Relvar Ellipta, 22 mcg+92 mcg/dose 30 doses

Mechanism of action

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

Pharmacodynamic effects

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

Pharmacological effects beta2-adrenoceptor agonists, including vilanterol, are at least in part related to stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3′,5′-adenosine monophosphate (cyclic AMP). Increase of cyclic AMP level leads to relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity reactions from cells (primarily from mast cells).

Fluticasone furoate is a synthetic trifluoride glucocorticosteroid with pronounced anti-inflammatory action. The exact mechanism of action to relieve symptoms of bronchial asthma and chronic obstructive pulmonary disease (COPD) is not known.

Glucocorticosteroids have demonstrated a broad spectrum of action on different cell types (e.g., eosinophils, macrophages, lymphocytes) and mediators (e.g., cytokines and chemokines involved in inflammation).

Molecular interactions occur between glucocorticosteroids and DDBAs, whereby the steroid hormones activate the beta2-adrenoreceptor gene, increasing the number of susceptible adrenoreceptors. DDBAs bind to the glucocorticosteroid receptor, ensuring its steroid-dependent activation and stimulating translocation to the cell nucleus.

These synergistic interactions result in enhanced anti-inflammatory activity as revealed in in vitro and in vivo experiments with various inflammatory cells involved in the pathophysiological processes of bronchial asthma and COPD. The results of clinical studies using airway biopsy specimens have also demonstrated the synergy of gducocorticosteroids and DDBA that occurs when these drugs are administered to patients with COPD at therapeutic doses.

Pharmacokinetics

Absorption

. The absolute bioavailability of vilanterol and fluticasone furoate when the combination of vilanterol and fluticasone furoate was inhaled averaged 15.2% and 27.3%. respectively. The oral bioavailability of both substances was low, averaging 1.26% and < 2%. respectively. Given the low oral bioavailability, the systemic effects of vilanterol and fluticasone furoate after inhalation are primarily due to absorption of a portion of the inhaled dose into the lungs.

Distribution

After intravenous administration, vilanterol and fluticasone furoate are actively distributed in the body, with mean equilibrium distributions of 165 L and 661 L, respectively.

The two substances have a low ability to bind to erythrocytes. In in vitro studies, the binding of vilanterol and fluticasone furoag to human plasma proteins was high, reaching an average > 93.9 % and 99.6 %. respectively. The degree of binding to plasma proteins in vitro was not reduced in patients with hepatic and renal dysfunction.

While vilanterol and fluticasone furoate are P-glycoprotein (P-gp) substrates, when combining vilanterol and fluticasone furoate with P-gp inhibitors is administered simultaneously, changes in systemic vilanterol or fluticasone furoate exposure are not considered likely, because both substances have good absorption capacity.

Metabolism

Based on in vitro experiments, it can be concluded that the key metabolic pathways of vilanterol and fluticasone furoate in humans are primarily mediated through the cytochrome CYP3A4 isoenzyme.

Vilanterol is predominantly metabolized by O-dealkylation to form a variety 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 glucocorticosteroid activity.

The clinical study of drug-drug interactions with cytochrome CYP3A4 isoenzyme was performed using combination of vilanterol and fluticasone furoate (22 mg + 184 mcg/dose) and strong cytochrome CYP3A4 isoenzyme inhibitor – ketoconazole (400 mg) in healthy volunteers. Co-administration of the drugs resulted in a 36% and 33% increase in mean area under the pharmacokinetic curve (AUC(0-24)) and mean Cmax of fluticasone furoate. respectively. Increased exposure to fluticasone furoate was associated with a 27% decrease in mean serum cortisol concentration. measured over a period of 0-24 hours.

The co-administration of a combination of vilanterol and fluticasone furoate and ketoconazole resulted in increases in mean AUC(0-t) and Cmax of vilanterol by 65 and 22 %. respectively. Increased exposure to vilanterol did not increase the systemic effects of beta-agonists, which are characteristic of heart rate, blood potassium, or corrected QT(QTcF) interval.

