Duaclyr Genevair, 340 mcg+11.8 mcg/dose 60 doses

Mechanism of action

Duaclir Jenaire contains two bronchodilators: aclydinium, a long-acting muscarinic receptor antagonist (also called anticholinergic), and formoterol, a long-acting β2-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 differences in the density of muscarinic and β2-adrenergic receptors in the central and peripheral airways, muscarinic receptor antagonists are more effective in relaxing the central airways and β2-adrenergic receptor agonists are more effective in relaxing the peripheral airways; thus, use of combination therapy may increase beneficial effects 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 the smooth muscles of the airways. Inhaled acridinium bromide acts locally
in the lungs as an M3-receptor antagonist of airway smooth muscle and causes bronchodilation.

The use of acolidinium in patients with chronic obstructive pulmonary disease (COPD) also causes a reduction in symptom severity, improvement in disease-associated health
conditions, decreased frequency of exacerbations and improved exercise tolerance. Since acolidinium bromide is rapidly broken down in plasma, the number of systemic anticholinergic side effects is low.Formoterol is a potent selective β2-adrenoreceptor agonist.

Bronchodilation is achieved by relaxation of airway smooth muscle due to increased levels of cyclic adenosine monophosphate after activation of adenylate cyclase. In addition to improving lung function, formoterol reduces symptoms and improves quality of life in patients with COPD.

Pharmacodynamics

Clinical studies have shown that Duaclir Genuair provides clinically significant improvement in lung function (as assessed by forced expiratory volume in 1 second (FEF1)) for more than 12 hours after administration.

Duaclir Jenaire has a rapid onset of action, within 5 minutes of first inhalation compared to placebo. The onset of action of Duaclir Jenaire was comparable to that of the fast-acting β2-adrenoreceptor agonist, formoterol, at a dose of 12 mcg. Maximum bronchodilation (maximal OEF1) compared with baseline was achieved from day 1 (304 mL) and was maintained throughout the duration of therapy over 6 months (326 mL).

Heart electrophysiology

There were no clinically significant effects of Duaclir Jenuair on electrocardiogram (ECG) parameters, including QT interval, compared with aclydinium, formoterol, and placebo, and on heart rate by daily Holter monitoring.

Clinical efficacy

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

In long-term safety studies, Duaclir Genuair showed sustained efficacy with more than 1 year of use, with no evidence of tachyphylaxis.

Impact on pulmonary function

Duaclir Januair (340 mcg + 11.8 mcg/dose twice daily) provided clinically significant improvement in pulmonary function (as assessed by SPH1, forced vital capacity and inspiratory capacity) compared to placebo. The clinically significant bronchodilator effect was achieved within 5 minutes after the first dose of the drug and was maintained throughout the interdose interval.

In the ACLIFORM-COPD study, Duaclir Jenaire provided an improvement in SPH1 1 hour after the dose compared with placebo and aclydinium, by 299 mL and 125 mL, respectively (p< 0.0001 in both comparisons), and improved residual SPH1 compared with placebo and formoterol, by 143 mL and 85 mL, respectively (p< 0.0001 in both comparisons). In the AUGMENT study, the improvement in SPH1 1 hour after dose compared with placebo and aclidinium, was 284 mL and 108 mL, respectively (p< 0.0001 in both comparisons), and the improvement in residual SPH1 compared with placebo and formoterol was 130 mL (p< 0.0001) and 45 mL (p=0.01), respectively.

Symptom relief and improvement in disease-related health conditions

Dyspnea and other symptoms

Duaclir Jenaire provided clinically meaningful improvement in dyspnea (assessed using the transient dyspnea index (TDI)), with an increase in TDI after 6 months of therapy compared with placebo of 1.29 units in the ACLIFORM-COPD study (p< 0.0001) and 1.44 units in the AUGMENT study (p< 0.0001).

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

. The drug Duaclir Jenaire improved daytime COPD symptoms, particularly dyspnea, chest symptoms, cough, and sputum separation (assessed using the overall E-RS index), and the overall severity of nighttime symptoms, early morning symptoms, and symptoms limiting activity in the early morning hours, compared with placebo, acolidinium, and formoterol, but this improvement was not always statistically significant. The acolidinium/formoterol combination showed no statistically significant reduction in the mean number of COPD-related nocturnal awakenings compared with placebo or formoterol.

