Annoro Ellipta® [Vilanterol, Umeclidinium]

Pharmacological properties

mechanism of action. anoro ellipt is a combination of a long-acting inhaled muscarinic receptor antagonist and a long-acting β2-adrenoreceptor agonist. after oral inhalation, both compounds act locally on the airways, resulting in an expansion of the bronchi due to various mechanisms of action.

Umeclidinium is an antagonist of long-acting muscarinic receptors (an anticholinergic), a derivative of quinuclidine with activity against numerous subtypes of muscarinic receptors. Umeclidinium exerts a bronchodilatory effect by competitively inhibiting the binding of acetylcholine to muscarinic receptors of smooth muscles of the respiratory tract. Preclinical models have a slow reversible effect on M₃human cholinergic receptors in vitro and long-term in vivo effects when directly introduced into the lungs.

Vilanterol. Vilanterol is a selective β agonist₂long-acting adrenoreceptors. Pharmacological effects of β agonists₂-adrenoreceptors, including vilanterol, is at least partially explained by the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3 ′, 5′-AMP (cAMP). An increase in cAMP causes relaxation of the smooth muscles of the bronchi and inhibits the release of immediate-type hypersensitivity mediators from cells, especially mast cells.

Pharmacokinetics With the inhalation administration of a combination of umeclidinium with vilanterol, its pharmacokinetics was similar to that of each active substance taken separately. Therefore, for pharmacokinetic purposes, each component can be considered separately.

Absorption

Umeklidinium. Following Inhalation of Umeclidinium to Healthy Volunteers C_max reached in 5-15 minutes. The bioavailability of inhalation omeclidinium averaged 13% of the dose with a small proportion of oral absorption. After inhalation of a repeated dose of Umeclidinium, the equilibrium state was reached within 7–10 days with 1.5–1.8-fold accumulation.

Vilanterol. Following Vilanterol Inhalation to Healthy Volunteers C_max reached in 5-15 minutes. The bioavailability of inhaled vilanterol was 27% with a small proportion of oral absorption. After a repeated dose of vilanterol, administered in the form of inhalations, the equilibrium state was reached within 6 days with a 2.4-fold accumulation.

Distribution

Umeklidinium. After administration to healthy volunteers, the average volume of distribution was 86 liters. In vitro binding to plasma proteins averaged 89%.

Vilanterol. After administration to healthy volunteers, the average volume of distribution in equilibrium was 165 liters. In vitro binding to plasma proteins averaged 94%.

Biotransformation

Umeklidinium. In vitro studies have shown that umeclidinium is mainly metabolized by cytochrome P450 2D6 (CYP 2D6) and is a substrate for the carrier of P-glycoprotein. The primary metabolic pathways for umeclidinium include oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc.), which leads to the formation of a number of metabolites either with reduced pharmacological activity or with unknown pharmacological activity. Systemic exposure to metabolites is low.

Vilanterol. In vitro studies have shown that vilanterol is mainly metabolized by cytochrome P450 3A4 (CYP 3A4) and is a substrate for the carrier of P-glycoprotein. The main metabolic pathway for vilanterol is O-dealkylation followed by the formation of a number of metabolites with significantly reduced β activity.₁- and β₂-adrenoreceptors.Plasma metabolic profiles after oral administration of vilanterol in a radioactive study in humans are consistent with high pre-system metabolism. The systemic effects of metabolites are low.

Excretion

Umeklidinium. Plasma clearance after iv administration was 151 l / h. After iv administration of the drug, about 58% of the dose labeled with a radioisotope (or 73% of the established radioactivity) was excreted with feces from the body after 192 hours. With urine, 22% of the administered dose labeled with a radioisotope was excreted after 168 hours (27% of the established radioactivity). Excretion of the material associated with the drug with feces after iv administration indicates its secretion into bile. After oral administration in healthy male volunteers, the majority of the total radioactivity was excreted mainly with feces (92% of the administered dose labeled with the radioisotope or 99% of the established radioactivity) 168 hours after the administration of the drug. Less than 1% of an oral dose (1% of established radioactivity) was excreted from the body in the urine, indicating a slight absorption after oral administration. T_½ after inhalation for 10 days, omeklidinium averaged 19 hours in healthy volunteers, with 3-4% excreted unchanged in the urine in equilibrium.

