Ellipt Relvar powder for inhalation 22 mcg + 92 mcg / dose + inhaler 30 doses 1 pc., Pack

Powder for inhalation

Active substance:

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

Excipients:

 magnesium stearate - 125 mcg;

lactose monohydrate - up to 12.5 mg

Mechanism of action

Vilanterol and fluticasone furoate belong to two different classes of drugs - synthetic glucocorticoid steroid and selective long-acting beta-adrenergic agonist.

Pharmacodynamic effects

Vilanterol belongs to the class of selective beta2-adrenergic agonists (DBA).

The pharmacological effects of beta2-adrenergic agonists, including vilanterol, are at least partially related to the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3 ', 5'-adenosine monophosphate (cyclic AMP). An increase in the level of cyclic AMP leads to relaxation of the smooth muscles of the bronchi and inhibition of the release of immediate-type hypersensitivity mediators from cells (primarily from mast cells).

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

Glucocorticosteroids have shown a wide range of effects on various types of cells (e.g., eosinophils, macrophages, lymphocytes) and mediators (e.g., cytokias and chemokines involved in the inflammation process).

Molecular interactions occur between glucocorticosteroids and DBL, as a result of which steroid hormones activate the beta2-adrenergic receptor gene, increasing the number of susceptible adrenergic receptors. DDBA binds to the glucocorticosteroid receptor, providing its steroid-dependent activation and stimulating translocation into the cell nucleus.

These synergistic interactions lead to an increase in anti-inflammatory activity, which is detected in in vitro and in vivo experiments with various inflammatory cells involved in the pathophysiological processes of the development of bronchial asthma and COPD. Clinical trials using airway biopsy specimens have also demonstrated synergies between corticosteroids and DBA arising from the administration of these drugs to patients with COPD in therapeutic doses.

Pharmacokinetics

Suction

The absolute bioavailability of vilanterol and fluticasone furoate after inhalation of a 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 <2%. respectively. Given the low oral bioavailability, the systemic effect of vilanterol and fluticasone furoate after inhalation is primarily due to the absorption of part of the inhalation dose delivered to the lungs.

Distribution

After intravenous administration of vilanterol and fluticasone, furoate is actively distributed in the body, while the average volume of distribution in the equilibrium state is 165 l 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 furoag to human plasma proteins was high and reached an average of> 93.9% and 99.6%. respectively. In vitro plasma protein binding did not decrease in patients with impaired liver and kidney function.

Despite the fact that vilanterolum and fluticasone furoate are substrates of P-glycoprotein (P-gp), while the combination of vilanterolum and fluticasone furoate with P-gp inhibitors is simultaneously prescribed, a change in the systemic exposure of vilanterolum or fluticasone furoate is considered unlikely, since both substances have good absorption ability.

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 substantially 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 of drug interactions with CYP3A4 cytochrome isoenzyme with long-term administration of a combination of vilanterol and fluticasone furoate (22 μg + 184 μg / dose) and a strong inhibitor of CYP3A4 cytochrome isoenzyme - ketoconazole (400 mg) using healthy volunteers as an example. Co-administration of drugs led to an increase in the average area under the pharmacokinetic curve (AUC (0-24)) and the average Cmax of fluticasone furoate by 36% and 33%. respectively. An increase in the exposure of fluticasone furoate was associated with a decrease in the average concentration of serum cortisol by 27%. measured over a period of 0-24 hours.

The combined administration of a combination of vilanterol and fluticasone furoate and ketoconazole led to an increase in the average AUC (0-t) and Cmax of Vilanterol by 65 and 22%. respectively. An increase in the exposure to vilanterol did not lead to an increase in the systemic effects characteristic of beta-agonists - the effect of heart rate, blood potassium content, or the corrected QT interval (QTcF).

Breeding

After oral administration of fluticasone, furoate in the human body was mainly metabolized with the formation of metabolites, which were mainly excreted through the gastrointestinal tract, with the exception of a dose of radioactive substance <1% excreted in the urine. The estimated plasma half-life of fluticasone furoate after inhalation was averaged 24 hours.

After oral administration, vilanterol in the human body was mainly metabolized with the formation of metabolites that were excreted in urine and feces, in a ratio of approximately 70% and 30% of the dose of the radioactive substance, respectively. The plasma half-life of Vilanterolum after inhalation administration 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 performed. In the framework of this analysis, the effect of demographic covariates (age, gender, weight, body mass index (BMI), race and ethnicity) on the pharmacokinetics of vilanterol and fluticasone furoate was evaluated.

