Relvar Ellipta (Powder) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

Glaxo Operations UK Limited (United Kingdom)

ATC Code

R03AK10 (Vilanterol and fluticasone furoate)

Active Substances

Fluticasone furoate (WHO Rec.INN)

Vilanterol (WHO Rec.INN)

Dosage Forms

	Relvar Ellipta	Powder for inhalation, metered dose, 22 mcg+92 mcg/1 dose: inhaler 30 doses
		Powder for inhalation, metered dose, 22 mcg+184 mcg/1 dose: inhaler 30 doses

Dosage Form, Packaging, and Composition

Powder for inhalation, metered dose 22 mcg+92 mcg/dose white in color.

Vilanterol strip (30 blisters)

Excipients : magnesium stearate – 125 mcg, lactose monohydrate – up to 12.5 mg.

Fluticasone furoate strip (30 blisters)

Excipients : lactose monohydrate – up to 12.5 mg.

30 doses – plastic inhalers with a dose counter (1) with two laminated aluminum strips (each with 30 blisters) – multi-layer containers made of aluminum foil (1) with an easy-open cap – cardboard packs.

Powder for inhalation, metered dose 22 mcg+184 mcg/dose white in color.

Vilanterol strip (30 blisters)

Excipients : magnesium stearate – 125 mcg, lactose monohydrate – up to 12.5 mg.

Fluticasone furoate strip (30 blisters)

Excipients : lactose monohydrate – up to 12.5 mg.

30 doses – plastic inhalers with a dose counter (1) with two laminated aluminum strips (each with 30 blisters) – multi-layer containers made of aluminum foil (1) with an easy-open cap – cardboard packs.

* during the production of the finished product, mixtures of active and excipient substances may be loaded into the final product with an excess of up to 8% to compensate for losses during blister filling.
** indicates the nominal amount of active substance loaded during the manufacturing process.

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Combined bronchodilator agent (selective beta₂-adrenomimetic + topical glucocorticosteroid)

Pharmacological Action

Mechanism of action

Vilanterol and fluticasone furoate belong to two different classes of drugs – a synthetic glucocorticoid and a long-acting selective beta₂-adrenomimetic.

Pharmacodynamic effects

Vilanterol trifenatate belongs to the class of long-acting selective beta₂-adrenomimetics (LABA).

The pharmacological effects of β₂-adrenoceptor agonists, including vilanterol trifenatate, are at least partially associated with the stimulation of intracellular adenylate cyclase – an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) into cyclic 3′,5′-adenosine monophosphate (cyclic AMP). An increase in cyclic AMP levels leads to relaxation of bronchial smooth muscle and inhibition of the release of immediate hypersensitivity reaction mediators from cells (primarily from mast cells).

Fluticasone furoate is a synthetic trifluorinated glucocorticoid with pronounced anti-inflammatory action. The exact mechanism of action that relieves the symptoms of bronchial asthma and chronic obstructive pulmonary disease (COPD) is unknown. Glucocorticoids have demonstrated a broad spectrum of action on various cell types (e.g., eosinophils, macrophages, lymphocytes) and mediators (e.g., cytokines and chemokines involved in the inflammatory process).

Molecular interactions occur between glucocorticoids and LABA, as a result of which steroid hormones activate the β₂-adrenoceptor gene, increasing the number of susceptible adrenoceptors. LABA bind to the glucocorticoid receptor, providing its steroid-dependent activation and stimulating translocation into the cell nucleus. These synergistic interactions lead to enhanced anti-inflammatory activity, as demonstrated in in vitro and in vivo experiments with various inflammatory cells involved in the pathophysiology of bronchial asthma and COPD. Results from clinical studies using airway biopsies have also demonstrated synergy between glucocorticoids and LABA that occurs when these drugs are administered to patients with COPD at therapeutic doses.

Pharmacokinetics

Absorption

The absolute bioavailability of vilanterol and fluticasone furoate following inhalation of the vilanterol and fluticasone furoate combination was on average 27.3% and 15.2%, respectively. The oral bioavailability of vilanterol and fluticasone furoate was low, averaging <2% and 1.26%, respectively. Given the low oral bioavailability, the systemic action of vilanterol and fluticasone furoate after inhalation is primarily due to the absorption of the portion of the inhaled dose that reaches the lungs.