After oral administration, fluticasone furoate was primarily metabolized in humans to form metabolites that were primarily excreted via the gastrointestinal tract, except for the radioactive dose < 1% excreted in the urine. The estimated plasma elimination half-life of fluticasone furoate after inhalation administration averaged 24 hours.

After oral administration, vilanterol was primarily metabolized in humans to form metabolites that were excreted in the urine and feces at a ratio of approximately 70% and 30% of the radioactive dose, respectively. The plasma elimination half-life of vilanterol after inhalation administration averaged 2.5 hours.

Particular patient groups

A population-based meta-analysis of the pharmacokinetics of vilanterol and fluticasone furoate in patients with bronchial asthma and COPD was conducted in phase III clinical trials. This analysis evaluated the effect of demographic covariates (age, sex, weight, body mass index (BMI), race, and ethnicity) on the pharmacokinetics of vilanterol and fluticasone furoate.

Race

In elderly patients with bronchial asthma or COPD, the AUC(0-24)fluticasone furoate was evaluated. Patients of the East Asian, Japanese, and South Asian races (12-14% of patients) were reported to have, on average, higher AUC(0-24) scores (higher by no more than 53%) compared with patients of the Caucasian race. However, in these populations, there was no evidence of higher systemic exposure, manifested by a more pronounced effect on urinary cortisol excretion over a 24-hour period. No effect of race on the pharmacokinetic parameters of vilanterol was detected in COPD patients.

The average Cmax of vilanterol was 220-287% higher, and the AUC(0-24)was comparable in patients of Asian origin compared with those in other racial groups, as assessed. However, the higher Cmax of vilanterol had no clinically significant effect on heart rate.

Children

There are no recommendations for dosing changes for adolescents (12 years or older). Pharmacoknetics of vilanterol and fluticasone furoate combination in patients younger than 12 years old have not been studied. Safety and efficacy of vilanterol and fluticasone furoate combination in children under 12 years old has not yet been established.

Elderly patients

The effect of age on the pharmacokinetics of vilanterol and fluticasone furoate was studied in a phase III clinical trial including patients with COPD and bronchial asthma.

In patients with bronchial asthma, there was no evidence of an effect of age (12-84 years) on the pharmacokinetic profile of fluticasone furoate and vilanterol.

Despite an increase (37%) in the AUC of vilanterol in patients with COPD throughout the observed age range of 41 to 84 years, there was no evidence of an effect of patient age on the pharmacokinetic profile of fluticasone furoate. In an elderly patient (aged 84 years) with a low body weight (35 kg), the AUC(0-24) of vilanterol would be 35% higher than the result calculated for the population (average COPD patient aged 60 years and 70 kg body weight), while the Cmax of vilanterol would remain unchanged. It is unlikely that these differences are clinically relevant.

Patients with impaired renal function

According to a clinical pharmacological study, severe impaired renal function (creatinine clearance < 30 ml min) does not significantly increase systemic exposure to vilanterol or fluticasone furoate or develop more pronounced systemic effects of glucocorticosteroids or beta2-agonists compared to healthy volunteers. Individual selection of the dose for patients with impaired renal function is not required.

The effect of hemodialysis is not studied.

Patients with impaired liver function

After continuous administration of the combination of vilanterol and fluticasone furoate for 7 days, increased systemic exposure to fluticasone furoate (as measured by AUC”>-24> DO three-fold) compared with healthy volunteers (according to the Child-Pugh classification of cirrhosis: A. cirrhosis stages. B or C). Increased systemic exposure to fluticasone furoate (when administered as a combination of vilanterol and fluticasone furoate at a dose of 22 mcg + 184 mcg/dose) in patients with moderate liver function impairment (Child-Pugh stage B) was associated with an average 34% reduction in serum cortisol concentration compared with healthy volunteers. The dose-normalized systemic exposure to fluticasone furoate in patients with moderate to severe hepatic impairment (Child-Puo stages B and C) was similar. Consequently, although patients with hepatic impairment do not require individualized dose selection, caution should be exercised when prescribing this medication to them.