Vilanterol. The plasma clearance of vilanterol after iv administration was 108 l / h. After oral administration of labeled vilanterol, 70% of the labeled dose was detected in urine and 30% in feces. T_½ vilanterol after administration as an inhalation for 10 days averaged 11 hours

Special patient groups

Elderly patients (≥65 years old). Pharmacokinetic analysis of population data showed similar pharmacokinetics of umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease (COPD) aged ≥65 years and patients aged 65 years.

Impaired renal and hepatic function. In patients with severe renal failure, as well as in patients with moderate impaired liver function (Child-Pugh classification B class), there were no signs of an increase in the systemic effect of umeclidinium or vilanterol (C_max and AUC) after administration of a combination of umeclidinium with vilanterol, where the dose of umeclidinium was 2 times higher than the recommended dose, and vilanterol was used at the recommended dose, with no signs of changes in plasma protein binding between patients with severe renal failure / moderate liver function impairment compared with healthy volunteers . The use of a combination of umeclidinium with vilanterol was not evaluated in patients with severe hepatic impairment.

Other special groups. Pharmacokinetic analysis of the population data showed that dose adjustment of umeclidinium or vilanterol should not be carried out in patients of different ages, race, gender, body weight using inhaled GCS. A study conducted for slow CYP 2D6 metabolizers showed no clinically significant effect of the genetic polymorphism of CYP 2D6 regarding the systemic effect of omeclidinium.

Indications

For maintenance bronchodilator therapy to alleviate symptoms in adult patients with the disease.

Application

Adults the recommended dose (it’s also the maximum) is one inhalation of the anoro ellipse 1 time per day at the same time every day to maintain the condition of the expanded bronchi.

Special patient groups

Elderly patients (≥65 years old). No dose adjustment is required.

Patients with impaired renal function. No dose adjustment required

Patients with impaired liver function. Dose adjustment is not required for patients with mild to moderate hepatic impairment. In patients with severe hepatic insufficiency, studies of the effects of the use of the drug Anoro Ellipt have not been conducted, so it should be used with caution.

Children. For the treatment of COPD in persons aged 18 years, the drug was not used.

Mode of application. The medicine Anoro Ellipta is intended only for inhalation.

Instructions for use: the Ellipt inhaler contains pre-distributed doses and is ready for use, packaged in a tray containing a bag with a desiccant to reduce humidity.The bag with a desiccant must be discarded; it must not be eaten or inhaled. The patient should be informed that the inhaler tray should not be opened until the patient is ready for dose inhalation.

When the inhaler is removed from the sealed tray, it is in the closed position.

The date of final use from the moment of opening the tray is 6 weeks and must be entered by the patient in a specially designated place marked "Do not use after:". Application after the specified line is prohibited. After opening, the tray can be discarded.

The dose is lost upon opening with further closure of the inhaler cap without inhaling the drug. The lost dose will be held securely inside the inhaler, but will no longer be available for inhalation.

It is impossible to accidentally take an additional amount of the drug or its double dose during a single inhalation.

Dose preparation

1. Open the lid when you are ready to take the dose. Do not shake the inhaler.

2. Slide the cover down until it clicks. The drug is ready for inhalation.

The dispenser counts back in steps of 1 to confirm the action. If this does not happen after a click, the inhaler will not ensure the delivery of the dose, it should be returned to the pharmacy for advice.

How to inhale a medicine. When exhaling, the inhaler should be kept at a convenient distance from the mouth. Do not exhale into the inhaler.

The mouthpiece should be between the lips, the lips should compress it tightly. Ventilation openings should not be blocked by fingers during use of the drug.

1. Take one long, even, deep breath, and then hold the breath for as long as possible (at least 3-4 seconds).

2. Remove the inhaler from the mouth.

3. Exhale slowly and gently.

The drug can not be tried or felt even with the correct use of the inhaler.

