1-year trial, the group receiving fluticasone propionate/salmeterol DISKUS 500/50 mcg had a significantly lower rate of moderate and severe exacerbations compared with placebo (25.4% reduction compared with placebo [95% CI: 13.5, 35.7]) but not when compared with its components (7.5% reduction compared with fluticasone propionate [95% CI: -7.3, 20.3] and 7% reduction compared with salmeterol [95% CI: -8.0, 19.9]). In the 3-year trial, the group receiving fluticasone propionate/salmeterol DISKUS 500/50 mcg had a significantly lower rate of moderate and severe exacerbations compared with each of the other treatment groups (25.1% reduction compared with placebo [95% CI: 18.6, 31.1], 9.0% reduction compared with fluticasone propionate [95% CI: 1.2, 16.2], and 12.2% reduction compared with salmeterol [95% CI: 4.6, 19.2]).

There were no trials conducted to directly compare the efficacy of fluticasone propionate/salmeterol DISKUS 250/50 mcg with fluticasone propionate/salmeterol DISKUS 500/50 mcg on exacerbations. Across trials, the reduction in exacerbations seen with fluticasone propionate/salmeterol DISKUS 500/50 mcg was not greater than the reduction in exacerbations seen with fluticasone propionate/salmeterol DISKUS 250/50 mcg.

Survival

A 3-year multicenter, international trial evaluated the efficacy of fluticasone propionate/salmeterol DISKUS 500/50 mcg compared with fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo on survival in 6,112 subjects with COPD. During the trial subjects were permitted usual COPD therapy with the exception of other ICS and long-acting bronchodilators. The subjects were aged 40 to 80 years with an established history of COPD, a pre- bronchodilator FEV1 <60% of predicted at trial entry, and <10% of predicted reversibility. Each subject who withdrew from double-blind treatment for any reason was followed for the full 3-year trial period to determine survival status. The primary efficacy endpoint was all-cause mortality. Survival with fluticasone propionate/salmeterol DISKUS 500/50 mcg was not significantly improved compared with placebo or the individual components (all-cause mortality rate 12.6% fluticasone propionate/salmeterol DISKUS versus 15.2% placebo). The rates for all-cause mortality were 13.5% and 16.0% in the groups treated with salmeterol 50 mcg and fluticasone propionate 500 mcg, respectively. Secondary outcomes, including pulmonary function (post- bronchodilator FEV1), improved with fluticasone propionate/salmeterol DISKUS 500/50 mcg, salmeterol 50 mcg, and fluticasone propionate 500 mcg compared with placebo.

SPL PATIENT PACKAGE INSERT SECTION

Fluticasone Propionate/Salmeterol DISKUS combines the inhaled corticosteroid (ICS) medicine fluticasone propionate and the long-acting beta2-adrenergic agonist (LABA) medicine salmeterol.

ICS medicines such as fluticasone propionate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems.

LABA medicines such as salmeterol help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.

**Fluticasone Propionate/Salmeterol DISKUS is not used to relieve sudden breathing problems** and will not replace a rescue inhaler.

It is not known if Fluticasone Propionate/Salmeterol DISKUS is safe and effective in children younger than 4 years.

Fluticasone Propionate/Salmeterol DISKUS is used for asthma and chronic obstructive pulmonary disease (COPD) as follows:
**Asthma:**

Fluticasone Propionate/Salmeterol DISKUS is a prescription medicine used to control symptoms of asthma and to prevent symptoms such as wheezing in adults and children aged 4 years and older.

Fluticasone Propionate/Salmeterol DISKUS contains salmeterol, the same medicine found in SEREVENT DISKUS (salmeterol xinafoate inhalation powder). LABA medicines such as salmeterol when used alone increase the risk of hospitalizations and death from asthma problems. Fluticasone Propionate/Salmeterol DISKUS contains an ICS and a LABA. When an ICS and LABA are used together, there is not a significant increased risk in hospitalizations and death from asthma problems.