Distribution

After IV administration, vilanterol and fluticasone furoate are widely distributed in the body, with mean steady-state V_d values of 165 L and 661 L, respectively.

Both substances – vilanterol and fluticasone furoate – have a low ability to bind to erythrocytes. In in vitro studies, the binding of vilanterol and fluticasone furoate to human plasma proteins was high, reaching on average 93.9% and >99.6%, respectively. The degree of plasma protein binding in vitro was not reduced in patients with hepatic or renal impairment.

Although vilanterol and fluticasone furoate are substrates of P-glycoprotein (P-gp), when the vilanterol and fluticasone furoate combination is administered concomitantly with P-gp inhibitors, a change in the systemic exposure of vilanterol or fluticasone furoate is considered unlikely, as both substances have good absorption capacity.

Metabolism

Based on in vitro data, it can be concluded that the primary metabolic pathways of vilanterol and fluticasone furoate in the human body are primarily mediated by the CYP3A4 isoenzyme.

Vilanterol is predominantly metabolized by O-dealkylation to form a number of metabolites with significantly lower beta₁– and beta₂-adrenomimetic activity.

Fluticasone furoate is predominantly metabolized by hydrolysis of the S-fluoromethylcarbothioate group to form metabolites with significantly lower glucocorticoid activity.

A clinical drug interaction study was conducted with the cytochrome CYP3A4 isoenzyme during continuous administration of the vilanterol and fluticasone furoate combination (22 mcg+184 mcg/dose) and a strong inhibitor of the cytochrome CYP3A4 isoenzyme – ketoconazole (400 mg) in healthy volunteers. Administration of the vilanterol and fluticasone furoate combination resulted in an increase in the mean AUC_(0-24) and mean C_max of fluticasone furoate by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% decrease in mean serum cortisol concentration measured over the 0-24 h period.

Administration of the vilanterol and fluticasone furoate combination and ketoconazole resulted in an increase in the mean AUC_(0-t) and C_max of vilanterol by 65% and 22%, respectively. The increase in vilanterol exposure did not lead to an increase in beta-agonist characteristic systemic effects on heart rate, blood potassium levels, or corrected QT interval (QT_cF).

Elimination

After oral administration, fluticasone furoate was metabolized in the human body, mainly forming metabolites that were predominantly excreted via the gastrointestinal tract, with the exception of <1% of the radioactive dose excreted in urine. The T_1/2 of fluticasone furoate from plasma after inhalation of the drug averaged 24 hours.

After oral administration, vilanterol was mainly metabolized in the human body, forming metabolites that were excreted in urine and feces, in a ratio of approximately 70% and 30% of the radioactive dose, respectively. The T_1/2 of vilanterol from plasma after inhalation of the vilanterol and fluticasone furoate combination averaged 2.5 hours.

Special patient groups

A population meta-analysis of the pharmacokinetics of vilanterol and fluticasone furoate in patients with asthma and COPD was conducted during phase III clinical trials. The population pharmacokinetic analysis assessed the influence of demographic covariates (age, sex, weight, BMI, race and ethnicity) on the pharmacokinetics of vilanterol and fluticasone furoate.

Race

Patients with asthma and COPD of East Asian, Japanese, and Southeast Asian origin (12-14% of patients) had on average higher AUC_(0-24) values (no more than 53% higher) compared to Caucasian patients. However, no signs of higher systemic exposure associated with a more pronounced effect on 24-hour urinary cortisol excretion were found in these populations. In patients with COPD, no effect of race on the pharmacokinetic parameters of vilanterol was found.

On average, the C_max of vilanterol was 220-287% higher, and the AUC_(0-24) was comparable in patients of Asian origin compared to other racial groups. However, the higher C_max of vilanterol had no clinically significant effect on heart rate.

Children

For adolescents (12 years or older), there are no recommendations for dose adjustment.

The pharmacokinetics of the vilanterol and fluticasone furoate combination in patients under 12 years of age have not been studied. The safety and efficacy of the vilanterol and fluticasone furoate combination in children under 12 years of age have not yet been established.

Elderly patients

The effect of age on the pharmacokinetics of vilanterol and fluticasone furoate was studied in phase III clinical trials, which included patients with COPD and asthma.

