Relvar ellipta®

Brand GlaxoSmithKline

In stock 1963 Items

Available since: 2019-09-19

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Clinical Pharmacology

Relvar Ellipta - bronchodilating, anti-inflammatory.

Pharmacodynamics

Mechanism of action

Vilanterol and fluticasone furoate belong to two different classes of drugs - synthetic GCS and selective beta.₂- long-acting adrenomimetic.

Pharmacodynamic effects

Vilanterol belongs to the class of selective beta₂long-acting adrenomimetic agents (DBA). Pharmacological effects of beta agonists₂-adrenoreceptors, including Vilanterol, are at least partially related to the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cAMP. An increase in cAMP leads to relaxation of the smooth muscles of the bronchi and inhibition of the release from cells (primarily from mast cells) of mediators of immediate-type hypersensitivity reactions.

Fluticasone furoate is a synthetic trifluoride GCS with a pronounced anti-inflammatory effect. The exact mechanism of action, allowing to arrest the symptoms of bronchial asthma and COPD, is unknown. GCS demonstrated a wide spectrum of action on various cell types (for example, eosinophils, macrophages, lymphocytes) and mediators (for example, cytokines and chemokines involved in the process of inflammation). Molecular interactions occur between the GCS and DBA, as a result of which steroid hormones activate the beta gene.₂-adrenoreceptor, increasing the number of susceptible adrenergic receptors. DBBA binds to the GCS receptor, providing its steroid-dependent activation and stimulating translocation to the cell nucleus. These synergistic interactions lead to increased anti-inflammatory activity, which is revealed in in vitro and in vivo experiments with various inflammatory cells involved in the pathophysiological processes of development of bronchial asthma and COPD. The results of clinical studies using biopsy specimens of the respiratory tract also demonstrated synergy of GCS and DABA arising from the administration of these drugs to patients with COPD in therapeutic doses.

Pharmacokinetics

Suction

The absolute bioavailability of Vilanterol and Fluticasone Furoate with the 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 <2%, respectively. Taking into account the low oral bioavailability, the systemic action of Vilanterol and Fluticasone Furoate after inhalation is primarily due to the absorption of part of the inhalation dose that has entered the lungs.

Distribution

After iv administration, vilanterol and fluticasone furoate are actively distributed in the body, with the average V_ss are 165 and 661 liters, 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 reached an average of> 93.9 and 99.6%, respectively. The degree of plasma protein binding in vitro did not decrease in patients with impaired liver and kidney function. Despite the fact that Vilanterol and Fluticasone Furoate are P-glycoprotein substrates (P-gp), while the combination of Vilanterol and Fluticasone Furoate with P-gp inhibitors is simultaneously prescribed, a systemic exposure of Vilanterol or Fluticasone Furoate is considered unlikely, 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 Cyochrome CYP3A4 isoenzyme.

Vilanterol is predominantly metabolized by O-dealkylation with the formation of 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 the combination of Vilanterol and Fluticasone Furoate (22 + 184 mcg / dose) and a strong inhibitor of the cytochrome CYP3A4 isoenzyme - ketoconazole (400 mg) using the example of healthy volunteers. Co-administration led to an increase in the average AUC_0–24 and medium C_maxfluticasone furoate at 36 and 33%, respectively. An increase in fluticasone furoate exposure was associated with a decrease in the mean serum cortisol concentration by 27%, measured over a period of 0-24 hours. Combined administration of the combination of Vilanterol and Fluticasone Furoate and ketoconazole increased the average AUC_{0 – t} and C_max Vilanterol at 65 and 22%, respectively. Increased exposure to Vilanterol did not lead to increased systemic effects characteristic of beta-agonists — effects on the CVS, blood potassium levels, or corrected QT interval (QTcF).

Removal

After oral administration of fluticasone, the furoate in the human body was mainly metabolized to form metabolites, which were mainly excreted through the gastrointestinal tract, with the exception of a dose of a radioactive substance <1% excreted in the urine. Estimated T_1/2 from plasma of fluticasone furoate after inhalation administration of the drug averaged 24 hours.

After oral administration, Vilanterol in the human body was mainly metabolized to form metabolites, which were excreted in the urine and feces, in a ratio of approximately 70 and 30% of the dose of the radioactive substance, respectively. T_1/2 from Vilanterol plasma after inhalation administration of the drug averaged 2.5 hours.

Special patient groups

During the third phase of clinical studies, a population-based meta-analysis of the pharmacokinetics of Vilanterol and Fluticasone Furoate was conducted in patients with bronchial asthma and COPD. As part of this analysis, the effect of demographic covariates (age, sex, weight, body mass index (BMI), racial and ethnicity) on the pharmacokinetics of Vilanterol and Fluticasone Furoate was evaluated.