Health-related quality of life In the AUGMENT study, Duaclyre Genuair provided statistically significant improvement in disease-related health status (assessed using the St. George’s Hospital Respiratory Questionnaire (SGRQ)), with a -4.35 unit improvement in the overall SGRQ index compared with placebo (p< 0.0001).

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

A combined analysis of data from the two studies showed a greater improvement in overall SGRQ index with Duaclir-Jenuair compared with formoterol (-1.7 units; p=0.018) or acolidinium (-0.79 units; p=0.273).

Reduced incidence of COPD exacerbations

. A pooled efficacy analysis of two 6-month studies demonstrated a statistically significant 29% reduction in the rate of moderate to severe exacerbations (requiring antibiotic or corticosteroid therapy, or leading to hospitalization) on therapy with Duaclir Genuair compared with placebo (rate per patient per year: 0.29 vs. 0.42, respectively; p=0.036), and increased time to first moderate to severe exacerbation compared with placebo (hazard ratio 0.70; p=0.027).

The use of emergency medications

Duaclir Januair reduced the need for emergency medication over 6 months compared with placebo (by 0.9 inhalations/day (p< 0.0001)), aclidinium (by 0.4 inhalations/day (p< 0.001)), and formoterol (by 0.2 inhalations/day (p=0.062)).

Pharmacokinetics

The pharmacokinetic parameters of aclydinium and formoterol when used inhaled in combination were not significantly different from those observed with the individual components. Absorption

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

The maximum equilibrium concentrations of acolidinium and formoterol in COPD patients treated with Duaclir Januair twice daily for 5 days were reached within 5 minutes of inhalation and were 128 pg/mL and 17 pg/mL, respectively.

Distribution

The total amount of acolidinium entering the lungs via the Jenweir inhaler was approximately 30% of the measured dose. The in vitro binding of acladinium to plasma proteins most likely corresponds to the binding of metabolites to proteins, due to the rapid hydrolysis of acladinium in 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 to albumin). No saturation of the binding centers in the range of concentrations achieved with the use of the drug in therapeutic doses was noted.

Biotransformation

Aclidinium is rapidly and intensively hydrolyzed to pharmacologically inactive alcohol derivative and carboxylic acid derivative. Chemical (non-enzymatic) 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 plasma after inhalation is approximately 100 times higher than the concentration of the alcoholic metabolite and the unchanged active substance.

The low absolute bioavailability of acolidinium when administered by inhalation (< 5%) is due to its intense systemic and presystemic hydrolysis both when in the lungs and when ingested.

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

Acklydinium or its metabolites have also been found in vitro not to be substrates or inhibitors of P-glycoprotein.

Formoterol is excreted primarily by metabolism. The main pathway is direct glucuronidation with O-demethylation followed by conjugation with glucuronide. CYP2D6, CYP2C19, CYP2C9 and CYP2A6 isoenzymes are involved in O-demethylation of formoterol. At therapeutically relevant concentrations formoterol does not inhibit the CYP450 isoenzymes.

Elevation

After inhalation of Duaclir Januair 340 µg + 11.8 µg/dose, the final half-life of aclydinium and formoterol is approximately 5 h and 8 h, respectively.

After intravenous administration of 400 mcg of radioactive isotope-labeled aclidinium to healthy volunteers, approximately 1% of the administered 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 of 200 mcg and 400 mcg of aclydinium by healthy volunteers and patients with COPD, urinary excretion of unchanged aclydinium was very low (approximately 0.1% of the administered dose), indicating that renal clearance plays a minor role in the total blood plasma clearance of aclydinium.

The bulk of the administered dose of formoterol was metabolized in the liver with subsequent excretion by the kidneys. After inhalation, 6% to 9% of the delivered dose of formoterol is excreted in the urine unchanged or as formoterol conjugates.

Particular patient populations

Elderly patients

There have been no studies of the pharmacokinetics of the acolidinium/formoterol combination in elderly patients. Because elderly patients do not require dose adjustments for acladinium or formoterol preparations, dose adjustments are also not required when using the acladinium/formoterol combination.

Patients with impaired renal or hepatic function

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

Indications

Duaklir Genuair is indicated as maintenance bronchodilator therapy to relieve symptoms of chronic obstructive pulmonary disease in adults.