In patients with asthma, no signs of an effect of age (12-84 years) on the pharmacokinetic profile of fluticasone furoate and vilanterol were found.

Despite an increase (37%) in the AUC_(0-24) of vilanterol in patients with COPD throughout the observed age range from 41 to 84 years, no signs of an effect of patient age on the pharmacokinetic profile of fluticasone furoate were found. In an elderly patient (84 years old) with low body weight (35 kg), the AUC_(0-24) of vilanterol is expected to be 35% higher than the result calculated for the population (on average, a COPD patient aged 60 years and weighing 70 kg), while the C_max of vilanterol remains unchanged. These differences are unlikely to be clinically relevant.

Patients with renal impairment

According to a clinical pharmacological study for vilanterol and fluticasone furoate, severe renal impairment (CrCl <30 ml/min) does not lead to a significant increase in the systemic exposure of vilanterol or fluticasone furoate or to the development of more pronounced systemic effects of glucocorticosteroids or beta₂-agonists compared to healthy volunteers. Dose adjustment is not required for patients with renal impairment.

The effect of hemodialysis has not been studied.

Patients with hepatic impairment

After continuous administration of the vilanterol and fluticasone furoate combination for 7 days in patients with hepatic impairment (according to Child-Pugh classification: stage A, B or C cirrhosis), an increase in the systemic exposure of fluticasone furoate (measured AUC_(0-24) up to three times) was observed compared to healthy volunteers. The increased systemic exposure of fluticasone furoate (when prescribing the vilanterol and fluticasone furoate combination at a dose of 22 mcg+184 mcg/dose) in patients with moderate hepatic impairment (Child-Pugh stage B) was associated with a decrease in serum cortisol concentration by an average of 34% compared to healthy volunteers. In patients with severe hepatic impairment (Child-Pugh stage C) receiving a lower dose of 11 mcg+92 mcg, no decrease in serum cortisol concentration was observed. For patients with moderate and severe hepatic impairment, the maximum dose is 22 mcg+92 mcg.

After continuous administration of the vilanterol and fluticasone furoate combination for 7 days in patients with mild, moderate, or severe hepatic impairment (Child-Pugh stages A, B and C), no significant increase in the systemic exposure of vilanterol (by C_max and AUC) was noted.

Compared to healthy volunteers, patients with mild or moderate hepatic impairment (taking vilanterol 22 mcg) or severe impairment (taking vilanterol 11 mcg) showed no clinically significant beta-adrenergic systemic effects (change in heart rate or serum potassium concentration) caused by taking the vilanterol and fluticasone furoate combination.

Sex, body weight, BMI

According to the results of a population pharmacokinetic analysis of phase III clinical trial data, which included 1213 patients with asthma (712 women) and 1225 patients with COPD (392 women), no signs of an effect of sex, body weight, or BMI on the pharmacokinetic profile of fluticasone furoate were found.

According to a population pharmacokinetic analysis involving 856 patients with asthma (500 women) and 1091 patients with COPD (340 women), no signs of an effect of sex, body weight, or BMI on the pharmacokinetic profile of vilanterol were found.

No dose adjustment is required based on sex, body weight, or BMI.

Indications

• Bronchial asthma (as maintenance therapy);
• COPD (as maintenance therapy for airway obstruction in patients with COPD, including chronic bronchitis and/or pulmonary emphysema). The use of Relvar Ellipta can reduce the number of COPD exacerbations in patients with a history of recurrent exacerbations.

ICD codes

Dosage Regimen

The drug Relvar Ellipta is intended for inhalation use only.

Relvar Ellipta should be used once daily at the same time, in the morning or evening.

After inhalation, rinse your mouth with water without swallowing.

Bronchial asthma

The patient should be informed about the need for regular use of Relvar Ellipta even in the case of asymptomatic disease.

If symptoms occur between doses of the drug, inhaled short-acting beta₂-agonists should be used as emergency therapy.

The physician should regularly assess the patient’s condition to ensure timely prescription of the optimal dose of Relvar Ellipta. The dose can only be changed on the recommendation of a doctor.

