Budesonide and Formoterol Fumarate Dihydrate

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE- budesonide and formoterol fumarate aerosol
RPK Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Treatment of Asthma

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is indicated for the treatment of asthma in patients 6 years of age and older.

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 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 inhaled corticosteroid and long-acting beta2-adrenergic agonist (LABA).

Important Limitations of Use:

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is NOT indicated for the relief of acute bronchospasm.

1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5 is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5 is also indicated to reduce exacerbations of COPD. BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5 is the only strength indicated for the treatment of COPD.

Important Limitations of Use:

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is NOT indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION

2.1 Administration Information

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL should be administered as 2 inhalations twice daily (morning and evening, approximately 12 hours apart), every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing.

Prime BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL before using for the first time by releasing two test 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 7 days or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing two test sprays into the air away from the face.

More frequent administration or a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is not recommended as some patients are more likely to experience adverse effects with higher doses of formoterol. Patients using BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL should not use additional LABA for any reason [see Warnings and Precautions (5.3, 5.12)].

2.2 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 12 Years of Age and Older

For patients 12 years of age and older, the dosage is 2 inhalations of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 80/4.5 or BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5 twice daily.

The recommended starting dosages for BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL for patients 12 years of age and older are based upon patients’ asthma severity or level of control of asthma symptoms, and risk of exacerbations on current inhaled corticosteroids.

The maximum recommended dosage in adult and adolescent patients 12 years and older is BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5, two inhalations twice daily.

Improvement in asthma control following inhaled administration of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL can occur within 15 minutes of beginning treatment, although maximum benefit may not be achieved for 2 weeks or longer after beginning 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 dose after 1-2 weeks of therapy with BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 80/4.5, replacement with BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5 may provide additional asthma control.

If a previously effective dosage regimen of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, (e.g., replacing the lower strength of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL with the higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids) should be considered.

Pediatric Patients Aged 6 to Less than 12 Years

For patients 6 to less than 12 years of age, the dosage is 2 inhalations of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 80/4.5 twice daily.

2.3 Chronic Obstructive Pulmonary Disease

For patients with COPD the recommended dose is BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL 160/4.5, two inhalations twice daily.

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

BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is available as a metered-dose inhaler containing a combination of budesonide (80 or 160 mcg) and formoterol (4.5 mcg) as an inhalation aerosol in the following two strengths: 80/4.5 and 160/4.5. Each dosage strength contains 120 actuations per/canister. Each strength of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL is supplied with a red plastic actuator with a gray dust cap.

4 CONTRAINDICATIONS

The use of budesonide and formoterol fumarate dihydrate is contraindicated in the following conditions:

Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
Hypersensitivity to any of the ingredients in BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL.

5 WARNINGS AND PRECAUTIONS

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations and 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. 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 to ICS alone (see Serious Asthma-Related Events with ICS/LABA).

Serious Asthma-Related Events with ICS/LABA

Four large, 26-week, randomized, blinded, 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 to ICS alone in patients with asthma. Three trials included adult and adolescent patients aged ≥12 years: one trial compared budesonide/formoterol (budesonide and formoterol fumarate dihydrate) to budesonide [see Clinical Studies (14.1)] ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death). A blinded adjudication committee determined whether events were asthma-related.

The three 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 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 three 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 Patients with Asthma Aged 12 Years and Older
*
Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis.
Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials.
Number of patients 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. Patients 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)*

ICS

(N = 17,552)*

ICS/LABA vs ICS

Hazard ratio (95% CI)

Serious asthma-related event

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

The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate /salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and 21/3101 (0.7%) patients 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 to 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 patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients 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.

Formoterol Monotherapy Studies

Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups.

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