Trelegy Ellipta (Powder) Instructions for Use

ATC Code

R03AL08 (Vilanterol, umeclidinium bromide and fluticasone furoate)

Active Substances

Vilanterol (Rec.INN registered by WHO)

Umeclidinium bromide (Rec.INN registered by WHO)

Fluticasone furoate (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Bronchodilator drug

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergics in combination with anticholinergic agents

Pharmacological Action

Combined drug. Fluticasone furoate, umeclidinium, and vilanterol belong to three different classes of drugs: a synthetic corticosteroid, a long-acting muscarinic receptor antagonist (also referred to as LAMA or anticholinergic agent), and a selective long-acting beta₂-adrenergic agonist (LABA), respectively.

Vilanterol is a selective LABA. The pharmacological effects of beta₂-adrenoceptor agonists, including vilanterol, are at least partially associated with stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). An increase in cyclic AMP concentration leads to relaxation of bronchial smooth muscles and inhibition of the release of immediate hypersensitivity reaction mediators from cells (primarily from mast cells).

Umeclidinium is a non-specific long-acting antagonist of m-cholinergic receptors. It exerts a bronchodilatory effect by competitively inhibiting the binding of acetylcholine to m-cholinergic receptors in the airway smooth muscle. It demonstrates slow reversibility of action on human m-cholinergic receptors of the M₃ subtype; the duration of action of umeclidinium after direct administration into the lungs has been shown.

Fluticasone furoate is a corticosteroid with pronounced anti-inflammatory action. The precise mechanism of action of fluticasone furoate that relieves the symptoms of COPD is unknown. Corticosteroids have demonstrated a broad spectrum of actions on various cell types (e.g., eosinophils, macrophages, lymphocytes) and mediators (e.g., cytokines and chemokines) involved in the inflammatory process.

The effect of the combination of vilanterol, umeclidinium, and fluticasone furoate on the QT interval duration was not evaluated in a thorough QT (TQT) study. TQT studies using the combination of vilanterol with fluticasone furoate and vilanterol with umeclidinium did not reveal a clinically significant effect on the QT interval when using the combination of vilanterol, umeclidinium, and fluticasone furoate at clinical doses.

No clinically significant effect on the QTc interval was identified upon ECG assessment in patients with COPD who used the combination of vilanterol, umeclidinium, and fluticasone furoate for up to 24 weeks, and in patients who used this combination for up to 52 weeks.

Pharmacokinetics

When the combination of vilanterol, umeclidinium, and fluticasone furoate was administered via inhalation from a single inhaler, the pharmacokinetics of each component were comparable to those observed when the active substances were administered as a combination of vilanterol with fluticasone furoate or a combination of vilanterol with umeclidinium.

Systemic concentrations of vilanterol, umeclidinium, and fluticasone furoate after their administration in combination via a single inhaler (triple combination) were within the range of values observed after administration of dual combinations (vilanterol with fluticasone furoate and vilanterol with umeclidinium) and when these active substances were administered in separate inhalers (fluticasone furoate, umeclidinium, and vilanterol).

After inhalation of the combination of vilanterol, umeclidinium, and fluticasone furoate, the C_max of vilanterol was reached in 7 minutes. The absolute bioavailability of vilanterol upon inhalation averaged 27%, accounting for minimal absorption from the oral cavity. After repeated inhalations of the combination of vilanterol and fluticasone furoate, steady state was reached within 6 days, with no more than 1.5-fold accumulation observed.

After inhalation of the combination of vilanterol, umeclidinium, and fluticasone furoate, the C_max of umeclidinium was reached in 5 minutes. The absolute bioavailability of umeclidinium upon inhalation averaged 13%, accounting for minimal absorption from the oral cavity. After repeated inhalations of umeclidinium, steady state was reached within 7-10 days with 1.5 to 2-fold accumulation.

After inhalation of the combination of vilanterol, umeclidinium, and fluticasone furoate, the C_max of fluticasone furoate was reached in 15 minutes. The absolute bioavailability of fluticasone furoate upon inhalation of the combination of vilanterol and fluticasone furoate averaged 15.2%, which is primarily due to absorption of the inhaled portion of the dose delivered to the lungs, accounting for minimal absorption from the oral cavity. After repeated inhalations of the combination of vilanterol with fluticasone furoate, steady state was reached within 6 days, with no more than 1.6-fold accumulation observed.