Adults and adolescents 12 years and older

The recommended dose of Relvar Ellipta

• 1 inhalation of 22 mcg+92 mcg once daily

Or

• 1 inhalation of 22 mcg+184 mcg once daily.

The initial dose of Relvar Ellipta 22 mcg+92 mcg is prescribed to patients who require low or medium doses of inhaled glucocorticoids used in combination with long-acting beta₂-agonists.

Relvar Ellipta at a dosage of 22 mcg+184 mcg should be prescribed to patients who require a higher dose of inhaled corticosteroids used in combination with long-acting beta₂-agonists.

If Relvar Ellipta at a dosage of 22 mcg+92 mcg does not provide adequate disease control, increasing the dose to 22 mcg+184 mcg is considered, which may improve the level of asthma control.

Children

The safety and efficacy of Relvar Ellipta in children under 12 years of age have not been established.

COPD

Adults

The recommended dose of Relvar Ellipta is 1 inhalation of 22 mcg+92 mcg once daily.

Relvar Ellipta at a dosage of 22 mcg+184 mcg is not indicated for the treatment of patients with COPD.

Children

The drug is not used for the indication of COPD in children.

Special patient groups

Elderly patients (over 65 years old) do not require dose adjustment of the drug.

Patients with renal impairment do not require dose adjustment of the drug.

According to a clinical pharmacological study, patients with mild, moderate and severe hepatic impairment have a three-fold increase in the degree of systemic exposure of fluticasone furoate (AUC). The drug should be used with caution in patients with hepatic impairment who are at higher risk of systemic adverse reactions caused by corticosteroids. For patients with moderate and severe hepatic impairment, the maximum dose is 22 mcg+92 mcg.

Instructions for Use

When using the Ellipta inhaler for the first time, there is no need to check its proper operation or perform any special preparation of the inhaler. Simply follow the usage instructions sequentially.

The Ellipta inhaler is packaged in a container. Do not open the container until you are ready to use the medication. When you are ready to use the inhaler, remove the lid from the container. The container includes a desiccant packet to reduce humidity. Do not open the packet; it is not for eating or inhalation and should be discarded.

When you remove the inhaler from the container, its cover is in the closed position. Do not open it until you are ready to take the medication.

In the designated “Use by” 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.

The following are step-by-step instructions for using the Ellipta inhaler.

I. Read the following information before use

Opening and closing the cover of the Ellipta inhaler without inhaling the medication results in the loss of one dose. This dose remains sealed inside the inhaler but will not be available for inhalation. It is not possible to accidentally get a larger dose or a double dose in one inhalation.

One dose of medication is ready for inhalation after each time the cover is opened.

The dose counter shows how many doses of medication remain in the inhaler.

Before first use, the dose counter shows the number 30.

Each time the cover is opened, the number of doses decreases by 1.

When fewer than 10 doses remain, half of the counter turns red.

After the last dose has been used, half of the counter is highlighted in red and the counter shows the number 0. This means the inhaler is empty.

If you open the cover after this, the dose counter will turn completely red.

II. Preparing a dose

Do not open the cover until you are ready to take the medication. Do not shake the inhaler.

1. Push the cover down until it clicks.

2. The dose is ready for inhalation, and the dose counter confirms this by decreasing the number of doses by one.

3. If the dose counter does not decrease the number of doses after you hear the click, the inhaler is not ready to deliver a dose of medication. In this case, you should contact the phone number or address provided in the “For further information” section.

4. Never shake the inhaler.

III. Inhaling the medication

1. Holding the inhaler away from your mouth, breathe out as fully as you can. Do not exhale into the inhaler.

2. Place the mouthpiece between your lips and close your lips firmly around it. Do not block the air vent with your fingers.

3. Take one deep, long, steady breath in through your mouth. Hold your breath for as long as possible (for at least 3-4 seconds).

4. Remove the inhaler from your mouth.

5. Breathe out slowly and gently.

You may not taste or feel the medication even when using the inhaler correctly.

IV. Closing the inhaler and rinsing your mouth

If you wish to wipe the mouthpiece, use a dry tissue before closing the cover.

1. Lift the cover upwards until it is fully closed and the mouthpiece is covered.

2. After inhalation, you should rinse your mouth with water. This will reduce the chance of developing side effects such as throat and mouth pain.

