Review of the anti-asthma drug Relvar Ellipta

How I got asthma

My story is probably no different from thousands of others, how I acquired asthma as a child. My grandfather on my father’s side and my mother are asthmatics, so it is not surprising that an “asthmatic” child appeared in our family. Against the backdrop of frequent bronchitis and the low availability of good drugs in Soviet and post-Soviet times, they did their job, and she took root firmly in my life. Back then they were still treating with euffilin, who knows, he will remember all the horror of the side effects of this terrible drug. The doctors at the hospital managed to inject it into my butt in the form of injections. It was just pure hell - pain, despair and fear.

How did you treat asthma?

Time passed, in adolescence and later I tried to find out from doctors how to cure this damn disease? To which all my pulmonologists loudly repeated: “This cannot be cured! It’s like a disability for life!” Evil doctors!!! Therefore, having tried several drugs that caused me a lot of side effects, I completely gave up on treating my illness, I just walked around with a Ventalin or Salbutamol balloon all the time. During acute attacks of suffocation, which began with any cold or acute respiratory viral infection, I called an ambulance, they relieved the attack.

How I found out about the drug Relvar Ellipta

And then a general practitioner accidentally appeared in my life, who had a different opinion about my illness. I came to him with an attack of suffocation, he prescribed me therapy in the form of a bunch of tablets and inhalations, which are aimed specifically at relieving acute bronchospasm. And at the same time, he prescribed the drug Relvar Ellipta, which had to be sprayed once a day.

Medicine Relvar Ellipta

After the acute condition was relieved, I started using this drug, and, lo and behold! I forgot what a Salbutamol and Ventalin balloon was! Out of habit, of course, I carried it with me; the fear of bronchospasm haunted me for some time. Finding myself far from home and seeing that I don’t have a sprinkler with me - this fear has been sitting in me since childhood! At the doctor’s appointment, I asked: “Vitaly Veniaminovich, will I ever be able to cure my illness?” He replied: “Yes, but a number of conditions must be met!” There is hope for a better life here!

Relvar Ellipta powder for inhalation dosed 22 mcg + 92 mcg/dose N30

Registration Certificate Holder

GlaxoSmithKline Trading (Russia)

Dosage form

Medicine - Relvar Ellipta

Description

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

Strip with vilanterol (30 cells)

1 dose

* vilanterol triphenatate micronized 40 mcg, incl. the nominal amount of vilanterol is 25 mcg**, which corresponds to a delivered dose of vilanterol of 22 mcg

Excipients

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

Strip with fluticasone furoate (30 cells)

1 dose

* micronized fluticasone furoate 100 mcg**, which corresponds to the delivered dose of fluticasone furoate 92 mcg

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 cells) - multilayer containers made of aluminum foil (1) with an easy-to-open lid - cardboard packs.

* during the production of the finished drug, mixtures of active and auxiliary substances can be added to the final product in excess of up to 8% to compensate for losses when filling the cells. ** indicates the nominal amount of active substance added during the production process.

Indications

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

Contraindications for use

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 at a dose of 22 mcg + 184 mcg/dose is not indicated for the treatment of COPD.

With caution:
when taking sympathomimetics, including the drug Relvar Ellipta, adverse events such as arrhythmia (for example, supraventricular tachycardia and extrasystole) may be observed in the cardiovascular system. In this regard, patients suffering from severe forms of cardiovascular disease should be prescribed Relvar Ellipta with caution.

Like other medicinal products that contain corticosteroids, Relvar Ellipta should be prescribed with caution to patients with pulmonary tuberculosis, as well as to patients with chronic or untreated infections.

pharmachologic effect

Mechanism of action

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

Pharmacodynamic effects

Vilanterol triphenatate

belongs to the class of selective long-acting beta2-adrenergic agonists (LABAs).

The pharmacological effects of β2-adrenergic agonists, including vilanterol triphenatate, are at least in part due to 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 level of cyclic AMP leads to relaxation of bronchial smooth muscles and inhibition of the release of mediators of immediate hypersensitivity reactions from cells (primarily from mast cells). Fluticasone furoate
is a synthetic trifluoride glucocorticoid with a pronounced anti-inflammatory effect. The exact mechanism of action to relieve 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 (eg, eosinophils, macrophages, lymphocytes) and mediators (eg, cytokines and chemokines involved in inflammation).

Molecular interactions occur between glucocorticoids and LABAs, as a result of which steroid hormones activate the β2-adrenergic receptor gene, increasing the number of receptive adrenergic receptors. LABAs 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, which has been demonstrated in in vitro and in vivo experiments with various inflammatory cells involved in the pathophysiological processes of asthma and COPD. The results of clinical studies using respiratory tract biopsies have also demonstrated the synergy of glucocorticoids and LABAs that occurs when these drugs are prescribed to patients with COPD at therapeutic doses.

Pros of using Relvar Ellipta

I have been using the drug Relvar Ellipta for two years at the time of writing this article. During this period, the attack occurred only once. It was a stupid coincidence and my carelessness. My husband and I moved to live in Anapa , but later, a year later, in late autumn, we returned to Kuzbass and stayed for the winter. The change in climate from warm to cold, plus smog from factories, plus FLU, brought me down, I even had to increase the dosage of the drug. But at the moment, I use the drug even every other day, it’s enough for me. By the way, when we lived in Anapa, I used Relvar Ellipta once every five days, while jogging and running 5-7 kilometers!

