Budesonide And Formoterol Fumarate Dihydrate

Introduction Overview

Generic Name

budesonide and formoterol fumarate dihydrate

Brand Name

Breyna

Dosage Form

metered-dose inhaler aerosol (oral inhalation)

Drug Class

Bronchodilator combinations (inhaled corticosteroid and long-acting beta2-adrenergic agonist)

Pharmacokinetics

Absorption

Budesonide is rapidly absorbed in the lungs after inhalation, reaching peak plasma concentrations within approximately 20 minutes. Oral administration of budesonide shows peak plasma concentration at 1 to 2 hours, but systemic availability is only 6%-13% due to extensive first-pass metabolism. Approximately 34% of the metered inhaled dose deposits in the lungs with systemic exposure at about 39% of the metered dose. Formoterol fumarate dihydrate is rapidly absorbed with peak plasma concentration achieved within 5 to 10 minutes post-inhalation, reflecting rapid pulmonary absorption; a portion of the dose is swallowed and absorbed via the gastrointestinal tract. Both compounds show proportional increases in plasma concentration with dose increments. In asthma and COPD patients, peak plasma concentrations for budesonide and formoterol occur within 15 to 30 minutes and 10 to 15 minutes respectively, with slight pharmacokinetic differences between populations noted but without clinically significant exposure changes.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg and is 85%-90% bound to plasma proteins, mainly albumin, without significant binding to corticosteroid-binding globulin. Formoterol exhibits plasma protein binding of about 46% for the RR and 58% for the SS enantiomers at concentrations above clinical plasma levels. Both drugs equilibrate readily with tissues but are primarily intended for local pulmonary effect.

Metabolism

Budesonide undergoes extensive hepatic metabolism primarily via cytochrome P450 3A4, producing inactive metabolites 16α-hydroxyprednisolone and 6β-hydroxybudesonide, which have less than 1% of the corticosteroid activity of the parent compound. Formoterol is metabolized through direct glucuronidation and O-demethylation primarily by CYP2D6 and CYP2C enzymes, converting it into inactive metabolites. No significant metabolic interaction occurs between the two components when co-administered.

Elimination

Budesonide metabolites are excreted primarily via urine (about 60%) and feces, with no unchanged budesonide detected in urine. The systemic clearance rate is approximately 1.4 L/min for the 22R epimer and 1.0 L/min for the 22S epimer. The elimination half-life is approximately 2 to 3 hours. Formoterol is eliminated mainly in urine (around 62%) and feces (24%). The elimination half-life supports twice-daily dosing. In hepatic impairment, elimination of both drugs may be reduced, requiring close monitoring.

Dosage Forms

Adults

For asthma in patients 12 years and older, recommended dosing is 2 inhalations of Breyna 80 mcg/4.5 mcg or 160 mcg/4.5 mcg twice daily, with the starting dose based on severity. The maximum is 2 inhalations of 160 mcg/4.5 mcg twice daily. For COPD maintenance treatment, dosing is 2 inhalations of Breyna 160 mcg/4.5 mcg twice daily. Breyna is not indicated for acute bronchospasm relief; short-acting beta2-agonists should be used for rescue therapy.

Adolescents

Safety and efficacy are established for adolescents aged 12 years and older with the same dosing as adults: 2 inhalations of Breyna 80 mcg/4.5 mcg or 160 mcg/4.5 mcg twice daily for asthma.

Special Populations

In pediatric patients aged 6 to less than 12 years, the recommended dose is 2 inhalations of Breyna 80 mcg/4.5 mcg twice daily for asthma. Safety and efficacy in children under 6 years have not been established. In geriatric patients, no dose adjustment is required but caution is advised in those with concomitant cardiovascular disease. Hepatic impairment may increase systemic exposure; such patients should be monitored closely. No specific dosage recommendations exist for renal impairment. Breyna should be tapered gradually when transferring from systemic corticosteroids to avoid adrenal insufficiency.

Mechanism Of Action

Breyna is a fixed-dose combination inhalation aerosol containing budesonide, an inhaled corticosteroid (ICS), and formoterol fumarate dihydrate, a long-acting beta2-adrenergic receptor agonist (LABA).

Budesonide acts as a potent anti-inflammatory agent by binding with high affinity to glucocorticoid receptors within airway epithelial and inflammatory cells. This receptor activation modulates gene expression, leading to the suppression of multiple inflammatory pathways, including inhibition of pro-inflammatory cytokines, reduction of mast cell, eosinophil, neutrophil, and lymphocyte infiltration, and decreased mediator release such as histamine and leukotrienes. These effects reduce airway inflammation, improve airway responsiveness, and limit chronic remodeling in asthma and COPD.

Formoterol selectively stimulates beta2-adrenergic receptors on bronchial smooth muscle, activating adenylate cyclase and increasing intracellular cyclic AMP concentrations. Elevated cAMP leads to relaxation of bronchial smooth muscle, resulting in bronchodilation. Formoterol also inhibits the release of mast cell mediators, such as histamine and leukotrienes, contributing to reduction in airway hyperresponsiveness. It has a rapid onset of action (within 5-15 minutes) and prolongs bronchodilation for approximately 12 hours, making it suitable for maintenance therapy.

The combination exploits complementary mechanisms: budesonide targets the inflammatory component, while formoterol provides symptomatic bronchodilation. This dual action improves lung function, reduces exacerbations, and offers superior efficacy compared to either component alone, as demonstrated in clinical studies. The combination also permits lower corticosteroid doses than monotherapy, reducing systemic side effects. Compared to other ICS/LABA combinations, budesonide and formoterol have a favorable balance of efficacy and safety, with rapid onset of action from formoterol and potent anti-inflammatory effects from budesonide.