After intravenous administration of vilanterol, the mean V_d at steady state was 165 liters. Plasma protein binding averaged 94%.

After intravenous administration of umeclidinium to healthy volunteers, the mean V_d was 86 liters. Plasma protein binding averaged 89%.

After intravenous administration of fluticasone furoate, the mean V_d was 661 liters. Plasma protein binding averaged more than 99.6%.

Vilanterol is metabolized mainly by the cytochrome P450 isoenzyme CYP3A4 and is a substrate of the P-glycoprotein (P-gp) transporter. The primary metabolic pathway is O-dealkylation, resulting in a number of metabolites with significantly lower beta₁– and beta₂-adrenergic agonist activity. The metabolic profile for plasma, determined in humans in a study using radioactive isotopes after oral administration of vilanterol, is consistent with high first-pass metabolism. Systemic exposure to metabolites is low.

Umeclidinium is metabolized mainly by the cytochrome P450 isoenzyme CYP2D6 and is a substrate of the P-gp transporter. The primary metabolic pathway for umeclidinium is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc.), resulting in a number of metabolites with lower pharmacological activity or metabolites whose pharmacological activity has not been established. Systemic exposure to such metabolites is low.

Fluticasone furoate is metabolized mainly by the cytochrome P450 isoenzyme CYP3A4 and is a substrate of the P-gp transporter. Fluticasone furoate is predominantly metabolized by hydrolysis of the S-fluoromethyl carbothioate group to form metabolites characterized by significantly lower glucocorticoid activity. Systemic exposure to metabolites is low.

After 10 days of vilanterol inhalations, the mean T_1/2 was 11 hours. The plasma clearance of vilanterol after intravenous administration was 108 L/h. After oral administration of radiolabeled vilanterol, 70% of the radioactivity was excreted by the kidneys and 30% via the intestine. The elimination of vilanterol occurred mainly via metabolism followed by excretion of metabolites by the kidneys and via the intestine.

After 10 days of umeclidinium inhalations, the mean T_1/2 was 19 hours, with 3% to 4% of the unchanged substance excreted by the kidneys at steady state. The plasma clearance of umeclidinium after intravenous administration was 151 L/h. After intravenous administration, approximately 58% of the administered dose of the radiolabeled substance was excreted via the intestine, and approximately 22% of the administered dose of the radiolabeled substance was excreted by the kidneys. Intestinal excretion of umeclidinium-related compounds after intravenous administration indicates their secretion into bile. After oral administration, 92% of the administered dose of the radiolabeled substance was excreted via the intestine. Less than 1% of the orally administered dose (1% of the excreted radioactivity) was excreted by the kidneys, indicating minimal absorption after oral administration.

The T_1/2 for fluticasone furoate after inhalation of vilanterol and fluticasone furoate averaged 24 hours. After intravenous administration, the T_1/2 averaged 15.1 hours. Plasma clearance after intravenous administration was 65.4 L/h. Renal excretion accounted for approximately 2% of the intravenously administered dose. After oral administration, fluticasone furoate is metabolized in humans mainly to form metabolites that are predominantly excreted via the intestine, with the exception of <1% of the radioactive dose excreted by the kidneys.

Indications

Maintenance therapy in adults with moderate to severe COPD who are not adequately responsive to therapy with combined inhaled corticosteroids and long-acting beta₂-agonists or combined long-acting beta₂-agonists and long-acting muscarinic receptor antagonists.

ICD codes

Dosage Regimen

Administer one inhalation once daily at the same time every day.

This product is for inhalation use only. Do not swallow the powder.

Open the inhaler just before use. Inhale the dose deeply and forcefully.

After inhalation, rinse your mouth with water without swallowing to reduce the risk of oral candidiasis.

Do not exceed the recommended dose. One inhalation per day is sufficient.

Use this medication regularly for maintenance therapy of COPD. Do not use it to relieve acute bronchospasm.

If you miss a dose, take it as soon as you remember. If it is almost time for the next dose, skip the missed dose and continue with your regular schedule. Do not take a double dose to make up for a forgotten one.

An increased need for a rescue inhaler indicates worsening disease control and requires medical consultation.

Do not discontinue therapy without consulting your doctor, as symptoms may recur.

Adverse Reactions

Infections and infestations: Common – pneumonia, upper respiratory tract infection, pharyngitis, rhinitis, influenza, nasopharyngitis; Uncommon – oral and throat candidiasis, viral respiratory tract infection.