Relvar Ellipta

Suction

The absolute bioavailability of vilanterol and fluticasone furoate after inhalation administration of the combination of vilanterol and fluticasone furoate averaged 27.3% and 15.2%, respectively. The oral bioavailability of vilanterol and fluticasone furoate was low, averaging <2% and 1.26%, respectively. Taking into account the low oral bioavailability, the systemic effect of vilanterol and fluticasone furoate after inhalation is primarily due to the absorption of the portion of the inhalation dose that reaches the lungs.

Distribution

After intravenous administration, vilanterol and fluticasone furoate are actively distributed in the body, with average volumes of distribution at steady state being 165 L and 661 L, respectively.

Both substances - vilanterol and fluticasone furoate - have a low ability to bind to red blood cells. in vitro studies

The binding of vilanterol and fluticasone furoate to human plasma proteins was high and reached an average of 93.9% and > 99.6%, respectively.
The degree of binding to plasma proteins in vitro
was not reduced in patients with impaired liver or kidney function.

Although vilanterol and fluticasone furoate are P-glycoprotein (P-gp) substrates, when a combination of vilanterol and fluticasone furoate is administered concomitantly with P-gp inhibitors, changes in the systemic exposure of vilanterol or fluticasone furoate are considered unlikely, since both substances are well absorbed ability.

Metabolism

Based on these in vitro experiments, it can be concluded that the main 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 glucocorticosteroid activity.

A clinical study was conducted to evaluate drug interactions with the CYP3A4 isoenzyme during repeated administration of a combination of vilanterol and fluticasone furoate (22 mcg + 184 mcg/dose) and a strong CYP3A4 isoenzyme inhibitor, ketoconazole (400 mg) in healthy volunteers. Co-administration of vilanterol with fluticasone furoate and ketoconazole resulted in an increase in the mean area under the pharmacokinetic curve (AUC(0-24)) and mean maximum concentration (Cmax) of fluticasone furoate by 36% and 33%, respectively. Increased exposure to fluticasone furoate was associated with a 27% decrease in mean serum cortisol concentrations measured over the 0-24 hour period.

Co-administration of vilanterol and fluticasone furoate with ketoconazole resulted in an increase in the mean AUC(0-t) and Cmax values of vilanterol by 65% and 22%, respectively. Increased exposure to vilanterol did not result in increased systemic effects of beta-agonists on heart rate, blood potassium, or corrected QT interval (QTcF).

Removal

After oral administration of fluticasone furoate in humans, it was metabolized primarily to form metabolites that were predominantly excreted through the gastrointestinal tract, with the exception of <1% radioactive dose excreted by the kidneys. The plasma half-life for fluticasone furoate after inhalation administration of the drug averaged 24 hours.

After oral administration, vilanterol in humans was mainly metabolized to form metabolites that were excreted by the kidneys and intestines in a ratio of approximately 70% and 30% of the radioactive dose, respectively. The plasma half-life for vilanterol after inhalation of the combination of vilanterol and fluticasone furoate averaged 2.5 hours.

Special patient groups

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

Race

Patients with asthma or COPD of East Asian, Japanese and Southeast Asian races (12-14% of patients) had on average higher AUC(0-24) scores (no more than 53% higher) compared with Caucasian patients. However, these populations did not show evidence of higher systemic exposure associated with greater effects on renal cortisol excretion over a 24-hour period. In patients suffering from COPD, the influence of race on the pharmacokinetic parameters of vilanterol was not detected.

On average, vilanterol Cmax was 220-287% higher and AUC(0-24) was comparable in Asian patients compared to other racial groups. However, higher Cmaxvilanterol did not have a clinically significant effect on heart rate.

Children

For adolescents (12 years of age or older), there are no recommendations for changing the dosage regimen.

The pharmacokinetics of the combination of vilanterol and fluticasone furoate in patients under 12 years of age have not been studied. The safety and effectiveness of the combination of vilanterol and fluticasone furoate 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 3 clinical studies that included patients with COPD and bronchial asthma.

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

Despite an increase (37%) in the AUC(0-24) of vilanterol in patients with COPD in the age range from 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 is predicted to be 35% higher than that calculated for the population (average COPD patient aged 60 years and weighing body 70 kg), while Cmax of vilanterol will remain unchanged. It is unlikely that these differences are clinically relevant.

Patients with impaired renal function

According to a clinical pharmacological study for vilanterol and fluticasone furoate, severe renal impairment (creatinine clearance < 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 with healthy volunteers. No dose adjustment is required for patients with impaired renal function.

The effect of hemodialysis has not been studied.

Patients with liver dysfunction

After repeated dosing of the combination of vilanterol and fluticasone furoate for 7 days in patients with impaired liver function (according to the Child-Pugh classification of cirrhosis stages A, B or C), an increase in systemic exposure to fluticasone furoate was observed (measured by AUC (0-24 ) up to three times) compared to healthy volunteers. An increase in systemic exposure to fluticasone furoate (when prescribing a combination of vilanterol and fluticasone furoate at a dosage of 22 mcg + 184 mcg/dose) in patients with moderate liver dysfunction (Child-Pugh stage B) was accompanied by a decrease in serum cortisol concentrations by an average of 34 % compared to healthy volunteers.