Pharmacological effect

Mechanism of action

Duaklir Genuair contains two bronchodilators: aclidinium, a long-acting muscarinic receptor antagonist (also called an anticholinergic), and formoterol, a long-acting β2-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 differences in the density of muscarinic and β2-adrenergic receptors in the central and peripheral airways, muscarinic receptor antagonists are more effective in relaxing the central airways, and β2-adrenergic receptor agonists are more effective in relaxing the peripheral airways; thus, the use of combination therapy may enhance the beneficial effects on pulmonary function.

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

The use of aclidinium in patients with chronic obstructive pulmonary disease (COPD) also causes a decrease in the severity of symptoms and an improvement in the condition associated with the disease
health, reducing the frequency of exacerbations and improving exercise tolerance. Because aclidinium bromide is rapidly destroyed in plasma, the incidence of systemic anticholinergic side effects is low. Formoterol is a potent selective β2-adrenergic receptor agonist.

Bronchodilation is achieved by relaxation of airway smooth muscle due to increased levels of cyclic adenosine monophosphate following activation of adenylate cyclase. In addition to improving lung function, formoterol reduces symptoms and improves quality of life in patients with COPD.

Pharmacodynamics

Clinical studies have shown that Duaklir Genuair provides clinically significant improvements in lung function (as measured by forced expiratory volume in 1 second (FEV1)) for more than 12 hours after dosing.

Duaklir Genuair has a rapid onset of action – within 5 minutes after the first inhalation compared to placebo. The onset of action of Duaklir Genuair was comparable to that of the fast-acting β2-adrenergic agonist, formoterol, at a dose of 12 mcg. Maximum bronchodilation (maximum FEV1) compared to baseline was achieved from the first day (304 ml) and was maintained throughout the entire treatment period of more than 6 months (326 ml).

Electrophysiology of the heart

There was no clinically significant effect of Duaklir Genuair on electrocardiogram (ECG) parameters, including the QT interval, compared with aclidinium, formoterol and placebo, or on heart rate during 24-hour Holter monitoring.

Clinical effectiveness

The Phase III clinical trial program, involving approximately 4000 patients with a clinical diagnosis of moderate to severe COPD, included two 6-month randomized placebo and active control trials (ACLIFORM-COPD and AUGMENT), a 6-month extension phase of the AUGMENT trial, and an additional 12-month randomized, controlled trial.

In long-term safety studies, Duaklir Genuair showed consistent effectiveness with a duration of use of more than 1 year, without signs of tachyphylaxis.

Effect on lung function

Duaklir Genuair (340 mcg + 11.8 mcg/dose twice daily) provided clinically significant improvements in lung function (measured by FEV1, forced vital capacity, and inspiratory capacity) compared with placebo. A clinically significant bronchodilator effect was achieved within 5 minutes after taking the first dose of the drug and was maintained throughout the entire interdose interval.

In the ACLIFORM-COPD study, Duaklir Genuair provided an improvement in FEV1 at 1 hour post-dose compared with placebo and aclidinium by 299 mL and 125 mL, respectively (p < 0.0001 in both comparisons), and an improvement in residual FEV1 compared with placebo and formoterol by 143 mL and 85 mL, respectively (p < 0.0001 in both comparisons). comparisons). In the AUGMENT trial, the improvement in FEV1 at 1 hour post-dose compared with placebo and aclidinium was 284 mL and 108 mL, respectively (p < 0.0001 in both comparisons), and the improvement in residual FEV1 compared with placebo and formoterol was 130 mL (p < 0.0001) and 45 mL (p = 0.01), respectively.

Relief of symptoms and improvement of health related to the disease

Shortness of breath and other symptoms

Duaklir Genuair provided a clinically significant improvement in dyspnea (as assessed by the Transient Dyspnea Index (TDI)), with an increase in TDI score after 6 months of treatment compared with placebo of 1.29 units in the ACLIFORM-COPD trial (p < 0.0001) and 1.44 units in the AUGMENT trial (p < 0.0001).

A pooled analysis of these two studies showed that Duaklir Genuair was associated with a statistically significant greater improvement in TDI compared with aclidinium (0.4 units; p=0.016) or formoterol (0.5 units; p=0.009).