Nervous system disorders: Common – headache.

Cardiac disorders: Uncommon – supraventricular tachyarrhythmia, tachycardia, atrial fibrillation.

Respiratory, thoracic and mediastinal disorders: Common – cough; Uncommon – oropharyngeal pain.

Musculoskeletal and connective tissue disorders: Common – arthralgia, back pain; Uncommon – fractures.

Contraindications

Patients with a history of severe allergic reactions to milk protein; patients with a history of hypersensitivity to the components of this combination product; children under 18 years of age.

With caution

Following the use of sympathomimetics and muscarinic receptor antagonists, including vilanterol and umeclidinium, adverse reactions such as arrhythmia (e.g., atrial fibrillation and tachycardia) may occur from the cardiovascular system. Therefore, this combination should be prescribed with caution to patients with severe cardiovascular diseases. Given the antimuscarinic activity of this combination, it should be prescribed with caution to patients with narrow-angle glaucoma or urinary retention.

Like other drugs containing corticosteroids, this combination should be prescribed with caution to patients with pulmonary tuberculosis, as well as to patients with chronic or untreated infections.

Use in Pregnancy and Lactation

Use during pregnancy is indicated only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

During treatment, the issue of discontinuing breastfeeding should be considered.

Use in Hepatic Impairment

Use with caution in patients with moderate and severe hepatic impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

The use of the combination of vilanterol, umeclidinium, and fluticasone furoate for the treatment of patients with bronchial asthma is not recommended.

The combination of vilanterol, umeclidinium, and fluticasone furoate is intended for the maintenance therapy of COPD. It should not be used to relieve acute symptoms, i.e., as emergency therapy for the treatment of acute episodes of bronchospasm. An inhaled short-acting bronchodilator should be used to relieve acute symptoms.

An increased need for short-acting bronchodilators to relieve symptoms indicates a worsening of disease control, in which case the patient requires medical consultation.

Treatment with this combination should not be discontinued without medical advice and supervision, as symptoms may recur after discontinuation of treatment.

As with other types of inhalation therapy, the use of this product may cause paradoxical bronchospasm, accompanied by a rapid increase in wheezing, which can be life-threatening. Treatment with the combination of vilanterol, umeclidinium, and fluticasone furoate should be discontinued immediately, the patient should be examined by a doctor, and alternative therapy should be prescribed if necessary.

Patients with moderate and severe hepatic impairment using this product require monitoring for the development of systemic adverse reactions associated with the use of corticosteroids.

When using inhaled corticosteroids (especially with long-term use in high doses), systemic side reactions may develop. Such reactions occur significantly less frequently than with oral corticosteroids. Manifestations of possible adverse systemic effects include: suppression of the hypothalamic-pituitary-adrenal axis function, decreased bone mineral density, cataracts, and glaucoma.

In accordance with the known class effect of inhaled corticosteroids, cases of pneumonia (including pneumonia leading to hospitalization) have been observed in patients with COPD using the combination of vilanterol, umeclidinium, and fluticasone furoate. In some cases, when using inhaled drugs containing the corticosteroid fluticasone furoate, including this combination, cases of fatal pneumonia have been reported. The possibility of pneumonia development in patients with COPD should be considered, since the clinical signs of this infectious disease coincide with the symptoms of COPD exacerbation. Risk factors for the development of pneumonia in patients with COPD using inhaled drugs containing corticosteroids include smoking, history of pneumonia, low body mass index, and severe COPD. These factors should be taken into account when prescribing therapy with the combination of vilanterol, umeclidinium, and fluticasone furoate, and therapy should be reviewed in case of pneumonia occurrence.

Drug Interactions

Beta-blockers may weaken or prevent the action of beta₂-adrenoceptor agonists such as vilanterol. If beta-blocker use is necessary, the possibility of using cardioselective beta-blockers should be considered; however, caution should be exercised with the concomitant use of both non-selective and selective beta-blockers.

Vilanterol and fluticasone furoate undergo rapid primary metabolism in the liver involving the cytochrome P450 isoenzyme CYP3A4.

Caution should be exercised when using this combination concomitantly with strong CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, ritonavir), as an increase in the systemic exposure of vilanterol and fluticasone furoate is possible, which in turn may lead to an increased risk of adverse reactions.

Concomitant use of this combination and other long-acting antimuscarinic drugs or long-acting beta₂-adrenoceptor agonists is not recommended, as it may increase adverse reactions.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.