Breztri Aerosphere (Aerosol) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca Dunkerque Production (France)

ATC Code

R03AL11 (Formoterol, glycopyrronium bromide, and budesonide)

Active Substances

Budesonide (Rec.INN registered by WHO)

Formoterol (Rec.INN registered by WHO)

Glycopyrronium bromide (Rec.INN registered by WHO)

Dosage Form

Breztri Aerosphere

Metered dose inhalation aerosol 160 mcg+7.2 mcg+5 mcg/1 dose: 10.7 g inhaler (120 doses)

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol white in color.

Excipients: porous particles (1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride), norflurane (HFA-134a).

10.7 g (120 doses) – inhalers (1) – laminated aluminum foil bags (1) – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator combination drug (selective beta₂-adrenergic agonist + m-cholinoreceptor blocker + glucocorticosteroid)

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergic agents for inhalation administration; adrenergic agents in combination with anticholinergic agents, including triple combinations with glucocorticoids

Pharmacological Action

Combined bronchodilator agent. Budesonide and formoterol have different mechanisms of action and exhibit an additive effect in reducing the frequency of exacerbations of bronchial asthma and COPD.

The specific properties of budesonide and formoterol allow their combination to be used simultaneously as maintenance therapy and for relieving attacks, or as maintenance therapy for bronchial asthma.

Budesonide is a glucocorticosteroid (GCS) that, after inhalation, exerts a rapid (within a few hours) and dose-dependent anti-inflammatory effect on the airways, reducing the severity of symptoms and the frequency of bronchial asthma exacerbations. When inhaled budesonide is prescribed, a lower incidence of serious adverse effects is observed compared to the use of systemic GCS. It reduces the severity of bronchial mucosal edema, mucus production, sputum formation, and airway hyperreactivity. The exact mechanism of the anti-inflammatory action of GCS is unknown.

Formoterol is a selective beta₂-adrenergic receptor agonist that, after inhalation, causes rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The dose-dependent bronchodilatory effect occurs rapidly, within 1-3 minutes after inhalation, and lasts for at least 12 hours after a single dose.

The addition of formoterol to budesonide reduces the severity of bronchial asthma symptoms, improves bronchial function, and reduces the frequency of disease exacerbations. The effect of this fixed combination on bronchial function corresponds to the effect of the combination of single-agent budesonide and formoterol and exceeds the effect of budesonide alone. In all cases, a short-acting beta₂-agonist was used to relieve attacks. No reduction in the anti-asthmatic effect over time was observed. The combination is characterized by good tolerability.

Glycopyrronium bromide is a bronchodilating agent, an m-cholinergic blocker. The mechanism of action is based on blocking the action of acetylcholine on airway smooth muscle cells, leading to a bronchodilatory effect. Glycopyrronium bromide, being an m-cholinergic blocker, has high affinity for m-cholinergic receptors of subtypes M1-3. Furthermore, glycopyrronium bromide has 4-5 times greater selectivity for M1 and M3 receptor subtypes compared to the M2 receptor subtype.

Pharmacokinetics

Budesonide and formoterol

There is no evidence of pharmacokinetic interaction between budesonide and formoterol.

Pharmacokinetic parameters for the respective substances are comparable after administration of budesonide and formoterol as single agents and as part of this combination. When administered as part of the combination, the AUC of budesonide is somewhat larger, absorption occurs faster, and the C_max in plasma is higher. The C_max of formoterol in plasma when administered as part of the combination coincides with that of the single agent.

Inhaled budesonide is rapidly absorbed and reaches C_max in plasma 30 minutes after inhalation. The average dose of budesonide reaching the lungs after inhalation is 32-44% of the delivered dose. Systemic bioavailability is approximately 49% of the delivered dose.

Inhaled formoterol is rapidly absorbed and reaches C_max in plasma 10 minutes after inhalation. The average dose of formoterol reaching the lungs after inhalation is 28-49% of the delivered dose. Systemic bioavailability is about 61% of the delivered dose.

