Treleji Ellipta inhalation powder dispensed with 22 µg+55 µg+92 µg/dose 30 doses, 1pc

Composition

1 dose contains:

Active ingredients:

Vilanterol triphenatate micronized 40 mcg,

Umeclidinium bromide micronized 74.2 mcg.

Auxiliary substances:

Magnesium stearate – 75 mcg,

Lactose monohydrate – up to 12.5 mg

Pharmacological action

Pharmacotherapeutic group: Drugs for the treatment of obstructive airway diseases, adrenomimetics in combination with anticholinergic and glucocorticosteroid agents. ATX code: R03AL08Pharmacological properties

Pharmacodynamics

Mechanism of action

Fluticasone furoate, umeclidinium, and vilanterol belong to three different drug classes: a synthetic glucocorticosteroid, a long-acting muscarinic receptor antagonist (also referred to as a DDAX or anticholinergic agent), and a long-acting selective beta-2-adrenomimetic (DDBA), respectively.

Vilanterol

Vilanterol is a selective DDBA. The pharmacological effects of beta-2-adrenergic agonists, including vilanterol, are at least partially related to the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic – 3’,5’-adenosine monophosphate (cyclic AMP). An increase in the concentration of cyclic AMP leads to relaxation of the smooth muscles of the bronchi and inhibition of the release of mediators of immediate hypersensitivity reactions from cells (primarily from mast cells).

Umeclidinium

Umeclidinium is a non-specific long-acting muscarinic receptor antagonist (also called an anticholinergic). Umeclidinium has a bronchodilator effect by competitively inhibiting the binding of acetylcholine to muscarinic acetylcholine receptors in the airway smooth muscle. In preclinical studies in in vitro models, this compound demonstrates slow reversibility of action on human muscarinic receptors of the mh subtype, and in vivo models showed the duration of drug exposure after use directly into the lungs.

Fluticasone furoate is a glucocorticosteroid with a pronounced anti-inflammatory effect. The exact mechanism of action of fluticasone furoate to relieve COPD symptoms is unknown. Glucocorticosteroids have demonstrated a broad spectrum of action on various cell types (e. g., eosinophils, macrophages, and lymphocytes) and mediators (e. g., cytokines and chemokines) involved in the inflammatory process.

Pharmacodynamic effects

Impact on the cardiovascular system

The effect of the combination of vilanterol, umeclidinium and fluticasone furoate on the duration of the QT interval was not evaluated in a detailed study of the effect on the QT interval (TQT). In TQT studies using a combination of vilanterol with fluticasone furoate and vilanterol with umeclidinium, there was no clinically significant effect on the QT interval when using a combination of vilanterol, umeclidinium and fluticasone furoate in clinical doses.

There was no clinically significant effect on the QTc interval when ECG was evaluated using a centralized method in 911 patients with COPD who used a combination of vilanterol, umeclidinium and fluticasone furoate for a period of up to 24 weeks, and in a subgroup of 210 patients who used the drug for a period of up to 52 weeks.

Pharmacokinetics

When inhaled a combination of vilanterol, umeclidinium and fluticasone furoate in one inhaler, the pharmacokinetics of each component in healthy volunteers were comparable to those observed with the use of active substances in the form of a combination of vilanterol with fluticasone furoate or a combination of vilanterol with umeclidinium.

A population-based pharmacokinetic analysis for the combination of vilanterol, umeclidinium, and fluticasone furoate was performed in a subset of 74 patients with COPD who participated in the phase III study. Systemic concentrations of vilanterol, umeclidinium and fluticasone furoate after the use of a combination of vilanterol, umeclidinium and fluticasone furoate with a single inhaler (triple combination) were in the range of values observed after the use of double combinations (vilanterol with fluticasone furoate and vilanterol with umeclidinium) and when using active substances in separate inhalers (fluticasone furoate, umeclidinium and vilanterol).