Race

In elderly patients with bronchial asthma or COPD, AUC (0-24) of fluticasone furoate was evaluated. According to the data obtained, patients of the East Asian, Japanese and South Asian races (12-14% of patients) had on average higher AUS (0-24) (higher than no more than 53%) compared with patients of the Caucasian race. However, in these populations, signs of a higher systemic exposure, manifested by a more pronounced effect on urinary excretion of cortisol over a 24-hour period, were not found. In patients with COPD, the effect of race on the pharmacokinetic parameters of vilanterol has not been identified.

On average, according to the results of Cmax assessment, vilanterol was 220-287% higher, and AUС (0-24) was comparable in patients of Asian origin compared with the indicators in other racial groups. However, a higher Cmax of Vilanterol did not have a clinically significant effect on heart rate.

Children

For adolescents (12 years or older), there are no recommendations for changing the dosage regimen. The pharmacokinetics of the combination of vilanterol and fluticasone furoate in patients younger than 12 years old has not been studied. The safety and effectiveness of the combination of vilanterol and fluticasone furoate 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 the third phase of clinical trials involving patients with COPD and 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 the increase (37%) in AUC of vilanterol in patients with COPD over the entire observed age range from 41 to 84 years, there were no signs of the influence of the age of patients on the pharmacokietic profile of fluticasone furoate. In an elderly patient (aged 84 years) with a low body weight (35 kg), AUC (0-24) of Vilanterol will be 35% higher than the result calculated for the population (on average, a patient with COPD at the age of 60 years and a body weight of 70 kg ), while Cmax of Vilanterol remains unchanged. It is unlikely that these differences are clinically relevant.

Patients with impaired renal function

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

The effect of hemodialysis is not studied.

Patients with impaired liver function

After continuous use of the combination of vilanterol and fluticasone furoate for 7 days, patients with impaired liver function showed an increase in the systemic exposure of fluticasone furoate (as measured by AUC "> - 24> TO three times) compared with healthy volunteers (according to the classification of liver cirrhosis according to Chill- I drink: stages of cirrhosis A. B or C). An increase in the systemic exposure of fluticasone furoate (when a combination of vilanterol and fluticasone furoate was administered at a dose of 22 μg + 184 μg / dose) in patients with impaired hepatic function of the liver (stage B according to the Child-Pyo classification) was associated with a decrease in average serum cortisol concentration 34% compared with healthy volunteers. Indicators of a dose-normalized systemic exposure of fluticasone furoate in patients with moderate to severe hepatic impairment (stages B and C according to the Child-Pyo classification) were similar. Therefore, although patients with impaired liver function do not need an individual dose selection, caution should be exercised when prescribing this drug.

After continuous use of the combination of vilanterol and fluticasone furoag for 7 days in patients with impaired liver function of mild, moderate or severe degree (stages A B and C according to the Child-Pugh classification), there was no significant increase in systemic exposure of vilanterol (according to Cmax and AUS (0- 24)).

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

Gender, body weight, body mass index (BMI)

According to the third phase of the population analysis of pharmacokinetics, which included 1213 patients with bronchial asthma (712 women) and 1225 patients with COPD (392 women), no signs of the influence of gender, body weight or BMI on the pharmacokipetic profile of fluticasone furoate were found.

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

Individual dose selection based on data on gender, body weight or BMI is not required.

- bronchial asthma;

- COPD (chronic obstructive pulmonary disease).

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

- severe allergic reactions to milk protein or hypersensitivity to active substances or any other component), which is a part of the drug in history;

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

Infectious and parasitic diseases: often - pneumonia, upper respiratory tract infections, bronchitis, flu, candidiasis of the oral cavity and pharynx.

From the nervous system: very often - a headache.

From the side of the heart: infrequently - extrasystole.

From the respiratory system, chest and mediastinal organs: very often - nasopharyngitis; often - oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia.

From the digestive tract: often - abdominal pain.

From the side of musculoskeletal and connective tissue: often - arthralgia, back pain, fractures.

General disorders and disorders at the injection site: often - fever.

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 when inhaled.

