Bretaris Januair, 322 mcg/dose 60 doses

Clinical efficacy studies have shown that Bretaris Jenaire’ provides clinically meaningful improvement in lung function (as measured by forced expiratory volume in one second [FEF1]) for more than 12 hours after morning and evening administration, which was evident within 30 minutes of the first dose (an increase in FEF1 from baseline of 124-133 ml). Maximum bronchodilation was achieved within 1-3 hours after the dose with an average peak of improvement in SPH1 relative to baseline of 227-268 ml at equilibrium.

Heart electrophysiology

When acolidinium bromide (200 mcg or 800 mcg) was administered to healthy volunteers once daily for 3 days, no effect on the QT interval (corrected by the Friedericia or Bazette method or individually) was observed.

There was also no clinically significant effect of Bretaris’ Januair on heart rate in 24-hour Holter monitoring in 336 patients (164 of whom received Bretaris Januair® twice daily at a dose of 322 mcg) after 3 months of using the drug.

Clinical efficacy

. The Bretaris® Januair® phase III clinical trial program included 269 patients treated with Bretaris® Januair® at a dose of 322 mcg twice daily in one 6-month placebo-controlled randomized trial and 190 patients treated with Bretaris® Januair® at a dose of 322 mcg twice daily in another 3-month placebo-controlled randomized trial. Efficacy was assessed for changes in lung function and clinical symptoms, such as dyspnea, diagnosis-related health status, use of emergency medications, and the presence of exacerbations. In long-term safety studies, Bretaris® Januair® demonstrated bronchodilator efficacy with a duration of use greater than 1 year.

Bronchodilatation

In a 6-month study, patients receiving Bretaris® Januair® at a dose of 322 mcg twice daily had clinically significant improvement in lung function (as measured by RHR]). The maximal bronchodilation effect was evident from day 1 and persisted throughout the 6-month therapy period of use. After 6 months of therapy, the mean improvement before morning dose (minimum) OEF] compared with placebo was 128 mL (95% CI=85-170; p

Similar observations were made for Bretaris® Genuair® during the 3-month study.

Disease-specific health status and symptomatic improvement

The Bretaris® Genuair® drug provided clinically meaningful improvement in dyspnea (assessed with the Transient Dyspnea Index [TDI]) and disease-specific health status (assessed with the St. George’s Hospital Respiratory Questionnaire [SGRQ]). The table below shows symptom reduction after 6 months of Bretaris® Januair®.

Variable

Treatment

Improvement compared to placebo

/p>

Value

P

Bretaris* ” _

” ” ® Placebo Januair

Transient dyspnea index

Percentage of patients with minimal clinically important difference3

/p>

56.9

45.5

1.68-fold increase in probability

0.004

Mean change from baseline

1.9

0.9

1.0 unit

St. George’s Hospital Respiratory Questionnaire. St. George’s Hospital Respiratory Questionnaire

Percentage of patients with minimal clinically important difference

57.3

41.0

1.87-fold

increase

probability

Average change from baseline

-7.4

-2.8

– 4.6 units

a) Minimum clinically important difference (MCID) of at least 1 unit change in Transient Dyspnea Index.

(b) Minimum clinically important difference (MCID) of at least 4 units of change on the St. George’s Hospital Respiratory Questionnaire.

c) Odds ratio, increased likelihood of achieving a Minimum Clinically Important Difference compared to placebo.

Patients who received Bretaris® Januair® required fewer emergency medications than patients who received placebo (0.95 fewer injections per day over 6 months [p=0.005]). Bretaris® Januair® also improved daytime COPD symptoms (dyspnea, cough, and sputum production) as well as nighttime and early morning clinical symptoms.

A pooled efficacy analysis of 6-month and 3-month placebo-controlled studies demonstrated a significant reduction in the incidence of moderate to severe exacerbations (requiring antibiotic or glucocorticosteroid therapy or leading to hospitalization) when taking 322 mcg acolidinium twice daily compared with placebo (incidence per patient per year: 0.31 vs 0.44, respectively; p=0.0149).

Performance tolerance

In a 3-week randomized, placebo-controlled crossover clinical trial, a statistically significant increase in exercise tolerance of 58 seconds was observed with Bretaris® Januair® compared to placebo (95% CI=9-108; p=0.021; pre-therapy values: 486 seconds).

A statistically significant reduction in excessive lung overstretch at rest was observed with Bretaris® Januair® (functional residual capacity [FOE]=0.197 L [95% CI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=:0.004]), and there was an improvement in minimum inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and a decrease in exercise dyspnea (Borg scale) (by 0.63 Borg units; 95% CI= 1.11, 0.14; p=0.012).