Duaklir Genuair improved daytime COPD symptoms such as shortness of breath, chest symptoms, cough and sputum production (assessed by E-RS total score), as well as total nighttime symptoms, early morning symptoms, and early morning activity limiting symptoms, compared with placebo, aclidinium, and formoterol, but the improvement was not always statistically significant. The aclidinium/formoterol combination did not show a statistically significant reduction in the mean number of COPD-related night awakenings compared with placebo or formoterol.

Health-related quality of life In the AUGMENT study, Duaklear Genuair provided a statistically significant improvement in disease-related health status (assessed by the St George’s Respiratory Questionnaire (SGRQ)), with an improvement in SGRQ total score of -4.35 units compared with placebo (p < 0.0001).

In the ACLIFORM-COPD study, there was only a small reduction in total SGRQ compared with placebo due to an unexpected response to placebo treatment (p=0.598), and the percentage of patients achieving clinically significant improvement from baseline was 55.3% in the Duaklir Jenuair group and 53.2% in the placebo group (p=0.669).

A pooled analysis of data from these two studies showed greater improvement in overall SGRQ with DuaklirGenuair compared with formoterol (-1.7 units; p=0.018) or aclidinium (-0.79 units; p=0.273).

Reducing the frequency of exacerbations of COPD

A pooled efficacy analysis of two 6-month studies demonstrated a statistically significant 29% reduction in the rate of moderate-to-severe exacerbations (requiring antibiotic or corticosteroid therapy or resulting in hospitalization) with Duaklir Genuair compared with placebo (rate per patient-year: 0.29 vs. 0.42, respectively; p=0.036), as well as an increase in time to first moderate-to-severe exacerbation compared with placebo. with placebo (hazard ratio 0.70; p=0.027).

Use of emergency medications

Duaklir Genuair reduced the need for rescue medication over 6 months compared with placebo (by 0.9 inhalations/day (p<0.0001)), aclidinium (by 0.4 inhalations/day (p<0.001)) and formoterol (by 0.2 inhalations/day (p=0.062)).

Pharmacokinetics

The pharmacokinetic parameters of aclidinium and formoterol when used in combination inhalation did not differ significantly from those observed when using the individual components. Absorption

After a single inhalation of Duaklir Genuair, aclidinium and formoterol were rapidly absorbed into the blood plasma, reaching maximum concentrations 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 patients with COPD who received Duaklir Genuair 2 times a day for 5 days were achieved within 5 minutes after inhalation and were 128 pg/ml and 17 pg/ml, respectively.

Distribution

The total amount of aclidinium reaching the lungs through the Genuair inhaler was approximately 30% of the metered 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. Plasma protein binding 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 concentration range achieved when using the drug in therapeutic doses.

Biotransformation

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

The low absolute bioavailability of aclidinium during inhalation administration (<5%) is due to its intense systemic and presystemic hydrolysis both when in the lungs and when taken orally.

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 has also been established in vitro that aclidinium or its metabolites are not substrates or inhibitors of P-glycoprotein.

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

Removal

Following inhalation of Duaklir Genuair 340 mcg + 11.8 mcg/dose, the terminal half-lives of aclidinium and formoterol are approximately 5 hours and 8 hours, respectively.

After intravenous administration of 400 μg 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 feces.

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

The bulk of the administered dose of formoterol was metabolized in the liver and subsequently excreted 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

Pharmacokinetic studies of the aclidinium/formoterol combination have not been conducted in elderly patients. Since elderly patients do not require dose adjustment of aclidinium or formoterol, no dose adjustment is required when using the aclidinium/formoterol combination.

Patients with impaired renal and liver function

There are no data on the specific use of the aclidinium/formoterol combination 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.

Special instructions

Bronchial asthma

Duaklir Genuair should not be used for bronchial asthma; Clinical studies of the drug Duaklir Genuair for bronchial asthma have not been conducted.

Paradoxical bronchospasm

In clinical studies, there were no cases of paradoxical bronchospasm during the use of Duaklir Genuair at the recommended dose. However, paradoxical bronchospasm has been observed with other inhalation therapy. If this occurs, discontinue use of the drug and consider alternative therapy.

The drug is not intended for the relief of acute attacks

Duaklir Genuair is not indicated for the treatment of acute bronchospasm attacks.

Effect on the cardiovascular system

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

In some patients, β2-adrenergic agonists may cause increased heart rate and blood pressure, ECG changes such as flattening of the T wave, ST segment depression, and prolongation of the QTc interval.