In patients with severe hepatic impairment (Child-Pugh stage C) receiving the lower dose of 11 mcg + 92 mcg, no decrease in serum cortisol concentrations was observed. For patients with moderate to severe liver dysfunction, the maximum dose is 22 mcg + 92 mcg (see section "Dosage and Administration").

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

Compared with healthy volunteers, patients with mild to moderate hepatic impairment (taking vilanterol 22 mcg) or severe hepatic impairment (taking vilanterol 11 mcg) did not experience clinically significant beta-adrenergic systemic effects (changes in heart rate or concentration). serum potassium) caused by taking a combination of vilanterol and fluticasone furoate.

Gender, body weight, body mass index (BMI)

According to the results of a population pharmacokinetic analysis of data from the third phase of clinical trials, which included 1213 patients with bronchial asthma (712 women) and 1225 patients with COPD (392 women), no evidence of influence of gender, body weight or BMI on the pharmacokinetic profile of fluticasone furoate was found.

According to a population pharmacokinetic analysis involving 856 patients with bronchial asthma (500 women) and 1091 patients with COPD (340 women), no evidence of the influence of gender, body weight or BMI on the pharmacokinetic profile of vilanterol was found.

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

What is the dosage of Relvar Ellipta?

This drug has two dosages 22mcg+92mcg and 22mcg+184mcg . This means that the active substance Vilanterol contains the same amount in both cases - 22 µg, and the substance Fluticasone furoate is contained in one case 92 µg, and in the second - 184 µg. Which is very important to know, because one dosage of 22+184 is not equal to a dosage of 22+94!!!

Relvar Ellipta large dosage 22mcg+184mcg

Why do you need an increased dosage of Relvar? In my case, my doctor prescribed a low dosage, but warned me that in the fall, winter or spring, I may need to take a higher dosage to alleviate my asthma. It is also necessary during acute respiratory diseases. Or when your favorite factories began releasing a lot of caustic exhaust into the atmosphere. In short, I take higher dosages under unfavorable circumstances that may cause uncontrolled bronchospasm. Consult your doctor, maybe he will prescribe a regimen for you so that you can breathe normally, deeply, in any situation.

Relvar Ellipta por d/ing 22 mcg+184 mcg/dose 30 doses No. 1 (inhaled)

Suction

The absolute bioavailability of vilanterol and fluticasone furoate after inhalation administration of the combination of vilanterol and fluticasone furoate averaged 15.2 and 27.3%, respectively. The oral bioavailability of both substances was low and averaged 1.26 and

Distribution

After IV administration, vilanterol and fluticasone furoate are actively distributed in the body, with average Vss being 165 and 661 L, respectively. Both substances have a low ability to bind to red blood cells. In in vitro studies, the binding of vilanterol and fluticasone furoate to human plasma proteins was high and averaged >93.9 and 99.6%, respectively. The degree of binding to plasma proteins in vitro was not reduced in patients with impaired liver or kidney function. Although vilanterol and fluticasone furoate are P-glycoprotein (P-gp) substrates, when co-administering a combination of vilanterol and fluticasone furoate with P-gp inhibitors, a change in the systemic exposure of vilanterol or fluticasone furoate is considered unlikely, 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 the human body are primarily mediated through the cytochrome 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 GCS activity.

A clinical study of drug interactions with the cytochrome CYP3A4 isoenzyme was conducted with long-term administration of a combination of vilanterol and fluticasone furoate (22 + 184 mcg/dose) and a strong inhibitor of the cytochrome CYP3A4 isoenzyme - ketoconazole (400 mg) - using healthy volunteers as an example. Coadministration of the drugs resulted in an increase in the mean AUC0-24 and mean Cmax of fluticasone furoate by 36 and 33%, respectively. Increased exposure to fluticasone furoate was associated with a 27% decrease in mean serum cortisol concentrations measured over a period of 0–24 hours. Coadministration of the combination of vilanterol and fluticasone furoate and ketoconazole resulted in an increase in mean vilanterol AUC0-t and Cmax by 65 and 22%, respectively. Increased exposure to vilanterol did not lead to an increase in the systemic effects characteristic of beta-agonists - effects on heart rate, blood potassium levels, or corrected QT interval (QTcF).

Removal

After oral administration of fluticasone furoate in the human body was mainly metabolized to form metabolites, which were predominantly excreted through the gastrointestinal tract, with the exception of the dose of radioactive substance

Following oral administration, vilanterol was primarily metabolized in humans to form metabolites that were excreted in urine and feces at approximately 70% and 30% of the radioactive dose, respectively. T1/2 of vilanterol plasma after inhalation of the drug averaged 2.5 hours.

Special patient groups

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

Race.