Intake

Aclidinium bromide is rapidly absorbed from the lungs, reaching maximum plasma concentration within 5 minutes of inhalation in healthy volunteers, and usually within the first 15 minutes in patients with COPD. The fraction of the inhaled dose that reaches systemic circulation as unchanged acolidinium is very low, less than 5%.

The maximum plasma concentration reached after inhalation of dry powder in patients with COPD at a single dose of 400 mcg acolidinium bromide was approximately 80 pg/mL. Equilibrium plasma concentrations were reached within 7 days when administered twice daily and, given the short elimination half-life, equilibrium concentrations could be reached soon after the first dose. No accumulation at equilibrium concentrations was observed with repeated dosing.

Distribution

The total amount of acolidinium bromide delivered to the lungs via the Bretaris Genuair inhaler was approximately 30% of the measured dose.

The in vitro binding of acledinium bromide to plasma proteins corresponds most likely to the binding of metabolites to proteins; due to the rapid hydrolysis of acledinium bromide in plasma, the binding to plasma proteins was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds acridinium bromide is albumin.

Biotransformation

Aklydinium bromide is rapidly and actively hydrolyzed to its pharmacologically inactive alcoholic derivatives and carboxylic acid derivatives. Both chemical hydrolysis (non-enzymatic) and enzymatic hydrolysis involving esterases take place. The main esterase involved in hydrolysis in humans is butyrylcholinesterase. The level of the acid metabolite in plasma after inhalation is about 100 times higher than the level of the alcohol metabolite and the unchanged active ingredient.

Low absolute bioavailability of acolidinium bromide by inhalation (

Biotransformation with the participation of cytochrome P450 isoenzymes (CYP450) plays a minor role in the total metabolic clearance of acolidinium bromide.

In vitro trials have shown that acolidinium bromide at therapeutic dose or its metabolites do not inhibit or induce any cytochrome P450 (CYP450) isoenzymes and do not inhibit esterase activity (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro tests have shown that acolidinium bromide or its metabolites are not substrates or inhibitors of P-glycoprotein.

Elimation

The final ionic elimination period of acolidinium bromide is about 2-3 hours.

After intravenous administration of 400 µg of radioactively labeled acolidinium bromide to healthy volunteers, about 1% of the dose was excreted unchanged in the urine.

Up to 65% of the dose was excreted as metabolites in the urine and up to 33% as metabolites in the feces.

After inhalation administration to healthy volunteers and patients with COPD, 200 mcg and 400 mcg of acolidinium bromide, very little, about 0.1% of the dose taken, was excreted unchanged in the urine, indicating that renal clearance plays a minor role in the total blood plasma clearance of acolidinium.

Linearity/nonlinearity

Aklydinium bromide has linear and time-independent pharmacokinetics in the therapeutic range.

Pharmacokinetic/pharmacodynamic relationship

As acolidinium bromide has local action in the lungs and is rapidly broken down in plasma, there is no direct relationship between pharmacokinetics and pharmacodynamics.

Special patient groups

Elderly patients

The pharmacokinetic properties of acolidinium bromide in patients with moderate to severe COPD are similar in patients aged 40 to 59 years and in patients aged 70 years or older. Therefore, no dose adjustment is required in elderly COPD patients.

Patients with impaired liver function

Tests have not been performed in patients with impaired liver function. Because acolidinium bromide is metabolized primarily by chemical and enzymatic breakdown in the plasma, it is very unlikely that impaired liver function alters its systemic effects. No dose adjustment is required in patients with COPD and impaired liver function.

Patients with impaired renal function

In patients with normal and impaired renal function no significant differences in pharmacokinetics have been found. Therefore, no dose adjustment and additional monitoring are required in patients with COPD and impaired renal function.

Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also called anticholinergic), with longer binding time to Mz receptors than to M2 receptors. Mz receptors mediate the contraction of the smooth muscles of the airways. Inhaled acridinium bromide acts locally in the lungs as an antagonist of Mz receptors to airway smooth muscle and causes bronchial dilation. Preclinical in vitro and in vivo studies have demonstrated rapid, dose-dependent, and prolonged inhibition of acetylcholine-induced bronchospasm by acolidinium bromide. Acolidinium bromide is rapidly degraded in plasma, so the number of systemic anticholinergic side effects is low.