Suction

Vilanterol

In healthy volunteers, after inhaling a combination of vilanterol, umeclidinium, and fluticasone furoate, the maximum plasma concentration (cmax) of vilanterol was reached after 7 minutes. The absolute bioavailability of vilanterol by inhalation was on average 27%, taking into account the insignificant absorption of the substance from the oral cavity. After repeated inhalations of the combination of vilanterol and fluticasone furoate, the equilibrium state was reached within 6 days, while no more than 1.5-fold accumulation was noted.

Umeclidinium

In healthy volunteers, after inhaling the combination of vilanterol, umeclidinium and fluticasone furoate, the Cmax of umeclidinium was reached after 5 minutes. The absolute bioavailability of umeclidinium by inhalation was on average 13%, taking into account the insignificant absorption of the substance from the oral cavity. After repeated inhalations of umeclidinium, the equilibrium state was reached within 7-10 days with 1.5-2-fold accumulation.

Fluticasone furoate

In healthy volunteers, after inhaling the combination of vilanterol, umeclidinium and fluticasone furoate, the cmax of fluticasone furoate was reached after 15 minutes. The absolute bioavailability of fluticasone furoate with inhaled use of a combination of vilanterol and fluticasone furoate averaged 15.2%, which is primarily due to the absorption of the inhaled portion of the dose that entered the lungs, taking into account insignificant absorption from the oral cavity. After repeated inhalations of the combination of vilanterol with fluticasone furoate, the equilibrium state was reached within 6 days, with no more than 1.6-fold accumulation.

Distribution

Vilanterol

After intravenous use of vilanterol to healthy volunteers, the average volume of distribution at steady state was 165 liters. Binding to human plasma proteins in vitro averaged 94%.

Umeclidinium

After intravenous use of umeclidinium to healthy volunteers, the average volume of distribution was 86 liters. Binding to human plasma proteins in vitro averaged 89%.

Fluticasone furoate

After intravenous use of fluticasone furoate to healthy volunteers, the average volume of distribution was 661 liters. Binding to human plasma proteins in vitro averaged more than 99.6%.

Metabolism

Vilanterol

In vitro studies have shown that vilanterol is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and is a substrate of the P-glycoprotein (P-gp) transporter. The main pathway of metabolism is O-dealkylation with the formation of a number of metabolites with significantly lower beta-1-and beta-2-adrenomimetic activity. The metabolic profile for blood plasma determined in humans during a study using radioactive isotopes after oral use of vilanterol is consistent with a high first-pass metabolism. Systemic exposure to metabolites is low.

Umeclidinium

In vitro studies have shown that umeclidinium is mainly metabolized by the cytochrome P450 isoenzyme CYP2D6 and is a substrate of the P-gp transporter. The main route of umeclidinium metabolism is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc. ), which leads to the formation of a number of metabolites with lower pharmacological activity or metabolites whose pharmacological activity has not been established. Systemic exposure to these metabolites is low.

Fluticasone furoate

In vitro studies have shown that fluticasone furoate is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and is a substrate of the P-gp transporter. Fluticasone furoate is mainly metabolized by hydrolysis of the S-fluoromethylcarbothioate group to form metabolites characterized by significantly lower glucocorticoid activity. Systemic exposure to metabolites is low.

Drug interactions

A clinical study was conducted with healthy volunteers to study the repeated use of a combination of vilanterol and fluticasone furoate (22 mcg + 184 mcg / dose) and a strong inhibitor of the CYP3A4 isoenzyme and a P-gp inhibitor – ketoconazole (400 mg). Concomitant use of the drugs resulted in an increase in the mean values of the average area under the pharmacokinetic curve (AUC (0-24)) and Cmax of fluticasone furoate by 36% and 33%, respectively. An increase in fluticasone furoate exposure was accompanied by a 27% decrease in the mean serum cortisol concentration measured over a 0-24-hour period. Concomitant use of a combination of vilanterol with fluticasone furoate and ketoconazole resulted in an increase in mean AUC values (0-t) and vilanterol Cmax by 65% and 22%, respectively. Increased exposure to vilanterol did not increase the systemic effects characteristic of beta-agonists, such as heart rate or blood potassium.

