ADVAIR HFA

ADVAIR HFA- fluticasone propionate and salmeterol xinafoate aerosol, metered
GlaxoSmithKline LLC

1 INDICATIONS AND USAGE

ADVAIR HFA is indicated for treatment of asthma in adult and adolescent patients aged 12 years and older. ADVAIR HFA 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).

Limitations of Use

ADVAIR HFA is not indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION

2.1 Administration Information

ADVAIR HFA should be administered by the orally inhaled route only. After inhalation, rinse mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

Priming

Prime ADVAIR HFA before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray. Avoid spraying in eyes.

2.2 Recommended Dosage

Adult and adolescent patients aged 12 years and older: 2 oral inhalations twice daily, approximately 12 hours apart.

The maximum recommended dosage is 2 inhalations of ADVAIR HFA 230 mcg/21 mcg twice daily.

General Dosing Recommendation

When choosing the starting dosage strength of ADVAIR HFA, 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.

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

Improvement in asthma control following inhaled administration of ADVAIR HFA 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 HFA 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 HFA with a higher strength, adding additional ICS, initiating oral corticosteroids) should be considered.

More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of ADVAIR HFA is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using ADVAIR HFA should not use additional LABA for any reason. [See Warnings and Precautions (5.3, 5.12).]

3 DOSAGE FORMS AND STRENGTHS

Inhalation aerosol: purple plastic inhaler with a light purple cap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter.

45 mcg fluticasone propionate/21 mcg salmeterol from the mouthpiece per actuation
115 mg fluticasone propionate/21 mcg salmeterol from the mouthpiece per actuation
230 mg fluticasone propionate/21 mcg salmeterol from the mouthpiece per actuation

4 CONTRAINDICATIONS

ADVAIR HFA is contraindicated in the following conditions:

Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)].
Hypersensitivity to any of the ingredients [see Warnings and Precautions (5.11), Adverse Reactions (6.2), 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 with fluticasone propionate inhalation powder, 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. 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 = 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.

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

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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