Beta-blockers can weaken or antagonize the action of beta2-adrenergic agonists. The simultaneous administration of non-selective and selective beta-blockers should be avoided, except in cases where their appointment is strictly necessary.

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

While prescribing the drug with strong inhibitors of the cytochrome CYP3A4 isoenzyme (for example, ketoconazole, ritonavir), caution should be exercised, since an increase in systemic exposure to vilanterol and fluticasone furoate may occur, which in turn can lead to an increased risk of developing adverse reactions (see “Pharmacokinetics”) .

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

Inhalation.

Relvar Ellipt® should be used once a day at the same time, in the morning or in the 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 in case of an asymptomatic course of the disease. If symptoms of the disease occur between doses of the drug, inhaled forms of short-acting beta2-agonists should be used as emergency treatment. The doctor should regularly evaluate the patient's condition to ensure timely appointment of the optimal dosage of Relvar Ellipt®. Dosage can be changed only on the recommendation of a doctor.

Adults and teenagers 12 years and older. The recommended dose of Relvar Ellipt® is one inhalation of 22 μg of vilanterol and 92 μg of fluticasone furoate 1 time per day or one inhalation of 22 μg of vilanterol and 184 μg of fluticasone furoate 1 time per day.

The initial dose of Relvar Ellipt® is 22 μg of Vilanterolum and 92 μg of fluticasone furoate is prescribed to patients who require low or medium doses of inhaled GCS used in combination with long-acting beta2-agonists.

Relvar Ellipta® at a dose of 22 μg of Vilanterolum and 184 μg of fluticasone furoate should be prescribed to patients who require a higher dose of inhaled GCS, used in combination with long-acting beta2-agonists. If Relvar Ellipta® at a dose of 22 micrograms of vilanterolum and 92 micrograms of fluticasone furoate does not provide adequate control of the disease, the question is about increasing the dose to 22 micrograms of Vilanterolum and 184 micrograms of fluticasone furoate, which can improve the level of control over the course of bronchial asthma.

Children. The safety and effectiveness of Relvar Ellipt® in children under 12 years of age has not been established.

COPD

Adults The recommended dose of Relvar Ellipt® is one inhalation of 22 micrograms of Vilanterolum and 92 micrograms of fluticasone furoate once a day.

Relvar Ellipta® at a dose of 22 μg of Vilanterolum and 184 μg of fluticasone furoate is not indicated for the treatment of patients with COPD.

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

Special patient groups

Elderly patients. Patients over 65 do not need an individual dose selection ..

Patients with impaired renal function. Patients with impaired renal function do not need an individual dose selection of the drug.

Patients with impaired liver function. According to clinical and pharmacological studies in patients with impaired liver function of mild, moderate and severe degrees, a three-fold increase in the degree of systemic exposure of fluticasone furoate (with an increase in indicators such as Cmax and AUC) is observed (see "Pharmacokinetics"). Patients with impaired liver function should be prescribed the drug with caution, because this group of patients has a higher risk of developing systemic adverse reactions caused by taking corticosteroids.

Recommendations for use

When using the Ellipt® Inhaler for the first time, there is no need to verify its proper operation or to prepare the inhaler specifically for use. Follow the recommendations for use listed below.

The Ellipt® Inhaler is packaged in a container containing a moisture-absorbing bag of silica gel, which is not intended for food or inhalation. This bag should be disposed of. After removing the inhaler from the container, its lid is in the closed position. Do not open it before taking the drug.

Detailed Instructions for Using the Ellipt® Inhaler

When you open and close the lid of the Ellipt® inhaler without taking the drug, one dose is lost. This dose remains closed inside the inhaler, but it will not be available. It is not possible to accidentally receive a large dose or a double dose in one inhalation.

One dose of the drug is ready for inhalation after each opening of the cap.

The dose counter shows how many doses of the drug remain in the inhaler. Before using the inhaler, the dose counter shows the number 30. Each time the lid is opened, the number of doses decreases by 1. When less than 10 doses remain, half of the counter turns red. After the last dose of the drug has been used up, half of the counter is highlighted in red, the counter shows the number 0. This means that the inhaler is empty. When you open the lid after that, the dose counter will turn completely red.

Dose preparation

Do not open the lid until ready to take the drug. Do not shake the inhaler.

1. Lower the cover down until it clicks.

2. The dose of the drug is ready for inhalation, and in confirmation of this, the counter reduces the number of doses per unit.