Fluticasone furoate, umeclidinium, and vilanterol are P-gp substrates. In a study evaluating drug interactions with repeated use in healthy volunteers treated with umeclidinium or a combination of vilanterol with umeclidinium and verapamil (240 mg) – an inhibitor of P-gp and the CYP3A4 isoenzyme-no clinically significant effect on the pharmacokinetics of vilanterol or umeclidinium was found.

The effect of genetically determined slow metabolism of the CYP2D6 isoenzyme on the pharmacokinetics of umeclidinium at steady state was evaluated in healthy volunteers (normal metabolism of the CYP2D6 isoenzyme and slow metabolism of the CYP2D6 isoenzyme). There was no clinically significant difference in the systemic exposure of umeclidinium (452 micrograms,8 times the therapeutic dose) after repeated daily inhalation doses in individuals with normal and slow metabolism of the CYP2D6 isoenzyme.

Deduction

Vilanterol

After inhalation of vilanterol for 10 days, the plasma half-life averaged 11 hours. The plasma clearance of vilanterol after intravenous use was 108 l/h. After oral use of vilanterol labeled with a radioactive isotope,70% of the radioactive substance was excreted by the kidneys and 30% – through the intestines. The elimination of vilanterol mainly occurred by the metabolic pathway, followed by excretion of metabolites by the kidneys and through the intestine.

Umeclidinium

After inhaling umeclidinium for 10 days, the half-life from blood plasma averaged 19 hours, while at steady state from 3 to 4% of the unchanged substance was excreted by the kidneys. Plasma clearance of umeclidinium after intravenous use was 151 l/h. After intravenous use, approximately 58% of the administered dose of the substance labeled with a radioactive isotope was excreted through the intestine, and approximately 22% of the administered dose of the substance labeled with a radioactive isotope was excreted by the kidneys. Intestinal excretion of drug-related compounds after intravenous use indicates their secretion into the bile. After oral use,92% of the dose of the substance labeled with a radioactive isotope was released through the intestine. Less than 1% of the oral dose (1% of the isolated radioactive substance) was excreted by the kidneys, which indicates insignificant absorption after oral use.

Fluticasone furoate

The plasma half-life of fluticasone furoate after inhaled use of vilanterol and fluticasone furoate was an average of 24 hours. After intravenous use, the average plasma half-life was 15.1 h. The plasma clearance after intravenous use was 65.4 l/h. Renal excretion was approximately 2% of the intravenous dose. After oral use of fluticasone, furoate was mainly metabolized in the human body to form metabolites that were mainly excreted through the intestine, with the exception of the dose of the radioactive substance

Special patient groups

Racial background

Among COPD patients, the AUC values (0-24) of fluticasone furoate were on average 23-30% higher in East Asian, Japanese, and South-East Asian patients(13-14% of patients) than in Caucasian patients. However, in this population, there was no evidence of an effect of higher systemic exposure on increased renal cortisol excretion over a 24-hour period. In patients with COPD, the effect of race on the pharmacokinetic parameters of umeclidinium or vilanterol was not revealed.

Elderly patients

The effect of age on the pharmacokinetics of vilanterol, umeclidinium, and fluticasone furoate was evaluated in a population pharmacokinetic analysis. There was no clinically significant effect requiring dose adjustment in elderly patients.

Patients with impaired liver function

The use of a combination of vilanterol, umeclidinium and fluticasone furoate in patients with impaired liver function was not evaluated. However, studies have been conducted using combinations of vilanterol with fluticasone furoate and vilanterol with umeclidinium.

The effect of using a combination of vilanterol and fluticasone furoate in patients with mild, moderate and severe hepatic impairment (Child-Pugh class A, B and C) was evaluated. A threefold increase in systemic exposure to fluticasone furoate was observed in patients with moderate hepatic impairment (treated with fluticasone furoate at a dosage of 184 mcg), and therefore patients with severe hepatic impairment were prescribed half the dose of fluticasone furoate (92 mcg), with no effect on systemic exposure to fluticasone furoate. Therefore, caution should be exercised when prescribing Treledji Ellipta to patients with moderate to severe hepatic impairment, but no dose adjustment is required for patients with hepatic impairment. No significant increase in systemic exposure to vilanterol was detected.