The AUC0–24 of fluticasone furoate was assessed in elderly patients with asthma or COPD. According to the data obtained, patients of East Asian, Japanese and South Asian races (12-14% of patients) had on average higher AUC0-24 scores (no more than 53%) compared to Caucasian patients. However, in these populations there was no evidence of higher systemic exposure manifested by a greater effect on urinary cortisol excretion over a 24-hour period. In patients suffering from COPD, the influence of race on the pharmacokinetic parameters of vilanterol was not detected. On average, vilanterol Cmax was 220% to 287% higher and AUC0-24 was comparable in Asian patients to other racial groups. However, the higher Cmax of vilanterol did not have a clinically significant effect on heart rate.

Children.

For adolescents (12 years of age or older), there are no recommendations for changing the dosage regimen. The pharmacokinetics of the combination of vilanterol and fluticasone furoate in patients under 12 years of age have not been studied. The safety and effectiveness of the combination of vilanterol and fluticasone furoate 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 3 clinical studies that included 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 AUC0-24 of vilanterol in patients with COPD throughout the observed age range from 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 AUC0-24 of vilanterol would be 35% higher than that calculated for the population (average COPD patient aged 60 years and weighing 70 kg), in while the Cmax of vilanterol will remain unchanged. It is unlikely that these differences are clinically relevant.

Renal dysfunction.

According to a clinical and pharmacological study, severe renal impairment (Cl creatinine

Liver dysfunction.

After continuous administration of the combination of vilanterol and fluticasone furoate for 7 days, patients with hepatic impairment experienced up to a threefold increase in systemic exposure to fluticasone furoate (as measured by AUC0-24) compared with healthy volunteers (according to the Child-Pugh classification of liver cirrhosis: stages cirrhosis A, B or C). An increase in systemic exposure to fluticasone furoate (when prescribing a combination of vilanterol and fluticasone furoate at a dosage of 22 + 184 mcg / dose) in patients with moderate hepatic impairment (Child-Pugh stage B) was associated with a decrease in serum cortisol concentrations by an average of 34 % compared to healthy volunteers. Dose-normalized systemic exposure to fluticasone furoate was similar in patients with moderate to severe hepatic impairment (Child-Pugh stages B and C). Therefore, although patients with impaired liver function do not require individual dosing, caution should be exercised when prescribing this drug to them. After continuous administration of the combination of vilanterol and fluticasone furoate for 7 days in patients with mild, moderate or severe hepatic impairment (Child-Pugh stages A, B and C), there was no significant increase in the systemic exposure of vilanterol (as measured by Cmax and AUC0- 24). Compared with healthy volunteers, patients with mild to moderate hepatic impairment (vilanterol 22 mcg) or severe hepatic impairment (vilanterol 11 mcg) did not experience clinically significant beta-adrenergic systemic effects (changes in heart rate or serum potassium concentrations). ) caused by taking a combination of vilanterol and fluticasone furoate.

Gender, body weight, BMI.

According to the third phase of population pharmacokinetic analysis, which included 1213 patients with bronchial asthma (712 women) and 1225 patients with COPD (392 women), there was no evidence of the influence of gender, body weight or BMI on the pharmacokinetic profile of fluticasone furoate. According to a population pharmacokinetic analysis involving 856 patients with bronchial asthma (500 women) and 1091 patients with COPD (340 women), there was no evidence of an effect of gender, body weight or BMI on the pharmacokinetic profile of vilanterol. Individual dose selection is not required based on gender, body weight or BMI.

What does Relvar Ellipta contain?

I am not a pharmacist, but I know that this is a glucocorticosteroid drug, it has anti-inflammatory and bronchodilator effects. There are two dosages. The tablet lists the active and excipients.

1 dose contains
Vilanterol	22 mcg
Fluticasone furoate	92 mcg or 184 mcg
Magnesium stearate	125 mcg
Lactose monohydrate	up to 12.5 mg

composition of the drug

Guide to using Relvar Ellipta

Instructions for use RELVAR™ ELLIPTA™ (RELVAR™ ELLIPTA™)

Mechanism of action

Fluticasone furoate and vilanterol are two classes of drugs (synthetic corticosteroid and long-acting selective β2-receptor agonist).

Pharmacodynamic action

Fluticasone furoate

Fluticasone furoate is a synthetic trifluorinated corticosteroid with pronounced anti-inflammatory effects. The exact mechanism of action of fluticasone furoate on symptoms of asthma and chronic obstructive pulmonary disease (COPD) is unknown. Corticosteroids are known to have broad effects on many cell types (eg, eosinophils, macrophages, lymphocytes) and mediators (eg, cytokines and chemokines involved in the inflammatory process).

Vilanterol triphenatate

Vilanterol triphenatate is a selective, long-acting beta2-agonist (LABA).

The pharmacological action of β2-adrenergic agonists, including vilanterol triphenatate, is at least in part due to stimulation of intracellular adenyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3',5'-adenosine monophosphate (cyclic AMP). Elevated levels of AMP cause relaxation of bronchial smooth muscle and inhibition of the release of immediate hypersensitivity mediators from cells, especially mast cells.