Race. Elderly patients with bronchial asthma or COPD evaluated AUC_0–24 fluticasone furoate. According to the data obtained, patients of the East Asian, Japanese, and South Asian races (12–14% of patients) had on average higher AUC scores._0–24 (higher by no more than 53%) compared with Caucasians. However, in these populations, no signs of a higher systemic exposure, manifested by a more pronounced effect on urinary excretion of cortisol over a 24-hour period, were found. In patients with COPD, the effect of race on the pharmacokinetic parameters of Vilanterol was not detected. On average, based on C scores_maxVilanterol was 220–287% higher, and AUC_0–24 was comparable in patients of Asian descent with rates in other racial groups. However, higher C_max Vilanterol had no clinically significant effect on heart rate.

Children. For adolescents (12 years or older), there are no recommendations for changing the dosing regimen. The pharmacokinetics of the combination of Vilanterol and Fluticasone Furoate have not been studied in patients under 12 years of age. The safety and effectiveness of the combination of Vilanterol and Fluticasone Furoate in children under 12 years of age 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 studies involving patients with COPD and bronchial asthma. In patients with asthma, there was no evidence of the influence of age (12–84 years) on the pharmacokinetic profile of fluticasone furoate and Vilanterol. Despite the increase (37%) AUC_0–24Vilanterol, in patients with COPD throughout the entire observed age range from 41 to 84 years, no evidence of the influence of patient age on the pharmacokinetic profile of fluticasone furoate was detected. In an elderly patient (aged 84) with a low body weight (35 kg) AUC_0–24 Vilanterol will be 35% higher than the result calculated for the population (on average, a patient with COPD is 60 years old and weighing 70 kg), while C_max Vilanterola will remain unchanged. It is unlikely that these differences are clinically relevant.

Impaired renal function. According to clinical and pharmacological studies, severe impaired renal function (Cl creatinine <30 ml="" min="" does="" not="" lead="" to="" a="" significant="" increase="" in="" systemic="" exposure="" vilanterol="" or="" fluticasone="" furoate="" the="" development="" of="" more="" pronounced="" effects="" gcs="" beta="" sub="">2agonists versus healthy volunteers. Individual dose selection for patients with impaired renal function is not required. The effect of hemodialysis has not been studied.

Liver dysfunction. After continuous use of the combination of Vilanterol and Fluticasone Furoate for 7 days, an increase in the systemic exposure of Fluticasone Furoate was observed in patients with impaired liver function (as measured by AUC_0–24 up to three times) in comparison with healthy volunteers (according to Child-Pugh classification of cirrhosis of the liver: stages A, B or C). Increased systemic exposure of fluticasone furoate (when prescribing a combination of Vilanterol and Fluticasone Furoate at a dosage of 22 + 184 μg / dose) in patients with moderate hepatic impairment (Child-Pugh classification stage B) was associated with an average decrease of 34 % compared to healthy volunteers. The dose-normalized systemic exposure of fluticasone furoate in patients with moderate and severe liver dysfunction (stages B and C according to Child-Pugh classifications) were similar. Consequently, although patients with impaired liver function do not require individual dose selection, caution should be exercised when prescribing this drug. After continuous use of the combination of Vilanterol and Fluticasone Furoate for 7 days in patients with mild, moderate or severe liver dysfunction (stages A, B, and C according to Child-Pugh), there was no significant increase in systemic exposure to Vilanterol (C_max and AUC_0–24). Compared with healthy volunteers, patients with mild or moderately impaired liver function (who received Vilanterol at a dose of 22 μg) or severe (who received Vilanterol at a dose of 11 μg) did not have clinically significant beta-adrenergic systemic effects (change in heart rate or serum potassium concentration ) caused by taking a combination of Vilanterol and fluticasone furoate.

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

Indications

bronchial asthma (drug Relvar Ellipt^® used as maintenance therapy for bronchial asthma);
chronic obstructive pulmonary disease (drug Relvar Ellipt^® used as maintenance therapy for airway obstruction in patients with chronic obstructive pulmonary disease, including chronic bronchitis and / or pulmonary emphysema). Use of the drug Relvar Ellipt^® reduces the number of exacerbations of chronic obstructive pulmonary disease in patients with repeated exacerbations in history.

Composition

Dosed inhalation powder, 22 + 184 mcg / dose	1 dose / cell^*
Strip with Vilanterol
active substance:
Vilanterola triphenate micronized	40 mcg
(equivalent to 25 mcg^** Vilanterola)
excipients: magnesium stearate - 125 mcg; lactose monohydrate - up to 12.5 mg
Fluticasone furoate strip
active substance:
fluticasone furoate micronized	200 mcg^**
excipient: lactose monohydrate - up to 12.5 mg
^* In the production of the finished product a mixture of active and auxiliary substances can be put into the final product with an excess of up to 8% to compensate for losses during the filling of the cells.
^** Indicated the nominal amount of active substance, laid in the production process; the amount delivered is 22 μg of Vilanterol, 92 and 184 μg of Fluticasone Furoate, which corresponds to the dosages indicated.