3. If the counter has not reduced the number of doses after a click, then the inhaler is not ready to deliver the dose of the drug. In this case, you should contact by phone or the address indicated in the subsection "For additional information, contact."

4. Do not shake the inhaler.

Drug inhalation

1. While holding the inhaler at a certain distance from the mouth, exhale as deep as possible. Do not exhale into an inhaler.

2. Place the mouthpiece between the lips and grip it tightly with your lips. Do not cover the ventilation hole with your fingers.

The lips should accurately follow the shape of the mouthpiece of the inhaler.

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

4. Remove the inhaler from the mouth.

5. Slowly and calmly exhale.

With proper use of the inhaler, the patient may not feel the taste or may not feel the flow of the drug.

Closing the inhaler and rinsing the mouth

If necessary, clean the mouthpiece; before closing the lid, use a dry paper towel.

1. Lift the cover all the way, making the mouthpiece fully closed.

2. After inhalation, rinse your mouth with water. This will reduce the likelihood of side effects such as sore throat and oral cavity.

Symptoms:  during clinical trials no data were obtained on an overdose of a combination of vilanterol and fluticasone furoate. Perhaps the development of symptoms and signs caused by the action of individual components of the drug and characteristic of an overdose of beta2-agonists and inhaled GCS.

Treatment: There is no specific treatment. Symptomatic therapy is prescribed and, if necessary, appropriate monitoring of the patient is provided. The use of cardioselective beta-blockers should be considered only in cases of strongly pronounced effects of overdose of vilanterol, which are clinically manifested by immunity to maintenance therapy. Cardioselective beta-blockers should be used with caution in patients who have had a history of bronchospasm.

Relvar Ellipt ^{® is}  not intended to relieve acute symptoms of bronchial asthma or exacerbation of COPD, in such cases, the appointment of short-acting bronchodilators is required. An increase in the frequency of taking short-acting bronchodilators in order to relieve symptoms indicates a worsening of control of the disease and the need to consult a doctor. Patients with bronchial asthma or COPD should not stop treatment with Relvar Ellipt ^®  without the supervision of a doctor, because withdrawal of therapy can lead to an exacerbation of the disease.

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

Against the background of treatment with Relvar Ellipt ^®  , undesirable phenomena associated with the course of bronchial asthma or an exacerbation of the disease may develop. Patients should be advised to continue treatment. In the absence of control of the disease or worsening of the condition after starting therapy with Relvar Ellipt ^®  , a doctor's consultation is necessary.

When using inhaled GCS (especially with prolonged use in high doses), systemic side effects may develop. Such side effects develop much less frequently than with oral administration of corticosteroids. The manifestations of a possible adverse systemic effect include: suppression of the function of the hypothalamic-pituitary-adrenal system, decrease in bone mineral density, slower growth rate in children and adolescents, cataracts and glaucoma.

In patients with COPD receiving Relvar Ellipt ^® , there was an increase in the incidence of pneumonia, as well as the incidence of severe forms of pneumonia requiring hospitalization of the patient. In some cases, clinical episodes of pneumonia were fatal. Doctors should remember the possibility of developing pneumonia in patients with COPD, not forgetting that the clinical signs of such an infectious disease are masked by symptoms of exacerbation of COPD. The  following groups of patients with COPD have the highest risk of developing pneumonia while taking Relvar Ellipt ^® : smokers, patients who previously had pneumonia, patients with BMI <25 kg / m ²  and patients with forced expiratory volume in the first second (FEV ₁) <50% of the required values. When prescribing therapy with Relvar Ellipt ^®  , the above factors should be considered, in case of pneumonia, treatment should be reviewed.

In patients with bronchial asthma, cases of pneumonia have been observed infrequently. Patients with bronchial asthma who received Relvar Ellipt ^®  at a dosage of 22 + 184 mcg / dose may have had a higher risk of developing pneumonia compared to patients who received a lower dose of Relvar Ellipt ^®  (22 + 92 mcg / dose), or with a placebo group. Risk factors not established.

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

Influence on the ability to drive vehicles and work with mechanisms. Studies to study the effect of Relvar Ellipt ^®  on the ability to drive vehicles and work with mechanisms have not been conducted. Based on the pharmacological data of vilanterol or fluticasone furoate, an adverse effect of the drug on these activities is not expected.