A molecular interaction occurs between corticosteroids and LABAs, causing the steroids to activate the β2 receptor gene, thereby increasing the number and sensitivity of the receptors. LABAs prepare the glucocorticoid receptor for steroid-dependent activation and enhance nuclear translocation in cells. These synergistic interactions are reflected in the enhanced anti-inflammatory effects observed in vitro and in vivo in a number of inflammatory cells relevant to the pathophysiology of both asthma and COPD. Fluticasone furoate and vilanterol airway biopsy studies also provided evidence of synergy between corticosteroids and LABAs at clinical doses in patients with COPD.

Clinical efficacy and safety

Asthma

Three randomized, double-blind, phase III studies (HZA106827, HZA106829, and HZA106837) of varying duration assessed the safety and efficacy of fluticasone furoate/vilanterol in adults and adolescents with persistent asthma. All patients had been taking an ICS (inhaled corticosteroid) with or without a LABA for at least 12 weeks prior to Visit 1. In Study HZA106837, all patients had at least one exacerbation in the year preceding Visit 1 that required oral corticosteroid therapy. The duration of the HZA106827 study was 12 weeks. The study assessed the effectiveness of the combination of fluticasone furoate/vilanterol 92/22 mcg [n=201] and fluticasone furoate 92 mcg [n=205]) compared with placebo [n=203]. All drugs were taken 1 time/day. The duration of the HZA106829 study was 24 weeks. The study assessed the effectiveness of the combination of fluticasone furoate/vilanterol 184/22 mcg [n=197] and fluticasone furoate 184 mcg [n=194]) when used once a day compared with fluticasone propionate 500 mcg twice a day [n= 195].

In studies HZA106827/HZA106829, the combined primary efficacy endpoints were change from baseline in trough FEV1 at the clinical visit (pre-bronchodilator and pre-dosing) at the end of the treatment period in all patients and the weighted mean of serial FEV1 at 0 -24 hours post-dose, calculated for the subset of patients at the end of the treatment period. Change in percentage of 24-hour rescue drug-free periods from baseline was the secondary endpoint. Results for the primary and key secondary endpoints of these studies are shown in Table 1.

Table 1. Results for primary and key secondary endpoints of studies HZA106827 and HZA106829

Study No.	HZA106829		HZA106827
Dose of FF/VI* (mcg)	FF/VI 184/22 1 time/day and FF 184 1 time/day	FF/VI 184/22 1 time/day and FP 500 2 times/day	FF/VI 92/22 1 time/day and FF 92 1 time/day	FF/VI 92/22 1 time/day and placebo 1 time/day
Change in trough FEV1 with last observation carried forward (LOC) from baseline
Differences between drugs P value (95% CI)	193 ml p<0.001 (108, 277)	210 ml p<0.001 (127, 294)	36 ml p=0.405 (-48, 120)	172 ml p<0.001 (87, 258)
Weighted mean of serial FEV1 0-24 hours after dosing
Differences between drugs P value (95% CI)	136 ml p=0.048 (1, 270)	206 ml p=0.003 (73, 339)	116 ml p=0.06 (-5, 236)	302 ml p<0.001 (178, 426)
Change in percentage of 24-hour periods without rescue medications from baseline
Differences between drugs P value (95% CI)	11.7% p<0.001 (4.9, 18.4)	6.3% p=0.067 (-0.4, 13.1)	10.6% p<0.001 (4.3, 16.8)	19.3% p<0.001 (13.0, 25.6)
Change in percentage of 24-hour symptom-free periods from baseline
Differences between drugs	8.4%	4.9%	12.1%	18.0%
P value (95% CI)	p=0.010 (2.0, 14.8)	p=0.137 (-1.6, 11.3)	p<0.001 (6.2, 18.1)	p<0.001 (12.0, 23.9)
Change in morning peak expiratory flow from baseline
Differences between drugs P value (95% CI)	33.5 l/min p<0.001 (22.3, 41.7)	32.9 l/min p<0.001 (24.8, 41.1)	14.6 l/min p<0.001 (7.9, 21.3)	33.3 l/min p<0.001 (26.5, 40.0)
Change in evening peak expiratory flow from baseline
Differences between drugs P value (95% CI)	30.7 l/min p<0.001 (22.5, 38.9)	26.2 l/min p<0.001 (18.0, 34.3)	12.3 l/min p<0.001 (5.8, 18.8)	28.2 l/min p<0.001 (21.7, 34.8)

*FF/VI = fluticasone furoate/vilanterol combination

FP = fluticasone propionate

Study HZA106837 used varying treatment durations (minimum duration 24 weeks, maximum duration 76 weeks; most patients received a minimum duration of treatment of 52 weeks). In study HZA106837, patients were randomized to receive fluticasone furoate/vilanterol 92/22 mcg [n=1009] or FF 92 mcg [n=1010]. Both drugs were taken 1 time/day. In study HZA106837, the primary endpoint was time to first severe asthma exacerbation. Severe asthma exacerbation was defined as worsening asthma requiring use of systemic corticosteroids for at least 3 days, inpatient hospitalization, or emergency department visit due to asthma requiring use of systemic corticosteroids. The adjusted mean change from baseline in trough FEV1 was also assessed as a secondary endpoint.