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Dosage and Administration

Inhalation.

The drug Relvar ellipta®^® should be applied 1 time per 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 the drug Relvar Ellipt^® even in the case of asymptomatic disease. In the event of symptoms of the disease in between doses of the drug, inhalation beta should be used as an emergency treatment.₂short acting agonists. The physician should regularly assess the patient’s condition in order to ensure timely administration of the optimal dosage of Relvar Ellipt.^®. The dosage can be changed only according to the recommendation of the doctor.

Adults and teenagers 12 years and older. The recommended dose of Relvar Ellipt^®: one inhalation of 22 mcg of Vilanterol and 92 mcg of fluticasone furoate 1 time per day or one inhalation of 22 mcg of Vilanterol and 184 mcg of fluticasone furoate once a day.

Initial dose of Relvar Ellipt^® 22 μg of Vilanterol and 92 μg of Fluticasone Furoate are indicated for patients who require low or medium doses of inhaled GCS used in combination with beta₂long-acting agonists.

The drug Relvar ellipta®^® at a dosage of 22 mcg of Vilanterol and 184 mcg of fluticasone furoate, should be prescribed to patients who require a higher dose of inhaled GCS used in combination with beta₂long-acting agonists. If the drug Relvar Ellipt^® at a dosage of 22 mcg of Vilanterol and 92 mcg of Fluticasone Furoate does not provide adequate control of the disease, the issue of increasing the dose to 22 mcg of Vilanterol and 184 mcg of Fluticasone Furoate is being considered, which can improve the level of control over the course of bronchial asthma.

Children. Safety and efficacy of the drug Relvar Ellipt^® in children under 12 years of age not established.

COPD

Adults. The recommended dose of Relvar Ellipt^®: one inhalation of 22 mcg of Vilanterol and 92 mcg of Fluticasone Furoate 1 time per day.

The drug Relvar ellipta®^® at a dosage of 22 mcg of Vilanterol and 184 mcg of Fluticasone Furoate, is not indicated for the treatment of patients with COPD.

Children. The drug for the indication of COPD in children does not apply.

Special patient groups

Elderly patients. Patients over 65 years of age do not require individual selection of the drug dose (see “Pharmacokinetics”, Special patient groups).

Patients with impaired renal function. Patients with impaired renal function do not require individual selection of the drug dose (see “Pharmacokinetics”).

Patients with impaired liver function. According to clinical and pharmacological studies in patients with mild, moderate and severe liver dysfunction, a threefold increase in the degree of systemic exposure of fluticasone furoate is observed (with such indicators as C_max and AUC) (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 the use of corticosteroids.

Recommendations for use

When using the Ellipt Inhaler for the first time^® there is no need to check the correctness of its work or special preparation of the inhaler for operation. Consistently follow the recommendations for use listed below.

Ellipt Inhaler^® Packed in a container that contains a moisture-absorbing silica gel bag that 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 opening and closing the lid of the Ellipt inhaler^® without taking the drug, a single dose is lost.This dose remains closed inside the nebulizer, but will not be available for admission. It is impossible to accidentally get a large dose or a double dose for one inhalation.

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

A dose counter shows how many doses of the drug are left in the inhaler. Before using 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 remain, half of the counter becomes red. After the last dose of the drug has been consumed, half of the counter is highlighted in red, the counter shows the number 0. This means that the inhaler is empty. When the cap is opened after this, the dose counter will turn completely red.

Dose preparation

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

1. Pull 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 meter does not reduce the number of doses after clicking, then the inhaler is not ready to deliver the dose of the drug. In this case, you should contact by phone or the address specified in the subsection "For more information contact."

4. Do not shake the inhaler.

Inhalation drug

1. Hold the inhaler at a distance from the mouth to exhale the maximum depth. Do not exhale into the inhaler.

2. Place the mouthpiece between the lips and tightly clasp it with your lips. Do not cover the vent with your fingers.

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

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

4. Remove the inhaler from the mouth.

5. Slowly and quietly exhale.

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

Closing the inhaler and rinsing the mouth

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

1. Raise the lid until it stops, having achieved complete closure of the mouthpiece.

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

Adverse reactions

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

From the nervous system: very often - a headache.

From the side of the heart: infrequently - extrasystole.

On the part of the respiratory system, organs of the chest and mediastinum: very often - nasopharyngitis; often - oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia.

On the part of the digestive tract: often - pain in the abdomen.