Pharmacological Actions

Potent anti-inflammatory activity via glucocorticoid receptor agonism reducing airway inflammation.
Selective beta2-adrenergic receptor agonist action causing bronchial smooth muscle relaxation (bronchodilation).
Inhibition of mast cell mediator release (e.g., histamine, leukotrienes) decreasing airway hyperresponsiveness.
Improvement in lung function parameters, including forced expiratory volume (FEV1) and peak expiratory flow (PEF).
Reduction in frequency and severity of asthma and COPD exacerbations.
Suppression of immune cell infiltration into airway tissue.
Mediation of symptom relief including reduction of wheezing, shortness of breath, and chest tightness.
Maintenance therapy to prevent airflow obstruction and control chronic symptoms in asthma and COPD patients.

Therapeutic Clinical Uses

Maintenance treatment of asthma in patients aged 6 years and older who require both inhaled corticosteroid and long-acting beta2-agonist therapy.
Management of chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema to improve lung function and reduce exacerbations.
Prevention of asthma symptoms and control of airway inflammation.
Reduction in frequency and severity of COPD flare-ups.
Not indicated for acute relief of bronchospasm or sudden asthma attacks.

Side Or Adverse Effects

Oral and oropharyngeal candidiasis (thrush) – localized fungal infection in mouth and throat.
Nasopharyngitis – inflammation of nasal passages and pharynx.
Headache and dizziness.
Upper respiratory tract infections such as sinusitis and bronchitis.
Pharyngolaryngeal pain and throat irritation.
Back pain and muscle cramps.
Nasal congestion and sinusitis.
Gastrointestinal discomfort including nausea, stomach discomfort, and vomiting.
Potential increased risk of pneumonia in COPD patients.
Cardiovascular effects such as tachycardia, palpitations, arrhythmias, and increased blood pressure.
Hypokalemia (low blood potassium) and hyperglycemia (elevated blood sugar).
Reduced growth velocity in pediatric patients with prolonged corticosteroid use.
Glaucoma and cataracts with long-term inhaled corticosteroid use.
Hypersensitivity reactions including rash, angioedema, bronchospasm.
Paradoxical bronchospasm (worsening of breathing after inhalation).

Precautions

Do not use for acute bronchospasm or sudden relief of asthma or COPD symptoms; use a short-acting bronchodilator instead.
Monitor patients for signs of oropharyngeal candidiasis; advise rinsing mouth post-inhalation.
Use caution in patients with cardiovascular disorders due to beta2-agonist stimulation.
Monitor for pneumonia development in COPD patients.
Use cautiously in patients with active infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections.
Gradually taper systemic corticosteroids when transferring to Breyna to avoid adrenal insufficiency.
Monitor bone mineral density in patients at risk for osteoporosis during long-term corticosteroid use.
Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, or ketoacidosis.
Closely monitor pediatric patients for growth suppression and adjust dose to the lowest effective.
Exercise caution when co-administering with strong CYP3A4 inhibitors due to increased corticosteroid systemic exposure.
Avoid concurrent use with other long-acting beta2-agonists to prevent overdose and adverse effects.

Warnings

Increased risk of asthma-related hospitalizations and death with LABA monotherapy; combination with ICS reduces this risk but vigilance required.
Do not initiate Breyna during rapidly deteriorating or potentially life-threatening asthma or COPD episodes.
Excessive use or use with other LABA may cause serious cardiovascular adverse effects, including death.
Potential for paradoxical bronchospasm which may be life-threatening; discontinue immediately if it occurs.
Serious hypersensitivity reactions including anaphylaxis may occur.
Risk of adrenal suppression and hypercorticism, especially at high doses or during prolonged use.
Monitor for worsening of infections and immunosuppression-related complications.
Potential reduction in bone mineral density and increased risk of fractures.
Monitoring required for glaucoma and cataracts during prolonged corticosteroid use.
May cause hypokalemia and hyperglycemia; monitor electrolytes and blood glucose.
Patients should not stop medication abruptly without physician guidance to avoid exacerbations.

Contraindications

Primary treatment of status asthmaticus or acute episodes requiring intensive measures.
Known hypersensitivity to budesonide, formoterol fumarate dihydrate, or any excipients in Breyna.
Use of Breyna concomitantly with other long-acting beta2-agonist containing products.
Not to be used as rescue or acute relief medication for bronchospasm.

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase systemic exposure to budesonide, raising risk of corticosteroid side effects.
Monoamine oxidase inhibitors and tricyclic antidepressants may potentiate cardiovascular effects of formoterol; use with caution.
Beta-adrenergic blocking agents (beta-blockers), especially non-selective types, may reduce bronchodilator efficacy and cause severe bronchospasm; caution advised.
Non-potassium-sparing diuretics (e.g., loop or thiazide diuretics) may worsen hypokalemia associated with beta2-agonists; monitor electrolytes carefully.
No significant pharmacokinetic interactions observed between budesonide and formoterol themselves when co-administered.
Concurrent use with other inhaled corticosteroids or bronchodilators should be monitored for additive effects and side effects.

Preparations Of The Drug

Metered-dose inhaler (MDI) aerosol containing budesonide and formoterol fumarate dihydrate.
Available in two strengths: 80 mcg budesonide / 4.5 mcg formoterol per inhalation and 160 mcg budesonide / 4.5 mcg formoterol per inhalation.
Each canister contains 120 inhalations.
Delivered via HFA 227 propellant with povidone K25 USP and polyethylene glycol 1000 NF as inactive ingredients.
Provided with a blue plastic actuator and grey dust cap, supplied inside a foil pouch with desiccant.
Should be primed before first use and after 7 days of non-use or if dropped.
Should be stored upright at controlled room temperature (20° to 25°C).
Discard inhaler after labeled number of inhalations or three months after removal from foil pouch, whichever comes first.