Inhaler closure. The mouthpiece of the inhaler can be cleaned with a dry cloth before closing the lid. Slide the cover all the way up to close the mouthpiece.

Contraindications

Hypersensitivity to active substances or any of the excipients.

Side effects

Security Profile Overview. nasopharyngitis (9%) was the most frequently reported adverse reaction when using a combination of umeclidinium with vilanterol.

Table list of adverse reactions. The safety profile of the drug Anoro Ellipta is based on the safety experience of the combination of umeclidinium with vilanterol and individual components based on a clinical research program including 6855 patients with COPD and post-marketing surveillance data (2354 patients who received a combination of umeclidinium with vilanterol 1 time per day in clinical trials at the stage phase 3 lasting 24 weeks or more, of which 1296 patients received the recommended dose in a 24-week study, 832 patients high dose of 113/22 ug in 24-week study, and 226 patients - 113 ug and 22 ug umeklidiniuma vilanterola for the 12-month study).

The frequency of adverse reactions is determined in the table, including indicators of the overall incidence rate observed when combining data from five 24-week studies and a 12-month safety study (table).

The following classification of the incidence of side effects is used: very often (≥1 / 10); often (≥1 / 100 and 1/10); infrequently (≥ 1/1000 and 1/100); rarely (≥1 / 10,000 and 1/1000); very rarely (1/10 000); unknown (impossible to determine from the available data).

Table

special instructions

Bah. the combination should not be used in patients with BA, since this drug has not been investigated for this group of patients.

Paradoxical bronchospasm. As with other types of inhalation therapy, the use of umeclidinium with vilanterol can lead to life-threatening paradoxical bronchospasm. Umeclidinium / vilanterol therapy should be stopped immediately if paradoxical bronchospasm develops and alternative therapy should be started if necessary.

Not for use in acute condition. Umeklidinium with vilanterol is not indicated for the treatment of acute episodes of bronchospasm.

The worsening of the course of the disease. An increase in the incidence of short-acting bronchodilators to alleviate symptoms indicates poor control. In the event of a worsening of COPD during treatment with umeclidinium with vilanterol, it is necessary to re-examine the patient and review the tactics of treatment of COPD.

Effect on the cardiovascular system. Following the administration of antagonists of muscarinic receptors and sympathomimetics, including omeclidinium with vilanterol, cardiac arrhythmias, such as atrial fibrillation and tachycardia, may occur. Patients with clinically significant uncontrolled cardiovascular diseases were excluded from clinical trials. Therefore, umeclidinium with vilanterol in such patients should be used with caution.

Antimuscarinic activity. Given antimuscarinic activity, omeclidinium with vilanterol should be used with caution in patients with urinary retention or angle-closure glaucoma.

Hypokalemia. The use of β agonists₂-adrenoreceptors in some patients can cause significant hypokalemia, leading to the development of adverse reactions from the cardiovascular system. Decreased plasma potassium levels are usually transient.

Clinically significant effects of hypokalemia were not observed in clinical studies using umeclidinium with vilanterol in the recommended therapeutic dose. Caution should be exercised when using omeklidinium with vilanterol with other drugs that also have the potential to develop hypokalemia (see INTERACTIONS).

Hyperglycemia. The use of β agonists₂β-adrenergic receptors may cause transient hyperglycemia in some patients.

No clinically significant effects on plasma glucose have been identified in clinical trials using the drug in the recommended therapeutic dose. After the start of treatment in patients with diabetes mellitus, it is necessary to control the level of glucose in the blood plasma more carefully.

Accompanying illnesses.The drug should be used with caution in patients with convulsive disorders or with thyrotoxicosis, as well as in patients who unusually respond to β agonists₂-adrenoreceptors.

Excipients. The drug contains lactose. Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not be prescribed the drug.

Use during pregnancy or lactation

Pregnancy. There is no data on the use of the drug in pregnant women. Umeklidinium with Vilanterolum should be used during pregnancy