Plasma protein binding of formoterol is 50%, budesonide – 90%. The V_d of formoterol is about 4 L/kg, budesonide – 3 L/kg.

Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed, mainly as inactivated conjugates). Budesonide undergoes intensive biotransformation (about 90%) during first-pass metabolism in the liver, forming metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6-β-hydroxybudesonide and 16-α-hydroxyprednisolone, does not exceed 1% of the activity of budesonide. There is no evidence of metabolite interaction or substitution reaction between budesonide and formoterol.

The main part of the formoterol dose is metabolized in the liver and then excreted by the kidneys. After inhalation, 8-13% of the delivered dose of formoterol is excreted unchanged in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min); T_1/2 of the drug averages 17 hours.

Budesonide is metabolized primarily by the CYP3A4 enzyme. Budesonide metabolites are excreted in the urine unchanged or as conjugates. Only a small amount of unchanged budesonide is found in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min).

Glycopyrronium bromide

After inhalation of glycopyrronium, pulmonary bioavailability was 10.5% (with activated charcoal intake), while its absolute bioavailability was 12.8% (without activated charcoal intake), confirming limited absorption of swallowed glycopyrronium from the gastrointestinal tract and showing that more than 80% of the systemic exposure to glycopyrronium is associated with its absorption in the lungs. With repeated inhalations of glycopyrronium in doses from 12.5 to 50 mcg twice daily via a metered-dose aerosol inhaler in patients with COPD, glycopyrronium showed linear pharmacokinetics with slight systemic accumulation at steady-state (median accumulation ratio 2.2-2.5).

The V_d of glycopyrronium bromide upon inhalation is 6420 L.

The metabolism of glycopyrronium bromide in vitro (liver microsomes and hepatocytes of humans, dogs, rats, mice, and rabbits) was comparable across species, and the main metabolic reaction was hydroxylation on the phenyl or cyclopentyl rings. CYP2D6 was found to be the only enzyme involved in the metabolism of glycopyrronium bromide.

The mean T_1/2 of glycopyrronium bromide upon inhalation at steady-state in patients with COPD ranged from 5 to 12 hours. In patients with COPD receiving repeated glycopyrronium inhalations twice daily, the percentage of the dose excreted in the urine at steady-state was from 13% to 14.5%. Mean renal clearance values were comparable across the entire range of tested doses, as well as after single and repeated inhalations (range of renal clearance fluctuations 281-396 mL/min).

Indications

As maintenance therapy for moderate to severe COPD in adult patients in whom adequate disease control has not been achieved with therapy combining an inhaled GCS and a long-acting beta₂-agonist or a combination of a long-acting beta₂-agonist and a long-acting m-cholinergic receptor antagonist.

To facilitate breathing, reduce the severity of COPD symptoms, and reduce the frequency and severity of disease exacerbations.

ICD codes

Dosage Regimen

Inhale the contents of two puffs from the inhaler twice daily, in the morning and in the evening.

This is the maximum recommended dosage; do not exceed two inhalations twice daily.

Ensure a minimum interval of approximately 12 hours between doses.

This medication is for maintenance treatment of COPD and is not indicated for relief of acute bronchospasm.

Always have a short-acting bronchodilator available for immediate relief of acute symptoms.

Rinse your mouth with water after each inhalation to reduce the risk of oropharyngeal candidiasis.

Do not stop therapy abruptly; dose reduction must be supervised by a physician.

If a previously effective dosage regimen fails to provide adequate relief, seek immediate medical attention.

Adverse Reactions

Nervous system disorders common – headache; uncommon – psychomotor agitation, anxiety, nausea, dizziness, sleep disorders; very rare – depression, behavioral disorders, taste disturbances.

Gastrointestinal disorders common – dry mouth, gastroenteritis, vomiting; uncommon – dyspepsia, dental caries.

Cardiovascular disorders common – palpitations; uncommon – tachycardia; rare – atrial fibrillation, supraventricular tachycardia, extrasystole; very rare – angina pectoris, blood pressure fluctuations.