Fluticasone Propionate/Salmeterol DISKUS is not for adults and children with asthma who are well controlled with an asthma control medicine, such as a low to medium dose of an ICS medicine. Fluticasone Propionate/Salmeterol DISKUS is for adults and children with asthma who need both an ICS and LABA medicine.
**COPD:**
Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg is a prescription medicine used to treat COPD. COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both. Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg is used long term as 1 inhalation 2 times each day to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days).

to relieve sudden breathing problems.

as a rescue inhaler.

if you have a severe allergy to milk proteins. Ask your healthcare provider if you are not sure.

if you are allergic to fluticasone propionate, salmeterol, or any of the ingredients in Fluticasone Propionate/Salmeterol DISKUS. See the end of this Patient Information for a complete list of ingredients in Fluticasone Propionate/Salmeterol DISKUS.

have heart problems.

have high blood pressure.

have seizures.

have thyroid problems.

have diabetes.

have liver problems.

have weak bones (osteoporosis).

have an immune system problem.

have or have had eye problems such as glaucoma, increased pressure in your eye, cataracts, or other changes in vision.

are allergic to milk proteins.

have any type of viral, bacterial, or fungal infection.

are exposed to chickenpox or measles.

are pregnant or plan to become pregnant. It is not known if Fluticasone Propionate/Salmeterol DISKUS may harm your unborn baby.

are breastfeeding. It is not known if the medicines in Fluticasone Propionate/Salmeterol DISKUS pass into your milk and if they can harm your baby.

**Do not** use Fluticasone Propionate/Salmeterol DISKUS unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.

Children should use Fluticasone Propionate/Salmeterol DISKUS with an adult’s help, as instructed by the child’s healthcare provider.

Fluticasone Propionate/Salmeterol DISKUS comes in 3 different strengths. Your healthcare provider prescribed the strength that is best for you.

Use Fluticasone Propionate/Salmeterol DISKUS exactly as your healthcare provider tells you to use it.**Do not** use Fluticasone Propionate/Salmeterol DISKUS more often than prescribed.

Use 1 inhalation of Fluticasone Propionate/Salmeterol DISKUS 2 times each day. Use Fluticasone Propionate/Salmeterol DISKUS at the same time each day, about 12 hours apart. 

If you miss a dose of Fluticasone Propionate/Salmeterol DISKUS, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at 1 time.

If you take too much Fluticasone Propionate/Salmeterol DISKUS, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.

**Do not use other medicines that contain a LABA for any reason.** Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines.

**Do not stop** using Fluticasone Propionate/Salmeterol DISKUS, even if you are feeling better, unless your healthcare provider tells you to.

**Fluticasone Propionate/Salmeterol DISKUS does not relieve sudden breathing problems.** Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.

Rinse your mouth with water**without swallowing** after each dose of Fluticasone Propionate/Salmeterol DISKUS. This will help lessen the chance of getting a yeast infection (thrush) in your mouth and throat.

Call your healthcare provider or get medical care right away if:

your breathing problems get worse.

you need to use your rescue inhaler more often than usual.

your rescue inhaler does not work as well to relieve your symptoms.

you need to use 4 or more inhalations of your rescue inhaler in 24 hours for 2 or more days in a row.

you use 1 whole canister of your rescue inhaler in 8 weeks.

your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you. 

you have asthma and your symptoms do not improve after using Fluticasone Propionate/Salmeterol DISKUS regularly for 1 week. 

**fungal infection in your mouth or throat (thrush).** Rinse your mouth with water**without swallowing** after using Fluticasone Propionate/Salmeterol DISKUS to help reduce your chance of getting thrush.

**pneumonia.** People with COPD have a higher chance of getting pneumonia. Fluticasone Propionate/Salmeterol DISKUS may increase the chance of you getting pneumonia. Call your healthcare provider right away if you have any of the following symptoms:

increase in mucus (sputum) production

change in mucus color

fever

chills

increased cough

increased breathing problems

**weakened immune system and increased chance of getting infections (immunosuppression).**

**reduced adrenal function (adrenal insufficiency).** Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an inhaled steroid (such as Fluticasone Propionate/Salmeterol DISKUS). During this transition period, when your body is under stress such as from fever, trauma (such as a car accident), infection, surgery, or worse COPD symptoms, adrenal insufficiency can get worse and may cause death.  

feeling tired

lack of energy

weakness

nausea and vomiting

low blood pressure (hypotension)

**sudden breathing problems immediately after inhaling your medicine.** If you have sudden breathing problems immediately after inhaling your medicine, stop using Fluticasone Propionate/Salmeterol DISKUS and call your healthcare provider right away.

**serious allergic reactions.** Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction:

rash

hives

swelling of your face, mouth, and tongue

breathing problems

**effects on heart.**

increased blood pressure

a fast or irregular heartbeat

chest pain

**effects on nervous system.**

tremor

nervousness

**bone thinning or weakness (osteoporosis).**

**slowed growth in children.** Your child’s growth should be checked regularly by the healthcare provider while using Fluticasone Propionate/Salmeterol DISKUS.