In study HZA106837, the risk of severe asthma exacerbation in patients receiving fluticasone furoate/vilanterol 92/22 mcg was reduced by 20% compared with patients receiving FF 92 mcg alone (hazard ratio 0.795, p=0.036 95% CI 0.642 , 0.985). The rate of severe asthma exacerbation per patient per year was 0.19 in the FF 92 mcg group (approximately 1 in every 5 years) and 0.14 in the fluticasone furoate/vilanterol 92/22 mcg group (approximately 1 in every 7 years). The ratio of the incidence of exacerbations when taking the combination of fluticasone furoate/vilanterol 92/22 mcg and FF 92 mcg was 0.755 (95th CI 0.603, 0.945). It follows that the reduction in the incidence of severe asthma exacerbations in patients receiving the combination of fluticasone furoate/vilanterol 92/22 mcg was 25% compared to patients receiving FF 92 mcg (p = 0.014). The 24-hour bronchodilator effect of the fluticasone furoate/vilanterol combination was maintained throughout the 1-year treatment period. There were no signs of loss of effectiveness (tachyphylaxis was absent). When using the combination of fluticasone furoate/vilanterol 92/22 mcg, there was a sustained improvement in trough FEV1 from 83 ml to 95 ml at 12, 36 and 52 weeks, as well as at the end point compared with indicators when using FF 92 µg (p<0.001 95% CI 52, 126 ml at end point). In 44% of patients in the fluticasone furoate/vilanterol 92/22 mcg group, asthma was well controlled (ACQ7 ≤0.75) at the end of therapy. In patients in the FF 92 mcg group, this figure was 36% (p<0.001 95% CI 1.23, 1.82).

Comparative studies with salmeterol/fluticasone propionate combination

In a 24-week study (HZA113091) in adults and adolescents with persistent asthma, improvements in pulmonary function compared to baseline were observed with both fluticasone furoate/vilanterol 92/22 mcg once daily in the evening and with salmeterol. /FP 50/250 mcg 2 times/day. Adjusted mean increases in weighted mean FEV1 over the period 0-24 hours of 341 ml during therapy compared to baseline (fluticasone furoate/vilanterol combination) and 377 ml (salmeterol/FP combination) indicated an overall improvement in pulmonary function over the course of treatment. 24 hours when using both types of therapy. The adjusted mean difference by treatment between groups of 37 mL was not statistically significant (p=0.162). In terms of trough FEV1, patients in the fluticasone furoate/vilanterol group experienced a change in mean limit from baseline of 281 mL, and patients in the salmeterol/FP group experienced a change of 300 mL from baseline; (adjusted mean difference 19 ml (95% CI:

-0.073, 0.034) was not statistically significant (p=0.485).

Comparative studies with salmeterol/FP or other ICS/LABA combinations have not been conducted to adequately compare the effects on asthma exacerbations.

Fluticasone furoate monotherapy

A randomized, double-blind, placebo-controlled, 24-week study (FFA112059) assessed the safety and efficacy of FF 92 mcg once daily [n=114] and FF 250 mcg twice daily [n=114] compared with placebo [n =115] in adult patients and adolescents with persistent asthma. All patients were required to have received a stable dose of ICS for at least 4 weeks prior to Visit 1 (screening visit). LABA use was not permitted for 4 weeks after Visit 1. The primary efficacy endpoint was the change from baseline in trough FEV1 at the clinical visit (pre-bronchodilator and pre-dosing) at the end of the treatment period. Change in percentage of 24-hour treatment-free periods from baseline over the 24-week treatment period was a secondary endpoint. At the 24 week time point, FF and AF increased trough FEV1 by 146 ml (95% CI 36, 257 ml, p=0.009) and 145 ml (95% CI 33, 257 ml, p=0.011), respectively. , compared to placebo. Both drugs (FF and FP) increased the percentage of 24-hour treatment-free periods by 14.8% (95% CI 6.9, 22.7, p<0.001) and 17.9% (95% CI 10.0, 25.7, p<0.001 ), respectively, compared to placebo.

Study of the reaction to a provocative test with an allergen

The bronchoprotective effects of the fluticasone furoate/vilanterol 92/22 mcg combination on early and late asthmatic responses to inhaled allergen were assessed in a placebo-controlled, four-period, multiple-dose crossover study (HZA113126) in patients with mild asthma. Patients were randomized to receive a combination of fluticasone furoate/vilanterol 92/22 mcg, FF 92 mcg, vilanterol 22 mcg, or placebo once daily for 21 days; 1 hour after the last dose, an allergen inhalation test was performed. The following allergens were used:

house dust mite, cat dander or birch pollen. The selection was made on the basis of screening tests. Serial FEV1 measurements were compared with those obtained after saline inhalation before the allergen test (baseline). Overall, the greatest effect on early asthmatic response was observed with the fluticasone furoate/vilanterol 92/22 mcg combination compared with FF 92 mcg or vilanterol 22 mcg monotherapy. Both the combination of fluticasone furoate/vilanterol 92/22 μg and FF 92 μg virtually eliminated the late asthmatic response compared with vilanterol monotherapy. The use of the fluticasone furoate/vilanterol 92/22 mcg combination provided significantly greater protection against allergen-induced bronchial hyperreactivity than FF or vilanterol monotherapy. Assessment was carried out on Day 22 using a methacholine challenge.