Indications

bronchodilator therapy

Pharmacological effect

Clinical efficacy studies have shown that Bretaris Genuair provides a clinically significant improvement in lung function (measured by forced expiratory volume in one second [FEV1]) for more than 12 hours after morning and evening dosing, which was evident within 30 minutes after the first dose (FEV1 increase from baseline is 124-133 ml). Maximum bronchodilation was achieved within 1-3 hours after dosing, with a mean peak improvement in FEV1 relative to baseline of 227-268 ml at steady state.

Electrophysiology of the heart

When aclidinium bromide (200 mcg or 800 mcg) was administered to healthy volunteers once daily for 3 days, no effect on the QT interval (corrected by the Fridericius or Bazetta method or individually) was observed.

There was also no clinically significant effect of Bretaris Genuair on heart rate during 24-hour Holter monitoring in 336 patients (164 of whom received Bretaris Jenuair twice daily at a dose of 322 mcg) after 3 months of drug use.

Clinical effectiveness

The Phase III clinical trial program for Bretaris Genuair included 269 patients treated with Bretaris Jenuair 322 mcg twice daily in one 6-month placebo-controlled randomized trial and 190 patients treated with Bretaris Genuair 322 mcg twice daily in another 3-month randomized placebo-controlled trial. Efficacy was assessed by changes in lung function and clinical symptoms such as shortness of breath, diagnosis-related health status, use of rescue medications, and the presence of exacerbations. In long-term safety studies, Bretaris® Genuair® demonstrated bronchodilator efficacy over a duration of use of more than 1 year.

Bronchodilation

In a 6-month study, patients receiving Bretaris Genuair 322 mcg twice daily had a clinically significant improvement in lung function (measured by FEV). The maximum bronchodilator effect was evident from the first day and persisted throughout the 6-month treatment period. After 6 months of therapy, the mean improvement in pre-morning dose (trough) FEV] compared with placebo was 128 ml (95% CI=85-170; p

Similar observations were made for Bretaris® Genuair® during a 3-month study.

Disease-specific health status and symptomatic improvement

Bretaris Genuair provided clinically significant improvements in dyspnea (assessed by the Transient Dyspnea Index [TDI]) and disease-related health status (assessed by the St. George’s Respiratory Questionnaire [SGRQ]). The table below shows the reduction in symptoms after 6 months of use of Bretaris® Genuair®.

Variable

Treatment

Improvement compared to placebo

Meaning

R

Bretharis* „ _

„ „ ® Placebo Genuair

Transient dyspnea index

Percentage of patients with minimal clinically important difference3

56.9

45.5

1.68x

promotion

probabilities

0.004

Average change from baseline

1.9

0.9

1.0 unit

St. George’s Hospital Respiratory Questionnaire

Percentage of patients with minimal clinically important difference

57.3

41.0

1.87 times

promotion

probabilities

Average change from baseline

-7.4

-2.8

– 4.6 units

a) Minimum Clinically Important Difference (MCID) of at least 1 unit change in the Transient Dyspnea Index.

b) Minimum Clinically Important Difference (MCID) of at least 4 unit change in the St. George’s Hospital Respiratory Questionnaire.

c) Odds ratio, increased odds of achieving the Minimum Clinically Important Difference compared to placebo.

Patients receiving Bretaris® Genuair® required fewer rescue medications than patients receiving placebo (0.95 administrations/day reduction at 6 months [p=0.005]). Bretaris® Genuair® also improved daytime COPD symptoms (shortness of breath, cough and sputum production), as well as nighttime and early morning clinical symptoms.

A pooled analysis of the efficacy of 6-month and 3-month placebo-controlled studies demonstrated a significant reduction in the incidence of moderate to severe exacerbations (requiring antibiotic or corticosteroid therapy or resulting in hospitalization) with aclidinium 322 mcg twice daily compared with placebo (incidence per patient-year: 0.31 vs. 0.44, respectively; P = 0.0149).

Exercise tolerance

In a 3-week, randomized, placebo-controlled, crossover clinical trial, Bretaris Genuair demonstrated a statistically significant increase in exercise duration of 58 seconds compared to placebo (95% CI=9-108; p=0.021; pre-treatment values: 486 seconds).

When using the drug Bretaris® Genuair®, there was a statistically significant reduction in excessive lung overdistension at rest (functional residual capacity [FRC] = 0.197 l [95% CI = 0.321, 0.072; p = 0.002]; residual volume [RV] = 0.238 l [95% CI = 0.396, 0.079; p=:0.004]), and there was also an improvement in minimum inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and a decrease in dyspnea during exercise (Borg scale) (by 0.63 Borg units; 95% CI= 1.11, 0.14; p=0.012).

