Duaclir Genevair powder for ing dosage 340mcg+11.8mcg/dose, 60 doses

Composition

One measured dose contains:

Active ingredients:

aclidinium bromide micronized (based on aclidinium) 0.400 mg (0.343 mg)* and formoterol fumarate dihydrate micronized 0.012 mg**.

Auxiliary substance:

lactose monohydrate 11.588 mg

. * the delivered dose of aclidinium bromide is 396 mcg, which corresponds to 340 mcg of aclidinium.

* * the delivered dose of formoterol fumarate dihydrate is 11.8 mcg.

Pharmacological action

Mechanism of action

Duaclir Generic contains two bronchodilators: aclidinium, a long-acting muscarinic receptor antagonist (also called an anticholinergic), and formoterol, a long-acting beta-2-adrenergic receptor agonist. The combination of these substances with different mechanisms of action provides an additive effect compared to the use of individual components.

Due to the difference in the density of muscarinic and beta-2-adrenergic receptors in the central and peripheral airways, muscarinic receptor antagonists are more effective in relaxing the central airways, and beta-2 – adrenergic receptor agonists are more effective in relaxing the peripheral airways; thus, the use of combination therapy may increase the beneficial effect on lung function.

Aclidinium is a competitive, selective muscarinic receptor antagonist with a longer binding time to M3 receptors than to M2 receptors. M3 receptors mediate the contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs as an antagonist of M3 smooth muscle receptors of the respiratory tract and causes bronchodilation.

The use of aclidinium in patients with chronic obstructive pulmonary disease (COPD) also reduces the severity of symptoms, improves the disease-related state of health, reduces the frequency of exacerbations, and improves exercise tolerance. Since aclidinium bromide is rapidly degraded in blood plasma, the number of systemic anticholinergic side effects is low. Formoterol is a potent selective beta-2-adrenergic agonist.

Bronchodilation is achieved by relaxing the smooth muscles of the airways due to an increase in the level of cyclic adenosine monophosphate after activation of adenylate cyclase. In addition to improving lung function, formoterol reduces the severity of symptoms and improves the quality of life in patients with COPD.

Clinical studies have shown that Duaclir Generic provides clinically significant improvement in lung function (measured by forced expiratory volume per 1 second (FEV 1)) for more than 12 hours after use.

The drug Duaclir Generic has a rapid onset of action – within 5 minutes after the first inhalation compared to placebo. The onset of action of Duaclir Generic was comparable to that of the fast-acting beta-2-adrenergic agonist formoterol at a dose of 12 micrograms. Maximum bronchodilation (maximum FEV 1) compared to baseline was achieved from the first day (304 ml) and maintained throughout the treatment period of more than 6 months (326 ml).

Electrophysiology of the heart

There was no clinically significant effect of Duaclir Generic on electrocardiogram (ECG) parameters, including QT interval, compared with aclidinium, formoterol and placebo, as well as on heart rate during daily Holter monitoring.

Clinical efficacy

A phase III clinical trial program involving approximately 4,000 patients with a clinical diagnosis of moderate or severe COPD included two 6-month randomized placebo-controlled trials (ACLIFORM-COPD and AUGMENT), a 6-month extended phase of the AUGMENT trial, and an additional 12-month randomized, controlled trial.

In long-term safety studies, Duaclir Generic has been shown to be consistently effective with a duration of use of more than 1 year, without signs of tachyphylaxis.

Effects on lung function

Duaclir Generic (340 mcg + 11.8 mcg / dose twice daily) provided clinically significant improvements in lung function (measured by FEV 1, forced vital capacity, and inspiratory capacity) compared to placebo. A clinically significant bronchodilating effect was achieved within 5 minutes after the first dose of the drug and was maintained throughout the entire inter-dose interval.

In the ACLIFORM-COPD study, Duaclir Generic provided an improvement in FEV1 at 1 hour post-dose compared to placebo and aclidinium, by 299 ml and 125 ml, respectively (p<0.0001 in both comparisons), and an improvement in residual FEV1 compared to placebo and formoterol, by 143 ml and 85 ml, respectively (p In the AUGMENT study, the improvement in FEV1 at 1 hour post-dose compared to placebo and aclidinium was 284 ml and 108 ml, respectively (p<0.0001 in both comparisons), and the improvement in residual FEV1 compared to placebo and formoterol was 130 ml (p

Relief of symptoms and improvement of the health condition caused by the disease

Shortness of breath and other symptoms

Duaclir Generic provided a clinically significant improvement in dyspnea (measured by the transient dyspnea index (TDI)), with an increase in TDI after 6 months of therapy compared to placebo of 1.29 units in the ACLIFORM-COPD study (p<0.0001) and 1.44 units in the AUGMENT study (p

A combined analysis of these two studies showed that the use of Duaclir Generic was associated with a statistically significant greater improvement in the TDI index compared to aclidinium (by 0.4 units; p=0.016) or formoterol (by 0.5 units; p=0.009).