After continuous administration of a combination of vilanterol and fluticasone furoag for 7 days, no significant increase in systemic vilanterol exposure (Cmax and AUC(0-24)) was observed in patients with mild, moderate, or severe hepatic impairment (Child-Pugh stages A B and C).

In comparison with healthy volunteer patients with mild to moderate hepatic dysfunction (who took vilanterol at a dose of 22 mcg) or severe (who took vilanterol at a dose of 11 mcg), no clinically significant beta-adrenergic systemic effects (changes in heart rate or serum potassium concentration) caused by vilanterol and fluticasone furoate combination were observed.

Gender, body weight, and body mass index (BMI)

. No evidence of an effect of sex, body weight, or BMI on the pharmacokinetic profile of fluticasone furoate was found in a phase III population-based pharmacokinetic analysis that included 1213 patients with bronchial asthma (712 women) and 1225 patients with COPD (392 women).

In a population-based pharmacokinetic analysis involving 856 patients with bronchial asthma (500 women) and 1091 patients with COPD (340 women), no evidence of an effect of sex, body weight, or BMI on the pharmacokinetic profile of vilanterol was found.

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

Indications

– Bronchial asthma;

– COPD (chronic obstructive pulmonary disease).

The use of Relvar Ellipt reduces the number of exacerbations of COPD in patients with a history of recurrent exacerbations.

Active ingredient

Composition

Powder for inhalation

Active ingredient:

vilanterol triphenatate micronized 40 µg(equivalent to 25 µg vilanterol);

Ancillary substances:

Magnesium stearate, 125 mcg;

Lactose monohydrate, up to 12.5 mg.

How to take, the dosage

Inhaled.

The drug Relvar Ellipt® should be used once a day 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 Ellipt® even if the disease is asymptomatic. If symptoms occur between doses, short-acting inhaled forms of beta2-agonists should be used as emergency therapy. The physician should regularly assess the patient’s condition to ensure that the optimal dosage of Relvar Ellipt® is prescribed in a timely manner. The dosage may be changed only on the doctor’s recommendation.

Adults and adolescents 12 years of age and older. The recommended dose of Relvar Ellipt® is one inhalation of 22 mcg vilanterol and 92 mcg fluticasone furoate once daily or one inhalation of 22 mcg vilanterol and 184 mcg fluticasone furoate once daily.

The starting dose of Relvar Ellipt® 22 mcg vilanterol and 92 mcg fluticasone furoate is indicated for patients who require low to medium doses of inhaled GCS used in combination with long-acting beta2-agonists.

Relvar Ellipt® at a dose of 22 mcg vilanterol and 184 mcg fluticasone furoate should be administered to patients who require a higher dose of inhaled GCS used in combination with long-acting beta2-agonists. If Relvar Ellipt® at a dose of 22 micrograms of vilanterol and 92 micrograms of fluticasone furoate does not adequately control the disease, increasing the dose to 22 micrograms of vilanterol and 184 micrograms of fluticasone furoate may improve bronchial asthma control.

Children. The safety and efficacy of Relvar Ellipt® in children younger than 12 years old has not been established.

COPD

Adults. The recommended dose of Relvar Ellipta® is one inhalation of 22 micrograms of vilanterol and 92 micrograms of fluticasone furoate once daily.

Relvar Ellipt® in a dose of 22 mcg vilanterol and 184 mcg fluticasone furoate is not indicated for the treatment of patients with COPD.

Children. The drug is not indicated for COPD in children.

Patient special groups

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

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

Patients with impaired hepatic function. According to clinical and pharmacological study in patients with liver dysfunction of mild, moderate and severe degree there is threefold increase of systemic exposure of fluticasone furoate (with increase of such parameters as Cmax and AUC) (see “Pharmacokinetics”). In patients with liver dysfunction the drug should be administered with caution since this group of patients has a higher risk of systemic adverse reactions caused by the use of GCS.