**eye problems**including glaucoma, increased pressure in your eye, cataracts, or other changes in vision. You should have regular eye exams while using Fluticasone Propionate/Salmeterol DISKUS.

**changes in laboratory blood levels (sugar, potassium, certain types of white blood cells).**

upper respiratory tract infection

throat irritation 

hoarseness and voice changes

thrush in your mouth or throat. Rinse your mouth with water without swallowing after use to help prevent this.

bronchitis

cough

headache 

nausea and vomiting

thrush in your mouth or throat. Rinse your mouth with water without swallowing after use to help prevent this.

throat irritation

hoarseness and voice changes

viral respiratory infections 

headache 

muscle and bone pain

Store Fluticasone Propionate/Salmeterol DISKUS at room temperature between 68°F and 77°F (20°C and 25°C). Keep in a dry place away from heat and sunlight.

Store Fluticasone Propionate/Salmeterol DISKUS in the unopened foil pouch and only open when ready for use.

Safely throw away Fluticasone Propionate/Salmeterol DISKUS in the trash 1 month after you open the foil pouch or when the counter reads**0**, whichever comes first.

INSTRUCTIONS FOR USE SECTION

**Figure A**

**Fluticasone Propionate/Salmeterol DISKUS is for oral inhalation use only.**

Take Fluticasone Propionate/Salmeterol DISKUS out of the foil pouch just before you use it for the first time. Safely throw away the pouch. The DISKUS will be in the closed position.

Write the date you opened the foil pouch in the first blank line on the label.**See Figure A.**

Write the “use by” date in the second blank line on the label.**See Figure A.** That date is 1 month after the date you wrote in the first line.

The counter should read**60**.

Hold the DISKUS in your left hand and place the thumb of your right hand in the thumb grip. Push the thumb grip away from you as far as it will go until the mouthpiece shows and snaps into place.**See Figure B**.

**Hold the DISKUS in a level, flat position** with the mouthpiece towards you. Slide the lever away from the mouthpiece as far as it will go until it**clicks**.**See Figure C.**

**Figure B**

The number on the counter will count down by 1. The DISKUS is now ready to use.

**Do not** close the DISKUS.

**Do not** tilt the DISKUS.

**Do not** move the lever on the DISKUS.

Before you breathe in your dose from the DISKUS, breathe out (exhale) as long as you can while you hold the DISKUS level and away from your mouth.**See Figure D.** Do not breathe into the mouthpiece.

Put the mouthpiece to your lips.**See Figure E.** Breathe in quickly and deeply through the DISKUS. Do not breathe in through your nose.

Remove the DISKUS from your mouth**and hold your breath for about 10 seconds,** or for as long as is comfortable for you. 

**Breathe out slowly as long as you can. See Figure D.**

The DISKUS delivers your dose of medicine as a very fine powder that you may or may not taste or feel.**Do not** take an extra dose from the DISKUS even if you do not taste or feel the medicine. 

Place your thumb in the thumb grip and slide it back towards you as far as it will go.**See Figure F.** Make sure the DISKUS clicks shut and you cannot see the mouthpiece.

The DISKUS is now ready for you to take your next scheduled dose in about 12 hours.**When you are ready to take your next dose, repeat Steps 1 through 4.**

**Rinse your mouth with water after breathing in the medicine.** Spit out the water. Do not swallow it.**See Figure G.**

**Figure G**
**When should you get a refill?**

**Figure H**
**For correct use of the DISKUS, remember:**

Always use the DISKUS in a level, flat position.

Make sure the lever firmly clicks into place.

Hold your breath for about 10 seconds after inhaling. Then breathe out fully.

After each dose, rinse your mouth with water and spit it out. Do not swallow the water.

**Do not** take an extra dose, even if you did not taste or feel the powder.

**Do not** take the DISKUS apart.

**Do not** wash the DISKUS.

Always keep the DISKUS in a dry place.

**Do not** use the DISKUS with a spacer device.
For more information about Fluticasone Propionate/Salmeterol DISKUS, call 1-866-525-0688. 
Trademarks are owned by or licensed to the GSK group of companies.
Manufactured for:
**Prasco Laboratories**
Mason, OH 45040 USA
Manufactured by:
GlaxoSmithKline
Durham, NC 27701
©2023 GSK group of companies or its licensor.
ADD-PS:6IFU