Duaclir Generic improved daytime symptoms of COPD, such as shortness of breath, chest symptoms, cough, and sputum discharge (assessed using the E-RS total Index), as well as the overall severity of nocturnal symptoms, early morning symptoms, and activity-limiting symptoms in the early morning hours, compared with placebo, aclidinium, and formoterol, but this improvement was not always statistically significant. The aclidinium/formoterol combination did not show a statistically significant reduction in the average number of nocturnal awakenings due to COPD compared to placebo or formoterol.

Health-related quality of life In the AUGMENT study, Duaclir Generic provided a statistically significant improvement in disease-related health (assessed using the St. George’s Hospital Respiratory Questionnaire (SGRQ)), with an overall SGRQ improvement of -4.35 units compared to placebo (p 

In the ACLIFORM-COPD study, only a small decrease in the overall SGRQ index compared to placebo was observed due to an unexpectedly pronounced response to placebo therapy (p=0.598), and the percentage of patients who achieved clinically significant improvement from baseline was 55.3% in the Duaclir Generic group and 53.2% in the placebo group (p=0.669).

A combined analysis of data from these two studies showed a greater improvement in the overall SGRQ index when using Duaclirgenuair compared to formoterol (-1.7 units; p=0.018) or aclidinium (-0.79 units; p=0.273).

Reducing the frequency of COPD exacerbations

The combined efficacy analysis of two 6-month trials showed a statistically significant 29% reduction in the incidence of moderate or severe exacerbations (requiring antibiotic or corticosteroid therapy, or leading to hospitalization) with Duaclir Generic compared to placebo (frequency per patient per year: 0.29 vs. 0.42, respectively; p=0.036), as well as an increase in the time to the first moderate or severe exacerbation compared to placebo (risk ratio 0.70; p=0.027).

Use of emergency medications

Duaclir Generic reduced the need for an emergency drug for more than 6 months compared to placebo (by 0.9 inhalations/day (p<0.0001)), aclidinium (by 0.4 inhalations/day (p

Pharmacokinetics

The pharmacokinetic parameters of aclidinium and formoterol when inhaled in combination did not significantly differ from those observed with the use of individual components. Absorption rate

After a single inhalation of Duaclir Generic, aclidinium and formoterol were rapidly absorbed into the blood plasma, reaching a maximum concentration within 5 minutes after inhalation in healthy volunteers and within 24 minutes after inhalation in patients with COPD.

The maximum steady-state concentrations of aclidinium and formoterol in COPD patients treated with Duaclir Generic twice daily for 5 days were reached within 5 minutes after inhalation and were 128 pg / ml and 17 pg/ml, respectively.

Distribution

The total amount of aclidinium entering the lungs through the Generic inhaler was approximately 30% of the measured dose. The binding of aclidinium to plasma proteins in vitro most likely corresponds to the binding of metabolites to proteins, due to the rapid hydrolysis of aclidinium in blood plasma. Binding to plasma proteins was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium is albumin.

The binding of formoterol to plasma proteins is 61% – 64% (34% – mainly with albumin). There was no saturation of binding sites in the range of concentrations achieved with the use of the drug in therapeutic doses.

Biotransformation

of Aclidinium is rapidly and intensively hydrolyzed to the pharmacologically inactive alcohol derivative and carboxylic acid derivative. Chemical (nonenzymatic) and enzymatic hydrolysis occurs under the action of esterases. The main esterase involved in hydrolysis in humans is butyrylcholinesterase. The concentration of the acidic metabolite in the blood plasma after inhalation is approximately 100 times higher than the concentration of the alcohol metabolite and the unchanged Active ingredient.

Low absolute bioavailability of aclidinium by inhalation ( 

Biotransformation involving cytochrome P450 (CYP450) isoenzymes plays a minor role in the overall metabolic clearance of aclidinium. In vitro studies have shown that aclidinium at a therapeutic dose or its metabolites do not inhibit or induce any CYP450 isoenzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase).

It was also found in vitro that aclidinium or its metabolites are not substrates or inhibitors of P-glycoprotein.

Formoterol is mainly excreted through metabolism. The main route is direct glucuronidation with O-demethylation followed by conjugation with glucuronide. The O-demethylation of formoterol involves the isoenzymes CYP2D6, CYP2C19, CYP2C9, and CYP2A6. At therapeutically significant concentrations, formoterol does not inhibit CYP450 isoenzymes.