Inhaled recommendations for use

The first time the Ellipt® inhaler is used, there is no need to check for proper operation or to prepare the inhaler specifically for use. You must consistently follow the recommendations for use listed below.

The Ellipt® Inhaler is packaged in a container that contains a desiccant sachet of silica gel that is not intended for food or inhalation. This bag should be disposed of. After removing the inhaler from the container, the lid is in the closed position. Do not open it before taking the medication.

Detailed instructions for use of the Ellipt® Inhaler

Opening and closing the lid of the Ellipt® Inhaler without taking the medication causes the loss of one dose. This dose remains closed inside the inhaler, but it will not be available for administration. It is not possible to accidentally get a large dose or a double dose in one inhalation.

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

The dose counter shows how many doses of medicine are left in the inhaler. Before you use the inhaler, the dose counter shows the number 30. Each time you open the lid, the number of doses decreases by 1. When less than 10 doses are left, half of the counter turns red. After the last dose of medication is used up, half of the counter is highlighted in red, the counter shows the number 0. This means that the inhaler is empty. If you open the lid after that, the dose counter will turn completely red.

Preparing the dose

Do not open the lid until you are ready to take the medicine. The inhaler should not be shaken.

Put the lid down until you hear a click.

2. The dose of medication is ready for inhalation and the counter decreases the number of doses by one to confirm this.

3 If the counter does not decrease the number of doses after the click, then the inhaler is not ready to deliver the dose of medication. If this happens, you should call or contact the address listed under “For more information, please call”.

4. Do not shake the inhaler.

Inhaling the medicine

1. Hold the inhaler some distance from your mouth and exhale as deeply as possible. You should not breathe into the inhaler.

2. Place the mouthpiece between your lips and wrap your lips tightly around it. Do not block the ventilation hole with your fingers.

Your lips should fit exactly into the shape of the mouthpiece of the inhaler.

3. take one deep, long, even breath. Hold your breath as long as possible (for at least 3-4 seconds).

4. remove the inhaler from your mouth.

5. Exhale slowly and calmly.

If the inhaler is used correctly, the patient may not taste or feel the medicine coming in.

Closing the inhaler and rinsing the mouthpiece

If the mouthpiece needs to be cleaned, a dry paper towel should be used before closing the lid.

1. Lift the lid as far as it will go, ensuring that the mouthpiece is completely closed.

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

Interaction

When prescribing the drug in therapeutic doses, clinically significant drug interactions of vilanterol or fluticasone furoate are considered unlikely due to the low plasma concentrations of the latter during inhalation.

Beta-adrenoblockers may weaken or antagonize the effects of beta2-adrenomimetics. Concomitant administration of non-selective and selective beta-blockers should be avoided unless their administration is strictly necessary.

Vilanterol and fluticasone furoate undergo rapid primary metabolism in the liver via the cytochrome isoenzyme system CYP3A4.

When concomitant administration of the drug with strong inhibitors of cytochrome CYP3A4 isoenzyme (e.g., ketoconazole, ritonavir) care should be taken because the systemic effects of vilanterol and fluticasone furoate may increase, which in turn may lead to increased risk of adverse reactions (see “Pharmacokinetics”).

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

Special Instructions

Relvar Ellipta® is not intended to relieve acute symptoms of bronchial asthma or exacerbations of COPD, in which case short-acting bronchodilators should be prescribed. An increase in the frequency of taking short-acting bronchodilators to relieve symptoms indicates a worsening of disease control and the need for medical consultation. Patients with bronchial asthma or COPD should not discontinue treatment with Relvar Ellipta® without medical supervision, as discontinuation of therapy may lead to exacerbation of the disease.