No data have been obtained to support increased systemic exposure to umeclidinium or vilanterol (Cmax or AUC) in patients with moderate hepatic impairment. The effect of umeclidinium in patients with severe hepatic impairment has not been evaluated.

Patients with impaired renal function

The use of a combination of vilanterol, umeclidinium and fluticasone furoate in patients with impaired renal function was not evaluated. However, studies have been conducted using combinations of vilanterol with fluticasone furoate and vilanterol with umeclidinium.

According to a clinical and pharmacological study for the combination of vilanterol and fluticasone furoate, severe renal impairment (creatinine clearance

In a study using a combination of vilanterol and umeclidinium in patients with severe renal impairment, there were no signs of increased systemic exposure to vilanterol or umeclidinium (Cmax and AUC). In vitro studies of binding to plasma proteins were conducted in patients with severe renal impairment and healthy volunteers, in which no clinically significant change in binding to plasma proteins was detected.

The effect of hemodialysis has not been studied.

Other patient characteristics

According to a population pharmacokinetic analysis, no dose adjustment of vilanterol, umeclidinium, or fluticasone furoate based on gender, body weight, or body mass index is required in patients with COPD who have used combinations of vilanterol with fluticasone furoate or vilanterol with umeclidinium. From the point of view of other patient characteristics, the study involving individuals with weak metabolic activity of the CYP2D6 isoenzyme did not provide data indicating a clinically significant effect of the genetic polymorphism of the CYP2D6 isoenzyme on the systemic exposure of umeclidinium.

Indications

Maintenance therapy in adults with moderate to severe chronic obstructive pulmonary disease (COPD) who do not respond sufficiently to therapy with combined inhaled glucocorticosteroids and long-acting beta-2 agonists or combined long-acting beta-2 agonists and long-acting muscarinic receptor antagonists.

Use during pregnancy and lactation

Use during pregnancy is indicated only in cases where the intended benefit to the mother exceeds the potential risk to the fetus. During the treatment period, it is necessary to decide whether to stop breastfeeding.

Recommendations for use

When using the Ellipte inhaler for the first time, there is no need to check its correct operation or prepare the inhaler for special use. Just consistently follow the recommendations for use listed below. The cardboard box of the Ellipta inhaler contains:

The inhaler is packed in a container. Do not open the container until you are ready to inhale the medicine. When you are ready to use the inhaler, remove the lid from the container. The container contains a dehumidifier bag to reduce humidity. Do not open this sachet, it is not intended for food or inhalation, and should be discarded.

When you remove the inhaler from the container, its lid is in the closed position. Do not open it until you are ready to inhale the medicine. In the designated “Use before” field on the inhaler label, write the date that corresponds to the opening date plus 6 weeks. Do not use the inhaler after this date.

Below are step-by-step instructions for using the Ellipta inhaler.

I. Please read the following information before using it

When opening and closing the lid of the Ellipte inhaler without taking the drug, one dose is lost. This dose remains sealed inside the inhaler, but it will not be available for use. It is not possible to accidentally get a large dose or a double dose in one inhalation.

II. Dose preparation

Do not open the lid until you are ready to take the medicine. Do not shake the inhaler.

III. Inhalation of a medicinal product

Even if you use the inhaler correctly, you may not be able to taste or feel the medication coming in. If you want to wipe the mouthpiece, do so before closing the lid, using a dry cloth.

IV. Closing the inhaler and rinsing the mouth

If stored in the refrigerator, the inhaler should be kept at room temperature for at least one hour before use.

Contraindications

Patients with a history of severe allergic reactions to milk protein;

patients with a history of hypersensitivity to the components of this combination agent;

children under 18 years of age.

With caution:

After the use of sympathomimetics and muscarinic receptor antagonists, including vilanterol and umeclidinium, adverse reactions such as arrhythmia (for example, atrial fibrillation and tachycardia) may occur from the cardiovascular system. In this regard, patients with severe forms of cardiovascular diseases should be prescribed Treledji Ellipta with caution. Given the antimuscarinic activity of this drug, it should be used with caution in patients with angle-closure glaucoma or urinary retention. Like other medications that contain glucocorticosteroids, Treledji Ellipta should be used with caution in patients with pulmonary tuberculosis, as well as in patients with chronic or untreated infections.