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

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

Contraindications

Carefully: when taking sympathomimetics, including the drug Relvar Ellipt^®, from the side of the cardiovascular system such undesirable phenomena as arrhythmia (for example, supraventricular tachycardia and extrasystole) can be observed. In this regard, patients suffering from severe cardiovascular disease, the drug Relvar ellipta®^® should be prescribed with caution. Like other drugs, which include the GCS, the drug Relvar Ellipt^® should be used with caution in patients with pulmonary tuberculosis, as well as in patients with chronic or untreated infections.

Drug interactions

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 may weaken or antagonize the effect of beta₂- adrenomimetics. The simultaneous use of non-selective and selective beta-blockers should be avoided, except for cases where their purpose is strictly necessary.

Vilanterol and fluticasone furoate undergo rapid primary metabolism in the liver through the cytochrome CYP3A4 isoenzyme system. With simultaneous administration of the drug with strong inhibitors of cytochrome CYP3A4 isoenzyme (for example, ketoconazole, ritonavir), caution should be exercised, since it is possible to increase the systemic effects of Vilanterol and Fluticasone Furoate, which in turn may lead to an increased risk of adverse reactions (see "Pharmacokinetics") .

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

Pregnancy and Lactation

Data on the use of the drug during pregnancy is limited. Use of the drug Relvar Ellipt^®in pregnant women is permissible only if the potential benefit to the mother outweighs the possible risk to the fetus.

Data on the excretion of Vilanterol or Fluticasone Furoate or their metabolites in human breast milk are insufficient. However, other GCS and beta₂agonists are determined in breast milk. The risk of penetration of the drug with milk into the body of a newborn or child can not be excluded.

Taking into account the ratio of benefits of therapy for the mother and breastfeeding for the child, it is necessary to resolve the issue of either discontinuing the drug or stopping breastfeeding.

Fertility

Data on the effect on human fertility are not available. In preclinical studies, the effect of Vilanterol and fluticasone furoate on fertility was not found.

Special instructions

The drug Relvar ellipta®^® not intended for the relief of acute symptoms of bronchial asthma or exacerbation of COPD, in such cases, the appointment of short-acting bronchodilators. The increase in the frequency of taking short-acting bronchodilators in order to relieve symptoms indicates a deterioration in the control of the disease and the need to consult a doctor. Patients with bronchial asthma or COPD should not discontinue treatment with Relvar Ellipt^® without medical supervision, because cancellation of therapy may exacerbate 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 appointment of a short-acting inhaled bronchodilator and the immediate cancellation of the drug Relvar Ellipt are shown.^®. The patient should be examined by a doctor and alternative therapy may be prescribed if necessary.

Against the background of drug treatment Relvar Ellipt^® adverse effects associated with the course of bronchial asthma or exacerbation of the disease may develop. Patients should be advised to continue treatment. In case of lack of control over the disease or deterioration after the start of therapy with Relvar Ellipt^® consultation of the doctor is necessary.

With the use of inhaled corticosteroids (especially with long-term use in high doses), systemic side effects may develop. Such side effects develop much less frequently than with oral administration of GCS.The manifestations of a possible adverse systemic action 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.

Patients with COPD who receive Relvar Ellipt^®, there was an increase in the incidence of pneumonia, as well as the incidence of severe forms of pneumonia, requiring the patient to be hospitalized. In some cases, the clinical episodes of pneumonia were fatal. Doctors should be aware of the possibility of developing pneumonia in patients with COPD, not forgetting that the clinical signs of such an infectious disease are masked by the symptoms of COPD exacerbation. The highest risk of developing pneumonia while taking the drug Relvar Ellipt^® have the following groups of patients with COPD: smoking patients, patients who have previously had pneumonia, patients with a BMI <25 kg="" m="" sup="">2 and patients with forced expiratory volume in the first second (FEV₁) <50% of proper values. In the appointment of drug therapy Relvar Ellipt^® The above factors should be considered, in case of pneumonia, treatment should be reviewed.

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

In clinical trials, patients with COPD had a low incidence of bone fractures in all treatment groups, but at the same time in all groups receiving the combination of Vilanterol and Fluticasone Furoate, it was slightly higher (2%) than in the group of who received Vilanterol monotherapy 22 μg (<1%).

Influence on ability to steer vehicles and work with mechanisms. Studies on the effect of the drug Relvar Ellipt^® on the ability to drive vehicles and work with mechanisms were not carried out. Based on the pharmacology of Vilanterol or fluticasone furoate, the adverse effect of the drug on these activities is not expected.

Overdosage

Symptoms: During clinical studies, no data were obtained on the overdose of the combination of Vilanterol and Fluticasone Furoate. May develop symptoms and signs due to the action of individual components of the drug and characteristic of an overdose of beta₂agonists and inhalation corticosteroids (see "Special instructions").

Treatment: 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 Vilanterol overdose, which are clinically manifested immunity to supportive therapy. Cardioselective beta-blockers should be used with caution in patients with a history of bronchospasm.