Suction

Aclidinium bromide is rapidly absorbed from the lungs, reaching maximum plasma concentrations within 5 minutes after inhalation in healthy volunteers, and usually within the first 15 minutes in patients with COPD. The fraction of the inhaled dose that reaches systemic circulation as unchanged aclidinium is very low, less than 5%.

The maximum plasma concentration achieved after inhalation of dry powder in patients with COPD with a single dose of 400 mcg aclidinium bromide was approximately 80 pg/ml. Steady-state plasma concentrations were achieved within 7 days when administered twice daily and, given the short half-life, steady-state concentrations may be reached soon after the first dose. No accumulation was observed upon repeated dosing at steady-state concentrations.

Distribution

The total amount of aclidinium bromide entering the lungs through the Bretaris Genuair inhaler was approximately 30% of the metered dose.

The binding of aclidinium bromide to plasma proteins in vitro most likely corresponds to the binding of metabolites to proteins, due to the rapid hydrolysis of aclidinium bromide in plasma, plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin.

Biotransformation

Aclidinium bromide is rapidly and extensively hydrolyzed to its pharmacologically inactive alcohol and carboxylic acid derivatives. Both chemical hydrolysis (non-enzymatic) and enzymatic hydrolysis occurs, with the participation of esterases. The main esterase involved in hydrolysis in humans is butyrylcholinesterase. The level of the acid metabolite in the blood plasma after inhalation is approximately 100 times higher than the level of the alcohol metabolite and unchanged active substance.

Low absolute bioavailability of aclidinium bromide after inhalation administration (

Biotransformation with the participation of cytochrome P450 isoenzymes (CYP450) plays a minor role in the overall metabolic clearance of aclidinium bromide.

In vitro tests have shown that aclidinium bromide at a therapeutic dose or its metabolites do not suppress or induce any cytochrome P450 (CYP450) isoenzymes and do not inhibit the activity of esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro testing has shown that aclidinium bromide or its metabolites are not substrates or inhibitors of P-glycoprotein.

Removal

The final period of elimination of aclidinium bromide is about 2-3 hours.

Following intravenous administration of 400 mcg of radiolabeled aclidinium bromide to healthy volunteers, approximately 1% of the dose was excreted unchanged in the urine.

Up to 65% of the dose was excreted as metabolites in the urine and up to 33% as metabolites in the feces.

Following inhalation administration of 200 mcg and 400 mcg aclidinium bromide to healthy volunteers and patients with COPD, a very small amount, about 0.1% of the administered dose, was excreted unchanged in the urine, indicating that renal clearance plays a minor role in the overall clearance of aclidinium from plasma.

Linearity/nonlinearity

Aclidinium bromide has linear and time-independent pharmacokinetics in its therapeutic range.

Pharmacokinetic/pharmacodynamic relationship

Considering that aclidinium bromide has a local effect in the lungs and is rapidly destroyed in the plasma, there is no direct relationship between pharmacokinetics and pharmacodynamics.

Special patient groups

Elderly patients

The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD are similar in patients aged 40 to 59 years and in patients aged 70 years and older. Therefore, no dose adjustment is required in elderly patients with COPD.

Patients with liver dysfunction

Trials have not been conducted in patients with impaired liver function. Since aclidinium bromide is metabolized primarily by chemical and enzymatic degradation in plasma, it is very unlikely that hepatic impairment would alter its systemic exposure. In patients with COPD and impaired liver function, no dose adjustment is required.

Patients with impaired renal function

In patients with normal renal function and those with impaired renal function, no significant differences in pharmacokinetics were found. Therefore, in patients with COPD and impaired renal function, dose adjustment and additional monitoring are not required.

Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also called anticholinergic), with a longer binding time at M3 receptors than at M2 receptors. M3 receptors serve as intermediaries during the contraction of smooth muscles of the respiratory tract. Inhaled aclidinium bromide acts locally in the lungs as an antagonist of M3 receptors in the smooth muscles of the respiratory tract and causes dilation of the bronchi. Preclinical in vitro and in vivo studies demonstrated rapid, dose-dependent, and long-lasting inhibition of acetylcholine-induced bronchoconstriction by aclidinium bromide. Aclidinium bromide is rapidly destroyed in plasma, so the incidence of systemic anticholinergic side effects is low.

Special instructions

Asthma

Bretaris Genuair should not be used for asthma; Clinical studies on the use of aclidinium bromide for the treatment of asthma have not been conducted.

Paradoxical bronchospasm

As with other inhaled therapy, the use of Bretaris Genuair may cause paradoxical bronchospasm. If this occurs, treatment with Bretaris Jenuair should be stopped and other therapy considered.