As with other types of inhalation therapy, paradoxical bronchospasm may develop after administration of the drug, accompanied by a rapid increase in wheezing. In this case, an urgent prescription of a short-acting inhaled bronchodilator and immediate withdrawal of Relvar Ellipt® are indicated. The patient should be seen by a physician and alternative therapy may be prescribed if necessary.

When treated with Relvar Ellipta® may develop adverse events associated with the course of bronchial asthma or exacerbation of the disease. Patients should be advised to continue treatment. If the disease is not controlled or worsens after starting therapy with Relvar Ellipta®, a physician should be consulted.

The use of inhaled GCSs (especially when taken at high doses for a long time) can lead to systemic side effects. These side effects occur much less frequently than with oral administration of GCS. Possible adverse systemic effects include: suppression of hypothalamic-pituitary-adrenal system function, decreased bone mineral density, growth retardation in children and adolescents, cataract and glaucoma.

In patients with COPD receiving Relvar Ellipta®, there has been an increased incidence of pneumonia as well as an increased incidence of severe pneumonia requiring patient hospitalization. In some cases, clinical episodes of pneumonia were fatal. Physicians should be aware of the possibility of pneumonia in patients with COPD, remembering that the clinical signs of this infectious disease are masked by symptoms of COPD exacerbation. The following groups of COPD patients have the highest risk of pneumonia when taking Relvar Ellipta®: Smoking patients, patients who have previously had pneumonia, patients with BMI <25 kg/m2 and patients with the volume of forced expiratory volume in the first second (OEF1) <50% of the proper values. The above factors should be considered when prescribing therapy with Relvar Ellipta® and treatment should be reconsidered if pneumonia occurs.

In patients with bronchial asthma, cases of pneumonia have been infrequently observed. Patients with bronchial asthma who received Relvar Ellipta® at a dose of 22 + 184 mcg/dose may have had a higher risk of pneumonia compared with patients who received a lower dose of Relvar Ellipta® (22 + 92 mcg/dose) or with the placebo group. No risk factors have been identified.

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

The effect on the ability to drive vehicles and operate mechanisms. Studies on the effect of the drug Relvar Ellipta® on the ability to drive vehicles and operate mechanisms have not been conducted. Based on the pharmacology of vilanterol or fluticasone furoate, adverse effects of the drug on these activities are not expected.

Contraindications

– severe allergic reactions to milk protein or a history of hypersensitivity to the active ingredient or any other component) in the drug;

– children under 12 years of age for the treatment of bronchial asthma;

– treatment of COPD at a dose of 22 mcg+184 mcg/dose.

With caution: adverse cardiovascular events such as arrhythmias (e.g., supraventricular tachycardia and extrasystoles) may occur when taking sympathomimetics, including Relvar Ellipta. Therefore, patients with severe forms of cardiovascular disease should be treated with caution with Relvar Ellipta.

Side effects

Infectious and parasitic diseases: often – pneumonia, upper respiratory tract infections, bronchitis, influenza, candidiasis of the mouth and throat.

Nervous system disorders: very often – headache.

Heart: infrequent – extrasystole.

Respiratory system, chest and mediastinum organs: very common – nasopharyngitis; common – oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia.

Gastrointestinal disorders: often – abdominal pain.

Skeletal, muscular and connective tissue: often – arthralgia, back pain, fractures.

General disorders and disorders at the site of administration: often – fever.

Overdose

Symptoms: In clinical studies, there have been no data on overdose of the combination of vilanterol and fluticasone furoate. The development of symptoms and signs due to the action of individual components of the drug and typical for overdose with beta2-agonists and inhaled GCS is possible.

treatment: s there is no specific treatment. Symptomatic therapy is prescribed and, if necessary, appropriate monitoring of the patient is ensured. The use of cardioselective beta-adrenoblockers should be considered only in cases of highly pronounced effects of vilanterol overdose, which are clinically manifested by insensitivity to supportive therapy. Cardioselective beta-adrenoblockers should be prescribed with caution in patients with a history of bronchospasm episodes.