Deduction

After inhalation of Duaclir Generic 340 mcg + 11.8 mcg / dose, the final elimination half-lives of aclidinium and formoterol are approximately 5 hours and 8 hours, respectively.

After intravenous use of 400 micrograms of radiolabeled aclidinium to healthy volunteers, about 1% of the administered dose was excreted unchanged in the urine. Up to 65% of the drug dose was excreted as metabolites in the urine and up to 33% – as metabolites in the faeces.

After inhalation of 200 mcg and 400 mcg of aclidinium in healthy volunteers and COPD patients, urinary excretion of unchanged aclidinium was very low (approximately 0.1% of the administered dose), indicating that renal clearance plays a minor role in the total clearance of aclidinium from blood plasma.

The main part of the administered dose of formoterol was metabolized in the liver, followed by excretion by the kidneys. After inhalation,6% -9% of the delivered dose of formoterol is excreted in the urine unchanged or in the form of formoterol conjugates.

Special patient populations

Elderly patients

The pharmacokinetics of the aclidinium/formoterol combination in elderly patients have not been studied. Since elderly patients do not need to adjust the dose of aclidinium or formoterol, when using the combination of aclidinium/formoterol, it is also not necessary to adjust the dose.

Patients with impaired renal and hepatic function

There are no specific data on the use of aclidinium/formoterol in patients with impaired renal or hepatic function. Since no dose adjustment of aclidinium or formoterol is required in patients with impaired renal or hepatic function, no dose adjustment is required when using the aclidinium/formoterol combination.

Indications

Duaclir Generic is indicated as a supportive bronchodilator therapy to relieve symptoms of chronic obstructive pulmonary disease in adults.

Use during pregnancy and lactation

Pregnancy

There are no data on the use of Duaclir Generic in pregnant women.

In animal studies, fetotoxicity was observed only at doses significantly higher than the maximum dose of aclidinium in humans, and undesirable effects in reproductive toxicity studies only at very high systemic exposure to formoterol.

During pregnancy, Duaclir Generic should only be used when the expected benefits outweigh the potential risks.

Breast-feeding period

It is not known whether aclidinium (and/or its metabolites) or formoterol is excreted in breast milk. Since preclinical studies have shown that small amounts of aclidinium (and / or its metabolites) and formoterol pass into milk, Duaclir Generic should only be used during breastfeeding when the expected benefit to the woman outweighs the potential risk to the infant.

Fertility

Preclinical studies have shown a small decrease in fertility only when used at doses significantly higher than the maximum doses of aclidinium and formoterol in humans. It is considered unlikely that the use of Duaclir Generic at the recommended dose will affect human fertility.

Contraindications

• Hypersensitivity to aclidinium bromide, formoterol or lactose.
• Children under 18 years of age (efficacy and safety have not been established).
• Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

WITH CAUTION

Myocardial infarction suffered during the previous 6 months, unstable angina, newly detected arrhythmia during the previous 3 months, hospitalization during the previous 12 months for NYHA functional class III and IV heart failure or other severe cardiovascular diseases, QTc interval (according to the Bazett method) > 470 ms, concomitant therapy with drugs that prolong the QTc interval, convulsive disorders, thyrotoxicosis, pheochromocytoma, symptomatic prostatic hyperplasia, urinary retention, angle-closure glaucoma, hypokalemia.

Side effects

The safety information presented below is based on the experience of using Duaclir Generic (at the recommended therapeutic dose of up to 12 months) and its individual components.

Security Profile Overview

Adverse reactions associated with the use of Duaclir Generic are similar to those observed with the use of its individual components. Since Duaclir Generic contains aclidinium and formoterol, the adverse reactions described for these components can be expected against the background of its use.

The most common adverse reactions reported with Duaclir Generic were nasopharyngitis (7.9%) and headache (6.8%).

Interaction

Medications for COPD treatment

Concomitant use of Duaclir Generic with other long-acting anticholinergic agents and/or beta-2-adrenergic receptor agonists has not been studied and is not recommended.

Although no formal in vivo drug interaction studies have been conducted on Duaclir Generic, it has been used concomitantly with other COPD medications, including short-acting beta-2-adrenergic receptor agonists, methylxanthines, and oral and inhaled glucocorticosteroids, without clinical signs of drug interaction.

Metabolic interactions

In vitro studies have shown that aclidinium at a therapeutic dose or its metabolites are not expected to interact with P-glycoprotein substrates (P-gp) and drugs metabolized by cytochrome P450 isoenzymes (CYP450) and esterases. At therapeutically significant concentrations, formoterol does not inhibit CYP450 isoenzymes (see section “Pharmacokinetics”).

Drugs that cause hypokalemia

Concomitant use of methylxanthine derivatives, steroids or potassium-sparing diuretics may increase the possible hypokalemic effect of beta-2-adrenergic agonists, so caution should be exercised when used together with these drugs (see the section “Special instructions”).

