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

Active ingredient

Composition

One measured dose contains:

Active ingredients:

aclydinium bromide micronized (per aclydinium) 0.400 mg (0.343 mg)* and formoterol fumarate dihydrate micronized 0.012 mg**.

Ancillary substance:

Lactose monohydrate 11.588 mg.

* The delivered dose of aclydinium bromide is 396 mcg, which corresponds to 340 mcg of aclydinium.

* The delivered dose of formoterol fumarate dihydrate is 11.8 µg.

How to take, the dosage

For inhaled use.

The recommended dose is one inhaled dose of Duaclir Januair 340 mcg + 11.8 mcg/dose twice daily.

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

Elderly patients

There is no need to adjust the dose of the drug in elderly patients (see section on Pharmacokinetics).

Renal dosage adjustment is not required in patients with impaired renal function (see section on Pharmacokinetics).

Hepatic impairment

There is no need to adjust the dose of the drug in patients with hepatic impairment (see section on Pharmacokinetics).

Children

The drug Duaclir Genuair is not indicated for use in children and adolescents less than 18 years of age with COPD.

Interaction

Drugs for the treatment of COPD

The co-administration of Duaclir Januair with other anticholinergic agents and/or long-acting β2-adrenergic receptor agonists has not been studied and is not recommended.

While there have been no formal in vivo drug interaction studies of Duaclir Januair, it has been used concomitantly with other COPD medications, including short-acting β2-adrenergic receptor agonists, methylxanthines, and oral and inhaled glucocorticosteroids, without clinical evidence of drug interaction.

Metabolic interactions

In in vitro studies it was found that no interaction of acolidinium at therapeutic dose or its metabolites with P-glycoprotein substrates (P-gp) and drugs metabolized by cytochrome P450 isoenzymes (CYP450) and esterases is expected. At therapeutically relevant concentrations formoterol does not inhibit CYP450 isoenzymes (see section “Pharmacokinetics”).

Drugs causing hypokalemia

The concomitant use of methylxanthine derivatives, steroids or potassium-sparing diuretics may increase the possible hypokalemic effect of β2-adrenoreceptor agonists; therefore caution should be exercised when combined with these drugs (see sect. See section “Special Precautions”).

β-adrenergic receptor blockers

The effects of β-adrenergic receptor blockers may weaken or offset the effects of β2-adrenergic receptor agonists. If β-adrenergic receptor blockers are necessary (including in the form of eye drops), the administration of cardioselective β-adrenergic receptor blockers is preferable, although they should also be used with caution.

Other pharmacodynamic interactions

. Caution should be exercised when using Duaclir Januair in patients receiving medications that prolong the QTc interval, such as monoamine oxidase inhibitors, tricyclic antidepressants, antihistamines, or macrolides, because they may potentiate the effects of formoterol on the cardiovascular system. Drugs that prolong the QTc interval increase the risk of ventricular arrhythmias.

Special Instructions

Bronchial asthma

Duaclir Januair should not be used in bronchial asthma; there have been no clinical studies of Duaclir Januair in bronchial asthma.

Paradoxical bronchospasm

In clinical studies, there have been no cases of paradoxical bronchospasm with Duaclir Januair at the recommended dose. However, paradoxical bronchospasm has been observed with other inhalation therapy. If this occurs, discontinue the drug and consider an alternative therapy.

The drug is not indicated for acute attacks

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

The effect on the cardiovascular system

Duaclir Januair should be used with caution in patients who have had a myocardial infarction within the previous 6 months, in patients with unstable angina pectoris, newly diagnosed arrhythmias within the previous 3 months, with a QTc interval (calculated by the Bazette method) > 470 ms or hospitalized within the previous 12 months for NYHA functional class III and IV heart failure, because these patients were not included in clinical trials.

In some patients the β2-adrenoreceptor agonists may produce elevated pulse rate, increased blood pressure, and ECG changes as T-wave flattening, ST-segment depression and QTc interval prolongation.

If these effects occur, early discontinuation of therapy may be necessary. Long-acting β2-adrenoceptor agonists should be used with caution in patients with current or past history of QTc interval prolongation or those receiving medications that affect QTc interval length (see section “Interaction with other medicinal products and other drug interactions”).

Systemic effects

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

High doses of β2-adrenoreceptor agonists may cause metabolic effects such as hyperglycemia and hypokalemia. In phase III clinical trials, the incidence of a significant increase in blood glucose concentrations with Duaclyre Jenaire 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 medicinal products and other drug interactions”). Hypokalemia may increase the risk of arrhythmias.

Due to its anticholinergic activity, Duaclir Jenaire should be used with caution in symptomatic prostatic hyperplasia, urinary retention or closed-angle glaucoma (although direct eye contact is very unlikely). Dry mouth noted on anticholinergic therapy may lead to tooth decay if prolonged.

Impact on the ability to operate vehicles and other machinery

Duaclir Jenaire has no or negligible effect on the ability to operate vehicles and machinery. The development of blurred vision or dizziness may affect the ability to drive or operate machinery.

Contraindications

WARNING

Myocardial infarction suffered within the previous 6 months,

Side effects

The safety information below is based on experience with Duaclir Genuair (in recommended therapeutic doses up to 12 months) and its individual components.

The safety profile review

The adverse reactions associated with Duaclir Genuair are similar to those observed with its individual components. Because Duaclir Januair contains aclydinium and formoterol, the adverse reactions described for these components may be expected with its use.

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

Overdose

There is limited experience with overdose treatment of Duaclir Januair. High doses of Duaclir Januair may increase the symptoms and manifestations of anticholinergic and/or β2-adrenergic effects; the most common are: blurred vision, dry mouth, nausea, muscle spasm, tremor, headache, palpitations and arterial hypertension.

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

Pregnancy use

Pregnancy

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

Fetotoxicity has been noted in animal studies only at doses significantly higher than the maximum dose of aclydinium in humans, and adverse effects in reproductive toxicity studies only at very high systemic exposure to formoterol.

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

Breastfeeding

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

Fertility

Preclinical studies have found a slight decrease in fertility only when used at doses significantly higher than the maximum doses of acolidinium and formoterol in humans. It is considered unlikely that use of Duaclir Genuair at the recommended dose would affect fertility in humans.