Chronic obstructive pulmonary disease

The following randomized controlled trials were included in the COPD clinical research program:

one of 12 weeks (HZC113107), two of 6 months (HZC112206, HZC112207) and two of 1 year (HZC102970, HZC102871) in patients with a clinical diagnosis of COPD. These studies examined measures of lung function, dyspnea, and moderate to severe exacerbations of the disease.

6 month studies

HZC112206 and HZC112207 were randomized, double-blind, placebo-controlled, parallel group studies of 24 weeks duration comparing the combination with vilanterol and FF alone and placebo. The HZC112206 study assessed the effectiveness of the combination of fluticasone furoate/vilanterol 46/22 μg [n=206] and the combination of fluticasone furoate/vilanterol 92/22 μg [n=206] in comparison with the effectiveness of FF 92 μg [n=206], vilanterol 22 μg [n=205] and placebo [n=207], all drugs were taken 1 time/day. The HZC112207 study assessed the effectiveness of the combination of fluticasone furoate/vilanterol 92/22 μg [n=204] and the combination of fluticasone furoate/vilanterol 184/22 μg [n=205] in comparison with FF 92 μg [n=204], FF 184 μg [ n=203] and vilanterol 22 mcg [n=203] and placebo [n=205], all drugs were taken 1 time/day.

Patients participating in the studies had the following requirements:

smoking history of at least 10 pack-years;
the FEV1/FGE ratio after salbutamol use is less than or equal to 0.70;
post-salbutamol FEV1 less than or equal to 70% predicted and dyspnea ≥2 (scale 0 to 4) on the modified British Medical Research Council (mMRC) questionnaire at screening. At screening, mean pre-bronchodilator FEV1 was 42.6% and 43.6% predicted, and mean reversibility was 15.9% and 12.0% in studies HZC112206 and HZC112207, respectively. The primary endpoints in both studies were weighted mean FEV1 values from 0 to 4 hours after the Day 168 dose and change from baseline in trough FEV1 to the Day 169 dose.

Based on the full analysis of both studies, it was concluded that the combination of fluticasone furoate/vilanterol 92/22 mcg resulted in a clinically significant improvement in lung function. At Day 169, the combination of fluticasone furoate/vilanterol 92/22 mcg and vilanterol resulted in an increase in adjusted mean trough FEV1 of 129 mL (95% CI: 91, 167 mL, p < 0.001) and 83 mL (95% CI: 91, 167 mL, p < 0.001) CI: 46, 121 ml, p <0.001), respectively, compared with placebo. The use of the combination of fluticasone furoate/vilanterol 92/22 mcg resulted in an increase in trough FEV1 by 46 ml compared with vilanterol (95% CI: 8.83 ml, p=0.017). On Day 168, the combination of fluticasone furoate/vilanterol 92/22 mcg and vilanterol resulted in an increase in adjusted weighted mean FEV1 at 0-4 hours by 193 mL (95% CI: 156, 230 mL, p <0.001) and 145 ml (95% CI: 108, 181 ml, p <0.001), respectively, compared with placebo. The use of the combination of fluticasone furoate/vilanterol 92/22 mcg resulted in an increase in the adjusted mean weighted mean FEV1 value over 0-4 hours by 148 ml compared with the use of FF alone (95% CI:

112, 184 ml, p <0.001).

12 month studies

Studies HZC102970 and HZC102871 were randomized, double-blind, parallel group studies of 52 weeks duration comparing fluticasone furoate/vilanterol 184/22 mcg, fluticasone furoate/vilanterol 92/22 mcg, fluticasone furoate/vilanterol 46/22 mcg. mcg and vilanterol 22 mcg (all drugs were used once a day) per annual rate of moderate/severe exacerbations of the disease in patients with COPD with a smoking history of at least 10 pack-years; the FEV1/FJE ratio after the use of salbutamol is less than or equal to 0.70; a post-salbutamol FEV1 of less than or equal to 70% predicted and a documented history of ≥1 exacerbation of COPD requiring antibiotic and/or oral corticosteroid therapy or hospitalization in the 12 months before visit 1. The primary endpoint was annual progression rate moderate and severe exacerbations of the disease. Moderate/severe exacerbations were defined as an increase in symptoms that required treatment with oral corticosteroids and/or antibiotics or hospitalization. Both studies had a 4-week run-in period during which all subjects received unmasked salmeterol/FP 50/250 twice daily to standardize COPD pharmacotherapy and stabilize disease prior to randomization to masked study drug for 52 weeks. Before the start of the run-in period, study participants stopped taking previously used medications for the treatment of COPD with the exception of short-acting bronchodilators. The use of concomitant long-acting inhaled bronchodilators (beta2-agonists and anticholinergics), combination drugs containing ipratropium/salbutamol, oral beta2-agonists and theophylline preparations was not permitted during the entire treatment period. The use of oral corticosteroids and antibiotics for the acute treatment of exacerbations of COPD was permitted according to specific guidelines. During the studies, participants used salbutamol as needed.

The results of both studies indicate that therapy with the combination of fluticasone furoate/vilanterol 92/22 mcg 1 time/day leads to a decrease in the annual rate of moderate/severe exacerbations of COPD compared to therapy with vilanterol (Table 2).