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

Adverse Reactions

Data from large clinical trials in patients with COPD and bronchial asthma were used to determine the frequency of adverse reactions associated with Relvar Ellipta. The clinical development program for the treatment of bronchial asthma included 7034 patients who underwent a comprehensive assessment of adverse reactions. The clinical development program for the treatment of COPD involved 6237 patients who underwent a comprehensive assessment of adverse reactions.

Excluding pneumonia and fractures, the safety profiles of the drug in patients with COPD and bronchial asthma were similar. According to clinical trial data, pneumonia and fractures were observed more frequently in patients suffering from COPD.

The adverse reactions listed below are presented according to organ system and frequency of occurrence. Frequency, according to the WHO classification, is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000, including isolated cases).

Frequency of adverse reactions

Infections and infestations: Common – pneumonia, upper respiratory tract infections, bronchitis, influenza, oral and pharyngeal candidiasis.

Nervous system disorders: Very common – headache.

Cardiac disorders: Uncommon – extrasystole.

Respiratory, thoracic and mediastinal disorders: Very common – nasopharyngitis; Common – oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia.

Gastrointestinal disorders: Common – abdominal pain.

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

General disorders and administration site conditions: Common – pyrexia.

Post-marketing surveillance data

Immune system disorders Rare – hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria.

Psychiatric disorders Rare – anxiety.

Nervous system disorders Rare – tremor.

Cardiac disorders Rare – palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders Rare – paradoxical bronchospasm.

Musculoskeletal and connective tissue disorders: Common – muscle spasms.

Contraindications

• Patients with a history of severe allergic reactions to milk protein or hypersensitivity to the active substances or any other component of the drug;
• Children under 12 years of age for the treatment of bronchial asthma;
• Relvar Ellipta in the dose of 22 mcg+184 mcg/dose is not indicated for the treatment of COPD.

With caution when taking sympathomimetics, including Relvar Ellipta, adverse events such as arrhythmia (e.g., supraventricular tachycardia and extrasystole) may be observed from the cardiovascular system. Therefore, Relvar Ellipta should be prescribed with caution to patients suffering from severe forms of cardiovascular diseases.

Like other medicines containing corticosteroids, Relvar Ellipta 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

Fertility

There are no data on the effects on human fertility. Preclinical studies found no effect of vilanterol and fluticasone furoate on fertility.

Pregnancy

Data on the use of the drug during pregnancy are limited.

The use of Relvar Ellipta in pregnant women is only acceptable if the potential benefit to the mother outweighs the possible risk to the fetus.

Breast-feeding

There is insufficient data on the excretion of vilanterol or fluticasone furoate or their metabolites into human breast milk. However, other glucocorticoids and beta₂-agonists are detected in breast milk. The risk of the drug passing into the newborn or infant via milk cannot be excluded.

Considering the benefit of therapy for the mother versus the benefit of breastfeeding for the child, a decision should be made either to discontinue the drug or to stop breastfeeding.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with impaired liver function, who have a higher risk of developing systemic adverse reactions caused by glucocorticosteroids.

Use in Renal Impairment

Patients with impaired renal function do not require individual dose adjustment of the drug.

Pediatric Use

The use of the drug in children under 12 years of age is contraindicated.

Geriatric Use

Patients over 65 years of age do not require individual dose adjustment of the drug.

Special Precautions

Exacerbations

Relvar Ellipta is not intended for the relief of acute symptoms of bronchial asthma or exacerbations of COPD; in such cases, short-acting bronchodilators are required. An increased need for short-acting bronchodilators to relieve symptoms indicates worsening control of the disease and the need to consult a doctor.

Patients with bronchial asthma or COPD should not stop treatment with Relvar Ellipta without medical supervision, as discontinuation of therapy may lead to a recurrence of symptoms.

During treatment with Relvar Ellipta, adverse events associated with the course of bronchial asthma or exacerbation of the disease may develop. Patients should be advised to continue treatment. If disease control is not achieved or the condition worsens after starting therapy with Relvar Ellipta, a doctor should be consulted.

Paradoxical bronchospasm

As with other types of inhalation therapy, paradoxical bronchospasm may develop after taking the drug, accompanied by a rapid increase in wheezing. In this case, emergency administration of an inhaled short-acting bronchodilator and immediate discontinuation of Relvar Ellipta are indicated. The patient should be examined by a doctor and, if necessary, may be prescribed alternative therapy.