Respiratory, thoracic and mediastinal disorders common – candidiasis of the oral mucosa and pharynx, mild throat irritation, cough, hoarseness, nasopharyngitis; uncommon – rhinitis, sinus congestion, productive cough, pharyngeal irritation, epistaxis; rare – bronchospasm.

Skin and subcutaneous tissue disorders: uncommon – skin rash.

Allergic reactions rare – urticaria.

Metabolism and nutrition disorders: very rare – hyperglycemia, symptoms of systemic action of GCS (including adrenal hypofunction).

Renal and urinary disorders common – urinary tract infection; uncommon – cystitis, dysuria, urinary retention.

Musculoskeletal and connective tissue disorders common – muscle pain; uncommon – limb pain, pain in skeletal muscles of the chest.

General disorders and administration site conditions uncommon – fatigue, asthenia.

Systemic effects of inhaled GCS may be observed when taking the drug in high doses for a prolonged period.

The use of beta₂-adrenergic agonists may lead to an increase in blood levels of insulin, free fatty acids, glycerol, and ketone derivatives.

Contraindications

Hypersensitivity to budesonide, formoterol, glycopyrronium bromide; childhood and adolescence under 18 years of age.

With caution

Pulmonary tuberculosis (active or inactive form), fungal, viral, or bacterial respiratory tract infections, thyrotoxicosis, pheochromocytoma, diabetes mellitus, uncontrolled hypokalemia, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm of any location or other severe cardiovascular diseases (coronary artery disease, tachyarrhythmia or severe heart failure), QT interval prolongation, thyroid dysfunction, closed-angle glaucoma, urinary retention, benign prostatic hyperplasia, impaired liver function, impaired renal function.

Use in Pregnancy and Lactation

During pregnancy, the budesonide/formoterol combination should be used only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus. Budesonide should be used at the minimum effective dose necessary to maintain adequate control of bronchial asthma symptoms.

Inhaled budesonide is excreted in breast milk, but no effects on the child have been observed when used at therapeutic doses. It is not known whether formoterol is excreted in human breast milk. The budesonide/formoterol combination can be prescribed to nursing women only if the expected benefit for the mother outweighs any possible risk to the child.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pediatric Use

Should not be used in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients. Dose adjustment is not required.

Special Precautions

It is recommended to gradually reduce the dose before discontinuing treatment. Abrupt withdrawal of treatment is not recommended.

The budesonide/formoterol combination is not used for initial therapy selection in the early stages of bronchial asthma treatment.

Taking formoterol may cause QT interval prolongation.

An increase in the frequency of use of bronchodilators as emergency medications indicates a worsening of the underlying disease and is a reason to review the treatment strategy for bronchial asthma. Unexpected and progressive worsening of bronchial asthma or COPD symptom control is a potentially life-threatening condition and requires urgent medical intervention. In this situation, the possibility of increasing the dose of GCS or adding systemic anti-inflammatory therapy, such as a course of oral GCS or antibiotic treatment in case of infection, should be considered. Patients are advised to always carry emergency medications (short-acting beta₂-agonists) with them.

Patients should be informed of the need to regularly take the drug containing the budesonide/formoterol combination according to the selected dose, even in the absence of disease symptoms.

Treatment should not be started during an exacerbation or significant worsening of bronchial asthma.

As with any other inhalation therapy, paradoxical bronchospasm with immediate worsening of wheezing after taking a dose of the combination drug may occur. Therefore, therapy should be discontinued, the treatment strategy reviewed, and, if necessary, alternative therapy prescribed.

Systemic effects may occur with the use of any inhaled GCS, especially when taking drugs in high doses over a long period of time. The manifestation of systemic effects is less likely with inhalation therapy than with the use of oral GCS. Possible systemic effects include adrenal suppression, decreased bone mineral density, cataracts, and glaucoma.

Due to the potential effect of inhaled GCS on bone mineral density, special attention should be paid to patients taking high doses of the drug for a long period with risk factors for osteoporosis. Long-term studies of inhaled budesonide use in children at an average daily dose of 400 mcg (metered dose) or in adults at a daily dose of 800 mcg (metered dose) did not show a significant effect on bone mineral density.

