Budesonide and formoterol: uses, appearance and warnings

BREYNA is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist indicated for: • Treatment of asthma in patients 6 years of age and older. ( 1.1 ) • Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. ( 1.2 ) Important limitations: • Not indicated for the relief of acute bronchospasm. ( 1.1 , 1.2 ) 1.1 Treatment of Asthma BREYNA is indicated for the treatment of asthma in patients 6 years of age and older. BREYNA 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 beta 2 -adrenergic agonist (LABA). Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease BREYNA 160 mcg/4.5 mcg is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. BREYNA 160 mcg/4.5 mcg is also indicated to reduce exacerbations of COPD. BREYNA 160 mcg/4.5 mcg is the only strength indicated for the treatment of COPD. Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm.

BREYNA is available as a metered-dose inhaler containing a combination of budesonide (80 mcg or 160 mcg) and formoterol fumarate dihydrate (4.5 mcg) as an inhalation aerosol in the following two strengths: 80 mcg/4.5 mcg and 160 mcg/4.5 mcg. Each dosage strength contains 120 actuations per/canister. Each strength of BREYNA is supplied with a blue plastic actuator with a grey dust cap. Metered-dose inhaler containing a combination of budesonide (80 mcg or 160 mcg) and formoterol fumarate dihydrate (4.5 mcg) as an inhalation aerosol. ( 3 )

BREYNA (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol is available in two strengths and is supplied in the following package sizes: Dosage Forms and Strengths Package Size NDC BREYNA Inhalations 80 mcg/4.5 mcg 120 0378-7502-32 BREYNA Inhalations 160 mcg/4.5 mcg 120 0378-7503-32 Each strength is supplied as a pressurized aluminum canister with an attached counting device, a blue plastic actuator body with a blue mouthpiece, and attached grey dust cap. Each 120 inhalation canister has a net fill weight of 10.3 grams. Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Patient Information leaflet. The BREYNA canister should only be used with the BREYNA actuator, and the BREYNA actuator should not be used with any other inhalation drug product. The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister (“float test”). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using. Keep out of the reach of children. Avoid spraying in eyes. CONTENTS UNDER PRESSURE. Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120ºF may cause bursting. Never throw container into fire or incinerator.

The use of BREYNA 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 BREYNA. • Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures ( 4 ) • Hypersensitivity to any of the ingredients in BREYNA ( 4 )

• Serious asthma-related events: Long-acting beta 2 -adrenergic agonists as monotherapy increase the risk. ( 5.1 ) • Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or COPD or to treat acute symptoms. ( 5.2 ) • Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose. ( 5.3 ) • Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Pneumonia: Increased risk in patients with COPD. Monitor patients for signs and symptoms of pneumonia and other potential lung infections. ( 5.5 ) • Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or 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 ) • Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to BREYNA. ( 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 BREYNA slowly. ( 5.8 ) • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with BREYNA. ( 5.9 ) • Paradoxical bronchospasm: Discontinue BREYNA and institute alternative therapy if paradoxical bronchospasm occurs. ( 5.10 ) • Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. ( 5.12 ) • Decreases in bone mineral density: Assess bone mineral density initially and periodically thereafter. ( 5.13 ) • Effects on growth: Monitor growth of pediatric patients. ( 5.14 ) • Glaucoma and cataracts: Close monitoring is warranted. ( 5.15 ) • Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.16 , 5.18 ) • Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.17 ) 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 inhalation aerosol) 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 ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist ICS/LABA (N = 17,537) Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. ICS (N = 17,552) ICS/LABA vs ICS Hazard Ratio (95% CI) Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials. Serious asthma-related event 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. …

LABA use 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 inhaled corticosteroid use may result in the following: • Candida albicans infection [see Warnings and Precautions (5.4) ] • Pneumonia or lower respiratory tract infections 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) ] • Growth effects in pediatric patients [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 dr …

In clinical studies, concurrent administration of budesonide and formoterol fumarate dihydrate inhalation aerosol and other drugs, such as short-acting beta 2 -agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with budesonide and formoterol fumarate dihydrate inhalation aerosol. • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. ( 7.1 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol on vascular system. ( 7.2 ) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) • Diuretics: Use with caution. …