Hepatic impairment

Patients with moderate to severe hepatic impairment should be prescribed the 22 mcg+92 mcg dose; such patients should be under medical supervision to monitor for systemic side effects associated with the use of corticosteroids.

Systemic effects of corticosteroids

When using inhaled corticosteroids (especially with long-term use in high doses), systemic side reactions may develop. Such side 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, slowed growth rate in children and adolescents, cataracts, and glaucoma.

Pneumonia

In COPD patients receiving Relvar Ellipta, an increased frequency of pneumonia was observed, as well as an increased frequency of severe pneumonia requiring patient hospitalization. In some cases, clinical episodes of pneumonia were fatal. Physicians should be aware of the possibility of pneumonia development in COPD patients, keeping in mind that the clinical signs of such an infectious disease can be masked by the symptoms of a COPD exacerbation. The following groups of COPD patients have a higher risk of developing pneumonia while taking Relvar Ellipta: smoking patients, patients with a history of pneumonia, patients with BMI <25 kg/m², and patients with forced expiratory volume in 1 second (FEV₁) <50% of predicted. The above factors should be taken into account when prescribing therapy with Relvar Ellipta; in case of pneumonia occurrence, treatment should be reconsidered.

In patients with bronchial asthma, cases of pneumonia were uncommon. Patients with bronchial asthma receiving Relvar Ellipta at a dosage of 22 mcg+184 mcg/dose may have had a higher risk of developing pneumonia compared to patients receiving a lower dose of Relvar Ellipta (22 mcg+92 mcg/dose) or the placebo group. Risk factors have not been established.

In clinical trials in patients with COPD, a low frequency of bone fractures was detected in all treatment groups, but it was slightly higher (2%) in all groups receiving the combination of vilanterol and fluticasone furoate compared to the group receiving vilanterol monotherapy 22 mcg (<1%).

Effect on ability to drive and use machines

Studies on the effect of Relvar Ellipta on the ability to drive vehicles and operate machinery have not been conducted. Based on the pharmacology of vilanterol and fluticasone furoate, an adverse effect on these activities is not expected.

Overdose

Symptoms

No data on overdose with the combination of vilanterol and fluticasone furoate were obtained during clinical trials.

Overdose of Relvar Ellipta may cause the development of symptoms and signs due to the action of the individual components of the drug and characteristic of overdose with beta₂-agonists and inhaled corticosteroids (see the “Special Precautions” section).

Treatment

There is no specific treatment for overdose with the combination of vilanterol and fluticasone furoate. In case of overdose, symptomatic therapy is prescribed and, if necessary, appropriate patient monitoring is provided.

The use of cardioselective beta-blockers should be considered only in cases of severely pronounced overdose effects of vilanterol that are clinically manifested as unresponsiveness to supportive therapy. Cardioselective beta-blockers should be prescribed with caution to patients who have had episodes of bronchospasm in their medical history.

Drug Interactions

When the drug is prescribed at therapeutic doses, clinically significant drug interactions of vilanterol or fluticasone furoate are considered unlikely due to their low plasma concentrations following inhalation.

Beta-blockers may weaken or antagonize the effect of beta₂-adrenergic agonists. Concurrent use of non-selective and selective beta-blockers should be avoided, except in cases where their prescription is strictly necessary.

Vilanterol and fluticasone furoate undergo rapid primary metabolism in the liver via the cytochrome CYP3A4 isoenzyme system. Caution should be exercised when co-administering the drug with strong inhibitors of the cytochrome CYP3A4 isoenzyme (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.

Vilanterol and fluticasone furoate are substrates of P-gp. According to the results of a clinical pharmacological study in healthy volunteers who were simultaneously prescribed vilanterol and the strong P-gp inhibitor and moderate cytochrome CYP3A4 isoenzyme inhibitor verapamil, no significant effect on the pharmacokinetics of vilanterol was found. Clinical pharmacological studies of the co-administration of a specific P-gp inhibitor and fluticasone furoate have not been conducted.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life of the unopened aluminum container is 2 years; of the opened aluminum container – 6 weeks.

Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.