If there is reason to believe that adrenal function was impaired during previous systemic GCS therapy, precautions should be taken when transferring patients to treatment with the budesonide/formoterol combination.

The benefits of inhalation therapy with budesonide generally minimize the need for oral steroids; however, in patients discontinuing oral GCS therapy, insufficient adrenal function may persist for a long time. Patients who previously required emergency high-dose GCS or received long-term treatment with high-dose inhaled GCS may also be in this risk group. Additional GCS administration should be considered during periods of stress or surgery.

The need for and dose of inhaled GCS should be reviewed in patients with active or inactive forms of pulmonary tuberculosis, fungal, viral, or bacterial respiratory tract infections.

When beta₂-adrenergic agonists are co-administered with drugs that may cause or enhance the hypokalemic effect, such as xanthine derivatives, steroids, or diuretics, the hypokalemic effect of beta₂-adrenergic agonists may be enhanced.

Special precautions should be observed in patients with unstable bronchial asthma using short-acting bronchodilators to relieve attacks during severe asthma exacerbations, as the risk of hypokalemia increases against the background of hypoxia and under other conditions where the likelihood of the hypokalemic effect manifestation increases. In such cases, it is recommended to monitor serum potassium levels.

Blood glucose concentration should be monitored in patients with diabetes mellitus during treatment.

Effect on ability to drive vehicles and operate machinery

The budesonide/formoterol combination may have a minor influence when adverse effects manifest. Caution should be exercised when driving vehicles and operating machinery during treatment.

Drug Interactions

Taking ketoconazole at a dose of 200 mg once daily increases the plasma concentration of orally administered budesonide (single dose 3 mg) when co-administered, on average, by 6 times. When ketoconazole was administered 12 hours after budesonide intake, the plasma concentration of the latter increased, on average, by 3 times. Information on such interaction with budesonide upon its inhalation is lacking, but a significant increase in the drug’s plasma concentration should be expected. Since data for dose adjustment recommendations are lacking, the above combination of drugs should be avoided. If possible, the time intervals between ketoconazole and budesonide administration should be maximized. The possibility of reducing the budesonide dose should also be considered. Other potent CYP3A4 inhibitors are also likely to significantly increase the plasma concentration of budesonide.

Beta-2-adrenergic receptor blockers can reduce the intensity of formoterol’s action. The formoterol + budesonide combination should not be prescribed concurrently with beta-blockers (including eye drops), except in forced cases.

Concomitant administration of the formoterol + budesonide combination and quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAO inhibitors, tricyclic antidepressants may prolong the QT interval and increase the risk of ventricular arrhythmias.

In addition, levodopa, levothyroxine, oxytocin, and alcohol may reduce the tolerance of the heart muscle to beta-2-adrenergic agonists.

Simultaneous use of MAO inhibitors, as well as drugs with similar properties, such as furazolidone and procarbazine, may cause an increase in blood pressure. There is an increased risk of arrhythmias in patients undergoing general anesthesia with halogenated hydrocarbon agents.

When using the budesonide/formoterol combination and other beta-adrenergic drugs simultaneously, it is possible to enhance the side effects of formoterol. As a result of the use of beta-2-adrenergic agonists, hypokalemia may develop, which may be enhanced by concomitant treatment with xanthine derivatives, corticosteroids, or diuretics. Hypokalemia may increase the predisposition to develop arrhythmias in patients taking cardiac glycosides.

Glycopyrronium bromide is primarily excreted through the kidneys, so drug interactions with drugs that impair renal excretion mechanisms are potentially possible. The effect of inhibiting organic cation transport in the kidneys (using cimetidine as a probing inhibitor of the OCT2 and MATE1 organic cation transporter proteins) during inhaled administration of glycopyrronium bromide showed a limited increase in its overall systemic exposure ( AUC_0-t) by 16% and a small reduction in renal clearance by 20% with concurrent cimetidine intake.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.