Increased symptoms of the disease

Aclidinium bromide is intended for the maintenance treatment of patients with COPD and should not be used as an emergency drug. If during treatment with aclidinium bromide the patient experiences a change in the severity of COPD symptoms that requires additional emergency therapy, the patient’s condition should be re-evaluated and treatment tactics reviewed.

Effect on the cardiovascular system

The safety profile in relation to the cardiovascular system is characterized by the presence of anticholinergic effects.

Like other m-anticholinergic drugs, Bretaris Jenuair should be prescribed with caution to patients who have had a myocardial infarction in the previous 6 months, with unstable angina, newly diagnosed arrhythmia in the previous 3 months, or to patients hospitalized in the previous 12 months for heart failure of functional classes III and IV according to the New York Heart Association classification, because such patients were excluded from clinical studies, and anticholinergic effects may influence the course of these diseases.

Anticholinergic effects

Dryness of the oral mucosa, observed with the use of anticholinergic drugs, may be associated with the development of dental caries over time.

Due to the presence of anticholinergic effects, aclidinium bromide should be administered with caution to patients with angle-closure glaucoma (although direct contact of the drug with the eyes is very unlikely), prostatic hyperplasia and bladder neck obstruction. Patients should be informed of the signs and symptoms of an acute attack of angle-closure glaucoma and the need to stop using the drug and consult a doctor if they occur.

Bretaris Genuair is intended for the maintenance treatment of patients with COPD. Due to the fact that in the general COPD population there is a significant predominance of patients over the age of 40 years, when prescribing the drug to patients under 40 years of age, spirometric confirmation of the diagnosis of COPD is required.

Impact on the ability to drive vehicles and other mechanisms

Aclidinium bromide may affect the ability to drive vehicles and use other machinery. Considering the possibility of developing such side effects as headache, dizziness, blurred vision, caution should be exercised when driving vehicles, other mechanisms, as well as when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Aclidinium bromide

Composition

Powder for inhalation

Active ingredient:

Aclidinium bromide;

Excipients:

Lactose monohydrate.

Contraindications

Hypersensitivity;
Age up to 18 years (efficacy and safety have not been established);
Galactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

Side Effects

The most common side effects when using Bretaris Genuair are headache (6.6%) and nasopharyngitis (5.5%).

The incidence of adverse events is based on estimates of the overall adverse event rates (i.e., events associated with the use of Bretaris Genuair) observed with Bretaris Genuair 322 mcg (636 patients) in a pooled analysis of one 6-month and two 3-month placebo-controlled randomized clinical trials.

The frequency of side effects is defined as follows: very often (≥1/10), often (from ≥1/100 to

Infectious and parasitic diseases: often – sinusitis, nasopharyngitis.

From the immune system: rarely – hypersensitivity reactions; frequency unknown – angioedema.

From the nervous system: often – headache; infrequently – dizziness.

From the side of the organ of vision: infrequently – blurred vision.

From the cardiovascular system: infrequently – tachycardia, palpitations.

From the respiratory system, chest and mediastinal organs: often – cough; infrequently – dysphonia.

From the gastrointestinal tract: often – diarrhea; infrequently – dryness of the oral mucosa, stomatitis.

From the skin and subcutaneous tissues: infrequently – rash, itching.

From the kidneys and urinary tract: infrequently – urinary retention.

Interaction

The simultaneous use of aclidinium bromide with other M-anticholinergic drugs has not been studied and is not recommended.

Despite the lack of in vivo studies, the use of inhaled aclidinium bromide is possible in combination with other drugs for the treatment of COPD, including sympathomimetics, bronchodilators, methylxanthines and inhaled or oral corticosteroids.

In vitro studies have demonstrated that aclidinium bromide at therapeutic doses or its metabolites do not interact with drugs that are P-glycoprotein substrates or drugs that are metabolized by cytochrome P450 (CYP450) isoenzymes and esterases.

Overdose

High doses of aclidinium bromide may lead to symptoms associated with anticholinergic effects.

However, a single inhaled dose of aclidinium bromide up to 6000 mcg in healthy volunteers did not result in systemic anticholinergic side effects. There were no clinically significant side effects after 7 days of treatment with aclidinium bromide in doses up to 800 mcg 2 times a day in healthy volunteers.

The development of acute intoxication in the event of an accidental overdose of aclidinium bromide is unlikely due to the low bioavailability when taken orally and by inhalation dosing of the drug Bretaris Genuair.

Treatment: symptomatic.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 °C.

Shelf life

2 years

Manufacturer

Industrias Pharmaceuticas Almiralle S.A., Spain