Side effects

Data obtained in clinical trials

The safety profile of Treledji Ellipta is based on data from 911 patients with COPD who used the drug at a dose of 22 mcg + 55 mcg + 92 mcg once a day for up to 24 weeks (of whom 210 patients used the drug at a dose of 22 mcg + 55 mcg + 92 mcg/dose once a day for up to 52 weeks) during the phase III clinical trial with the active reference drug.

The adverse reactions listed below are listed according to the lesion of organs and organ systems and frequency of occurrence. The frequency of occurrence is determined as follows: very common (≥1/10), common (≥1/100 and <1/10), infrequent (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (

Frequency of adverse reactions:

Infectious and parasitic diseases

• are common: pneumonia, upper respiratory tract infection, pharyngitis, rhinitis, flu, nasopharyngitis.
• Infrequently: candidiasis of the oral cavity and throat, viral infection of the respiratory tract.

Nervous system disorders: Common: headache.

Cardiac disorders: Infrequently: supraventricular tachyarrhythmia, tachycardia, atrial fibrillation.

Respiratory, thoracic and mediastinal disorders:

• Often: cough.
• Infrequently: oropharyngeal pain.

Musculoskeletal and connective tissue disorders:

• Common: arthralgia, back pain.
• Infrequently: fractures.

Description of individual adverse reactions

Pneumonia

Of 1810 patients with late-stage COPD (mean forced expiratory volume (FEV 1) at screening after bronchodilator use was 45% of the predicted value, standard deviation (CO) 13%), of which 65% of patients had moderate/severe exacerbation of COPD during the year preceding inclusion in the study, the incidence of pneumonia was higher in patients using Treledji Ellipta (20 patients,2%) than in patients using the combination of budesonide with formoterol (7 patients,

Pneumonia requiring hospitalization occurred in 1% of patients treated with Treledji Ellipta and less than 1% of patients treated with budesonide and formoterol for up to 24 weeks. One case of pneumonia with a fatal outcome was registered in a patient who used Treledji Ellipta. In the subgroup of 430 patients treated for up to 52 weeks, the incidence of pneumonia was in the groups receiving the drug Telegi of Ellipta and the combination of budesonide with formoterol, was the same and amounted to 2%.

The incidence of pneumonia with the use of the drug Telegi of Ellipta comparable to the frequency observed in the group treated with a combination of vilanterol furoate with fluticasone at a dose of 22 µg + 92 µg/dose in clinical trials using combination vilanterol and fluticasone furoate in patients with COPD.

Interaction

Interaction with beta-blockers:

Beta-blockers can weaken or inhibit the action of beta-2-adrenergic agonists, such as vilanterol. If the use of beta-blockers is necessary, the use of cardioselective beta-blockers should be considered; however, caution should be exercised when using both non-selective and selective beta-blockers simultaneously.

Interaction with inhibitors of the CYP3A4 isoenzyme:

Vilanterol and fluticasone furoate-components of Treledji Ellipta-undergo rapid primary metabolism in the liver with the participation of the cytochrome P450 isoenzyme CYP3A4. Caution should be exercised when concomitantly using the drug with strong inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, ritonavir), since it is possible to increase the systemic exposure of vilanterol and fluticasone furoate, which in turn can lead to an increased risk of adverse reactions.

Other long-acting antimuscarinic drugs and long-acting beta-2-adrenergic agonists:

Concomitant use of Treledji Ellipta with other long-acting antimuscarinic drugs or long-acting beta-2-adrenergic agonists has not been studied and is not recommended, as it may increase adverse reactions.

How to take, course of use and dosage

Treleji Ellipta is intended for inhalation use only.

After inhalation, the patient should rinse his mouth with water, without swallowing it.

Adults

The recommended and maximum dose is one inhalation of Treledji Ellipta once a day at the same time of day every day.

Children and teenagers

This drug is not used for the treatment of patients under 18 years of age, taking into account the indications for use.