Table 2: Analysis of the incidence of exacerbations after 12 months of therapy

End point	HZC102970		HZC102871		HZC102970 and HZC102871 (integrated analysis)
End point	Vilanterol (n=409)	fluticasone furoate/vilanterol 92/22 (n=403)	Vilanterol (n=409)	fluticasone furoate/vilanterol 92/22 (n=403)	Vilanterol (n=818)	fluticasone furoate/vilanterol 92/22 (n=806)
Moderate and severe exacerbations
Adjusted average annual level	1.14	0.90	1.05	0.70	1.11	0.81
Correlation with VI 95% CI p value % reduction (95% CI)	0.79 (0.64, 0.97) 0.024 21 (3, 36)	0.66 (0.54, 0.81) <0.001 34 (19, 46)	0.73 (0.63, 0.84) <0.001 27 (16, 37)
Absolute difference in quantity per year compared with vilanterol (95% CI)	0.24 (0.03, 0.41)	0.36 (0.20, 0.48)	0.30 (0.18, 0.41)
Time to first exacerbation: Risk ratio (95% CI) % risk reduction p value	0.80 (0.66, 0.99) 20 0.036	0.72 (0.59, 0.89) 28 0.002	0.76 (0.66, 0.88) 24 p<0.001

In an integrated analysis of studies HZC102970 and HZC102871 at week 52, fluticasone furoate/vilanterol 92/22 mcg showed an improvement in adjusted mean trough FEV1 compared with vilanterol 22 mcg (42 mL 95% CI:

19, 64 ml, p<0.001). The 24-hour bronchodilator effect of the fluticasone furoate/vilanterol combination was maintained from the first dose through the 1-year treatment period. There were no signs of loss of effectiveness (tachyphylaxis was absent).

Taken together, in the two studies, a history of cardiovascular disease or risk factors for cardiovascular disease was noted in 2009 (62%) patients during the selection process. The incidence of cardiovascular disease/risk factors was similar in all treatment groups, with the most commonly reported conditions being hypertension (46%), hypercholesterolemia (29%), and diabetes mellitus (12%). Similar reductions in moderate and severe exacerbations were observed in this subgroup compared with the overall population. In patients with a history of cardiovascular disease and risk factors, the combination of fluticasone furoate/vilanterol 92/22 mcg resulted in a significant reduction in the annual incidence of moderate/severe exacerbations of COPD compared with vilanterol (adjusted mean annual incidence rates of 0.83 and 1.18, respectively , 30% reduction (95% CI 16, 42%, p<0.001)). At week 52, fluticasone furoate/vilanterol 92/22 mcg also demonstrated an improvement in adjusted mean trough FEV1 compared with vilanterol 22 mcg (44 mL 95% CI:

15, 73 ml, (p=0.003)).

Comparative studies with salmeterol/fluticasone propionate combination

In a 12-week study (HZC113107) in patients with COPD, improvements in pulmonary function compared to baseline were observed with both the combination of fluticasone furoate/vilanterol 92/22 mcg once daily in the morning and with the combination of salmeterol/FP 50/ 500 mcg 2 times/day. Adjusted mean increases in weighted mean FEV1 over the period 0-24 hours of 130 ml during therapy compared to baseline (fluticasone furoate/vilanterol combination) and 108 ml (salmeterol/FP combination) indicated an overall improvement in pulmonary function over the course of treatment. 24 hours when using both types of therapy. Adjusted mean difference by treatment between groups 22 ml (95% CI:

-18, 63 ml) was not statistically significant (p=0.282). The adjusted mean change from baseline in trough FEV1 at Day 85 was 111 mL in the fluticasone furoate/vilanterol group and 88 mL in the salmeterol/FP group;
the difference of 23 ml (95% CI: -20, 66) between treatment groups was not clinically or statistically significant (p=0.294).

Comparative studies with salmeterol/FP combinations or other conventional bronchodilators have not been conducted to adequately compare the effect on exacerbations of COPD.

Children

The European Medicines Agency has waived the mandatory reporting of results from studies of Relvar™ Ellipta™ in all subsets of the pediatric COPD population (see Dosage Regimen for information on use in pediatric patients).

The European Medicines Agency has deferred the mandatory reporting of results from studies of Relvar™ Ellipta™ in all subsets of the pediatric population in relation to asthma (for information on use in pediatric patients, see Dosage Regimen).

How to use the drug

It's actually very easy to use. Once a day in the morning or evening, open the lid, exhale to the side and inhale the dose through the mouthpiece and hold your breath for 10-15 seconds. After this, be sure to gargle and gargle your mouth, otherwise it will hurt!

Ready to use Relvar Ellipta

Guide on how to use Relvar Ellipta

How much does Relvar Ellipta cost?

Prices vary in different pharmacies. Prices vary from 1650 to 2000 rubles for a small dosage, and from 2000 to 2500 rubles for a large dosage. I usually use the services of apteka.ru. Usually it’s cheaper there, and you can sometimes order it at a discount at the nearest pharmacy. By the way, I have an article on how to buy medicines cheaper , you can read it by following the link.

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