If these effects develop, early cessation of therapy may be required. Long-acting β2-adrenergic agonists should be used with caution in patients with a current or history of prolongation of the QTc interval, or receiving medications that affect the duration of the QTc interval (see section “Interaction with other drugs and other types of drug interactions”).

System effects

Duaklir Genuair should be used with caution in patients with severe cardiovascular disorders, seizure disorders, thyrotoxicosis and pheochromocytoma.

When using high doses of β2-adrenergic receptor agonists, metabolic effects in the form of hyperglycemia and hypokalemia may develop. In phase III clinical trials, the incidence of significant increases in blood glucose concentrations with Duaklir Genuair 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

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

Due to its anticholinergic activity, Duaklir Genuair should be used with caution in symptomatic prostatic hyperplasia, urinary retention or closed-angle glaucoma (although direct contact of the drug with the eyes is very unlikely). Dry mouth, observed during anticholinergic therapy, if persisted for a long time, can lead to dental caries.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND OTHER MECHANISMS

The drug Duaklir Genuair does not affect or only slightly affects the ability to drive vehicles and operate machinery. The development of blurred vision or dizziness may affect the ability to drive or operate machinery.

Active ingredient

Aclidinium bromide, Formoterol

Composition

One measured dose contains:

Active substances:

micronized aclidinium bromide (calculated as aclidinium) 0.400 mg (0.343 mg)* and micronized formoterol fumarate dihydrate 0.012 mg**.

Excipient:

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.

Pregnancy

Pregnancy

There are no data on the use of Duaklir Genuair in pregnant women.

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

During pregnancy, Duaklir Genuair should only be used when the expected benefits outweigh the potential risks.

Breastfeeding 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 are excreted in milk, Duaklir Jenuair should be used during breastfeeding only in cases where the expected benefit to the woman outweighs the potential risk to the infant.

Fertility

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

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 within the previous 6 months
unstable angina, newly diagnosed arrhythmia within the previous 3 months, hospitalization within the previous 12 months for heart failure of NYHA functional classes III and IV 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 experience with the use of Duaklir Genuair (at the recommended therapeutic dose for up to 12 months) and its individual components.

Security Profile Overview

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

The most frequently reported adverse reactions with Duaklir Genuair were nasopharyngitis (7.9%) and headache (6.8%).

Interaction

Medicines for the treatment of COPD

Concomitant use of Duaklir Genuair with other anticholinergics and/or long-acting β2-adrenergic agonists has not been studied and is not recommended.

Although formal in vivo drug interaction studies have not been conducted with Duaklir Genuair, it has been used concomitantly with other drugs for the treatment of COPD, including short-acting β2-adrenergic agonists, methylxanthines, and oral and inhaled corticosteroids, without clinical evidence of drug interactions.

Metabolic interactions

In vitro studies have determined that therapeutic doses of aclidinium or its metabolites are not expected to interact with P-glycoprotein (P-gp) substrates 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 enhance the possible hypokalemic effect of β2-adrenergic agonists, so caution should be exercised when used together with these drugs (see section “Special Instructions”).

β-adrenergic receptor blockers

β-adrenergic receptor blockers may weaken or neutralize the effect of β2-adrenergic receptor agonists. If it is necessary to use beta-adrenergic receptor blockers (including in the form of eye drops), the administration of cardioselective beta-adrenergic receptor blockers is preferable, although they should be used with caution.

Other pharmacodynamic interactions

Duaklir Genuair should be used with caution in patients receiving drugs that prolong the QTc interval, such as monoamine oxidase inhibitors, tricyclic antidepressants, antihistamines or macrolides, as they may potentiate the cardiovascular effects of formoterol. Drugs that prolong the QTc interval increase the risk of developing ventricular arrhythmias.

Overdose

Experience in the treatment of overdose with Duaklir Genuair is limited. High doses of Duaklir Genuair may lead to increased symptoms and manifestations of anticholinergic and/or β2-adrenergic effects; the most common of which are: blurred vision, dry mouth, nausea, muscle spasms, tremors, headache, palpitations and hypertension.

In case of overdose, use of Duaklir Genuair should be discontinued. Supportive and symptomatic therapy is indicated.

Storage conditions

At a temperature not exceeding 30 °C.

Shelf life

2 years

Manufacturer

Industrias Pharmaceuticas Almiralle S.A., Spain