Special patient groups

• Elderly patients
• No dose adjustment is required for patients over 65 years of age.
• Patients with impaired renal function
• No dose adjustment is required in patients with impaired renal function.
• Patients with impaired liver function
• No dose adjustment is required in patients with hepatic impairment. Studies evaluating the use of umeclidinium in patients with severe hepatic impairment have not been conducted.

Overdose

Clinical studies have not revealed data on overdose with Treledji Ellipta. Symptoms and Signs Overdose with Treledji Ellipta may cause signs, symptoms, or undesirable effects due to the pharmacological action of individual components of the drug. Treatment There is no specific treatment for overdose with Treledji Ellipta. In case of overdose, if necessary, maintenance treatment should be carried out with proper supervision. The possibility of using cardioselective beta-blockers should be considered only in the case of severe effects of vilanterol overdose, which are of clinical significance and do not respond to maintenance therapy measures. Cardioselective beta-blockers should be used with caution in patients with a history of bronchospasm episodes. Further management should be carried out in accordance with clinical indications.

Special instructions

Studies to evaluate the use of Treledji Ellipta in patients with bronchial asthma have not been conducted, so it is not recommended to use this drug for therapy in this group of patients.

Exacerbations

Treledji Ellipta is intended for the maintenance therapy of COPD. The drug should not be used for the relief of acute symptoms, i. e. as an emergency therapy for the treatment of acute episodes of bronchospasm. To relieve acute symptoms, a short-acting inhaled bronchodilator should be used. An increase in the frequency of using short-acting bronchodilators to relieve symptoms indicates a deterioration in disease control, in which case the patient needs to consult a doctor. Patients should not discontinue treatment with Treledji Ellipta without a doctor’s recommendation and supervision, as symptoms may resume after discontinuation of treatment.

Paradoxical bronchospasm

As with other types of inhalation therapy, the use of the drug can cause paradoxical bronchospasm, accompanied by a rapid increase in wheezing, and it can be life-threatening. Treatment with Treledji Ellipta should be stopped immediately, the patient should be examined by a doctor, and alternative therapy should be prescribed if necessary.

Patients with impaired liver function

Patients with moderate to severe hepatic impairment using Treledji Ellipta should be monitored for the development of systemic adverse reactions associated with the use of glucocorticosteroids.

Systemic effects of glucocorticosteroids

When using inhaled glucocorticosteroids (especially when taken for a long time in high doses), systemic adverse reactions may develop. Such reactions develop much less frequently than with oral use of glucocorticosteroids. Possible adverse systemic effects include suppression of the hypothalamic-pituitary-adrenal system, decreased bone mineral density, cataracts, and glaucoma.

Pneumonia

Consistent with the known effect of the inhaled glucocorticosteroid class, cases of pneumonia (including pneumonia leading to hospitalization) have been reported in patients with COPD using Treledji Ellipta. In some cases, fatal cases of pneumonia have been reported with inhaled medications containing the glucocorticoid fluticasone furoate, including Treledji Ellipta. Doctors should be aware of the possible development of pneumonia in patients with COPD, since the clinical signs of this infectious disease coincide with the symptoms of COPD exacerbation Risk factors for developing pneumonia in patients with COPD who use inhaled medications containing glucocorticosteroids include smoking, a history of pneumonia, low body mass index and severe COPD. When prescribing therapy with Treledji Ellipta, these factors should be taken into account, and in case of pneumonia, treatment should be reviewed.

Form of production

Powder for inhalation dosed,22 mcg + 55 mcg + 92 mcg/dose.

30 doses each in a plastic inhaler with a light gray body, beige mouthpiece cover and dose counter. The inhaler contains two aluminum laminated strips, each of which consists of 30 cells that contain a white powder. The inhaler is placed in a multi-layer aluminum foil container containing a desiccant bag. The container is sealed with an opening lid.

Storage conditions

Store at a temperature not exceeding 30 °C.

Keep out of reach of children.

Shelf

life is 2 years. After opening the aluminum container – 6 weeks.

Do not use after the expiration date indicated on the package.

Active ingredient

Vilanterol, Umeclidinium bromide, Fluticasone Furoate

Conditions of release from pharmacies

By prescription

Dosage form

powder for inhalation