ADVAIR DISKUS

ADVAIR DISKUS- salmeterol xinafoate and fluticasone propionate powder
GlaxoSmithKline LLC

1 INDICATIONS AND USAGE

1.1 Treatment of Asthma

ADVAIR DISKUS is indicated for the twice-daily treatment of asthma in patients aged 4 years and older. ADVAIR DISKUS should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta2 -adrenergic agonist (LABA).

Important Limitation of Use

ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.

1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease

ADVAIR DISKUS 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. ADVAIR DISKUS 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. ADVAIR DISKUS 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength ADVAIR DISKUS 500/50 over ADVAIR DISKUS 250/50 has not been demonstrated.

Important Limitation of Use

ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION

ADVAIR DISKUS should be administered as 1 inhalation twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of ADVAIR DISKUS is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using ADVAIR DISKUS should not use additional LABA for any reason. [See Warnings and Precautions (5.3, 5.12).]

2.1 Asthma

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2 -agonist should be taken for immediate relief.

Adult and Adolescent Patients Aged 12 Years and Older

For patients aged 12 years and older, the dosage is 1 inhalation twice daily, approximately 12 hours apart.

When choosing the starting dosage strength of ADVAIR DISKUS, consider the patients’ disease severity, based on their previous asthma therapy, including the ICS dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.

The maximum recommended dosage is ADVAIR DISKUS 500/50 twice daily.

Improvement in asthma control following inhaled administration of ADVAIR DISKUS can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of ADVAIR DISKUS with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of ADVAIR DISKUS with a higher strength, adding additional ICS, initiating oral corticosteroids) should be considered.

Pediatric Patients Aged 4 to 11 Years

For patients with asthma aged 4 to 11 years who are not controlled on an ICS, the dosage is 1 inhalation of ADVAIR DISKUS 100/50 twice daily, approximately 12 hours apart.

2.2 Chronic Obstructive Pulmonary Disease

The recommended dosage for patients with COPD is 1 inhalation of ADVAIR DISKUS 250/50 twice daily, approximately 12 hours apart.

If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2 -agonist should be taken for immediate relief.

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains a combination of fluticasone propionate 100, 250, or 500 mcg and salmeterol 50 mcg per blister.

4 CONTRAINDICATIONS

The use of ADVAIR DISKUS is contraindicated in the following conditions:

Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)].
Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients [see Warnings and Precautions (5.11), Adverse Reactions (6.3), Description (11)].

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 (ADVAIR DISKUS) 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.

Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older

ICS/LABA

(n = 17,537)a

ICS

(n = 17,552)a

ICS/LABA vs. ICS

Hazard Ratio (95% CI)b

Serious asthma-related eventc

116

105

1.10 (0.85, 1.44)

Asthma-related death

2

0

Asthma-related intubation (endotracheal)

1

2

Asthma-related hospitalization (≥24-hour stay)

115

105

ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2 -adrenergic Agonist.

a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis.

b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.

c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related.

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.

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