Beta-adrenergic receptor blockers

Beta-adrenergic receptor blockers can weaken or neutralize the effect of beta-2-adrenergic receptor agonists. If necessary, the use of beta-adrenergic receptor blockers (including in the form of eye drops) is preferable to prescribe cardioselective beta-adrenergic receptor blockers, although they should also be used with caution.

Other pharmacodynamic interactions

Duaclir Generic should be used with caution in patients receiving medications that prolong the QTc interval, such as monoamine oxidase inhibitors, tricyclic antidepressants, antihistamines, or macrolides, as they may potentiate the effect of formoterol on the cardiovascular system. Medications that prolong the QTc interval increase the risk of ventricular arrhythmia.

How to take it, course of use and dosage

For inhalation use.

The recommended dose is one inhalation of Duaclir Generic 340 mcg + 11.8 mcg / dose 2 times a day.

If a missed dose is missed, the missed dose should be taken as soon as possible, and the next dose should be taken at the usual time. Do not take a double dose to compensate for the missed one.

Elderly patients

No dose adjustment is required in elderly patients (see section “Pharmacokinetics”).

Impaired renal function

No dose adjustment is required in patients with impaired renal function (see section “Pharmacokinetics”).

Impaired liver function

No dose adjustment is required in patients with hepatic impairment (see section “Pharmacokinetics”).

Children

Duaclir Generic is not intended for use in children and adolescents under 18 years of age with COPD.

Overdose

Experience in treating overdose with Duaclir Generic is limited. High doses of Duaclir Generic medications can lead to increased symptoms and manifestations of anticholinergic and / or beta-2-adrenergic effects, the most common of which are: blurred vision, dry mouth, nausea, muscle spasm, tremor, headache, palpitation and hypertension.

In case of overdose, the use of Duaclir Generic should be discontinued. Supportive and symptomatic therapy is indicated.

Special instructions

Bronchial asthma

Duaclir Generic should not be used for bronchial asthma; clinical studies of Duaclir Generic for bronchial asthma have not been conducted.

Paradoxical bronchospasm

In clinical studies, there were no cases of paradoxical bronchospasm with the use of Duaclir Generic at the recommended dose. However, paradoxical bronchospasm was observed during other inhalation therapy. If it occurs, the use of the drug should be discontinued and alternative therapy should be considered.

The drug is not intended for relief of acute attacks

Duaclir Generic is not indicated for the treatment of acute bronchospasm attacks.

Impact on the cardiovascular system

Duaclir Generic should be used with caution in patients who have had a myocardial infarction within the previous 6 months, in patients with unstable angina, newly diagnosed arrhythmia within the previous 3 months, with a QTc interval (calculated using the Bazett method) > 470 ms, or who were hospitalized during the previous 12 months for NYHA functional class III and IV heart failure, since these patients were not included in clinical studies.

In some patients, beta-2-adrenergic agonists may cause an increase in pulse rate and blood pressure, ECG changes in the form of flattening of the T wave, ST-segment depression, and prolongation of the QTc interval.

If these effects develop, early discontinuation of therapy may be required. Long-acting beta-2-adrenergic agonists should be used with caution in patients who are currently or have a history of prolongation of the QTc interval, or who are receiving medications that affect the duration of the QTc interval (see the section “Interactions with other drugs and other types of drug interactions”).

System effects

Duaclir Generic should be used with caution in patients with severe cardiovascular disorders, convulsive disorders, thyrotoxicosis and pheochromocytoma.

When using high doses of beta-2-adrenergic agonists, metabolic effects in the form of hyperglycemia and hypokalemia may develop. In phase III clinical trials, the frequency of significant increases in blood glucose concentrations during the use of Duaclir Generic was low (0.1%) and similar to the placebo group. Hypokalemia is usually transient and does not require additional therapy. In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant therapy (see section

“Interactions with other drugs and other types of drug interactions”). Hypokalemia may increase the risk of arrhythmia.

Due to its anticholinergic activity, Duaclir Generic should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention, or angle-closure glaucoma (although direct contact with the eyes is very unlikely). Dry mouth, which was observed on the background of anticholinergic therapy, if maintained for a long time, can lead to tooth decay.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND OTHER MECHANISMS

The drug Duaclir Generic does not affect or slightly affects the ability to drive vehicles and mechanisms. The development of blurred vision or dizziness can affect the ability to drive vehicles or work with mechanisms.

Storage conditions

At a temperature not exceeding 30 °C.

Shelf life

2 years

Active ingredient

Aclidinium bromide, Formoterol

Conditions of release from pharmacies

Prescription