Anoro Ellipta por d/ingal doses 22 mcg+55 mcg/dose 30 doses x1
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINE ANORO ELLIPTA Registration number: LP-002548. Trade name of the drug: Anoro Ellipta / Anoro Ellipta. Group name: vilanterol + umeclidinium bromide / vilanterol + umeclidinium bromide. Dosage form: dosed powder for inhalation. COMPOSITION 1 dose contains: Name of components Quantity in one cell 1, mcg Strip with vilanterol Active ingredient Vilanterol triphenatate micronized 40 (in terms of vilanterol) 25 2 Excipients: Magnesium stearate 125 Lactose monohydrate up to 12.5, mg Strip with umeclidinium Active ingredient Umeclidinium bromide micronized 74.2 (in terms of umeclidinium) 62.5 2 Excipients Magnesium stearate 75 Lactose monohydrate up to 12.5 mg Notes: 1. To compensate for losses when filling cells, a mixture of vilanterol and excipients can be added when filling cells into the finished product with an excess of up to 8.%, a mixture of umeclidinium and excipients - with an excess of up to 6.%. 2. The nominal amount of the active substance is indicated, the delivered amount of vilanterol is 22.mcg, umeclidinium is 55.mcg, which corresponds to the indicated dosage. DESCRIPTION Plastic inhaler with a light gray body, red mouthpiece cap and dose counter, packaged in a foil container containing a desiccant sachet. The container is sealed with an easy-to-open lid. The inhaler contains two strips, each strip consists of 30 evenly distributed cells, each of which contains white powder. PHARMACOTHERAPEUTIC GROUP Adrenergic agonists in combination with anticholinergics. ATX code: R03AL03. PHARMACOLOGICAL PROPERTIES Pharmacodynamics Mechanism of action The drug Anoro Ellipta is a combination of an inhaled long-acting muscarinic cholinergic receptor antagonist and a long-acting inhaled beta 2-adrenergic agonist (ACDD/LABA). After inhalation, both compounds have local effects on the respiratory tract, causing bronchodilation through different mechanisms of action. Vilanterol belongs to the class of selective long-acting beta 2 adrenergic receptor agonists (beta 2 agonists). The pharmacological effects of beta2-adrenergic agonists, including vilanterol, 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). Umeclidinium is a long-acting muscarinic receptor antagonist (also called an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist that acts on various muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilator effect by competitively inhibiting the binding of acetylcholine to muscarinic acetylcholine receptors on airway smooth muscle. In preclinical studies using in vitro models, this compound demonstrates a slow reversibility of action on human muscarinic receptors of the m3 subtype, and in vivo models have demonstrated the duration of action of the drug after administration directly to the lungs. Pharmacodynamic effects: In a placebo-controlled clinical efficacy study, an increase in forced expiratory volume in the first second (FEV 1 ) was observed after the first dose of the combination of vilanterol and umeclidinium on the first day. This indicator increased by 0.11 l 15 minutes after using the drug compared to the same indicator when using placebo (p <, 0.001). The difference between baseline and peak FEV1, determined within 6 hours after drug administration, on the first day and at the 24th week of the experiment was 0.27.l and 0.32.l for the combination of vilanterol and umeclidinium, respectively. When using placebo, similar figures were 0.11.l (day 1) and 0.10.l (week 24). The effect of the combination of vilanterol and umeclidinium on the QT interval was assessed in a placebo- and moxifloxacin-controlled study. 103 ,healthy volunteers used a combination of vilanterol and umeclidinium for 10 ,days once daily at a dosage of 22,+,113,μg/dose or 88,+,452,μg/dose. The maximum mean difference in QT interval prolongation (Frederick-corrected, QTcF) from placebo, taking into account baseline parameters, was 4.3 ms (90% CI = 2.2−6.4) 10 minutes after drug administration at a dosage of 22,+,113,μg/dose and 8.2,ms (90,% CI,=,6.2−10.2) 30,minutes after using the drug at a dosage of 88,+,452,μg/ dose. There was no clinically significant effect on the duration of the QT interval (corrected using the Frederick method). In addition, there was no clinically significant effect of the combination of vilanterol and umeclidinium on heart rate on 24-hour Holter ECG monitoring in 281 patients receiving the drug at a dosage of 22,+,113,mcg/dose once daily for up to 12 months. Pharmacokinetics: When using a combination of umeclidinium and vilanterol by inhalation, the pharmacokinetics of each compound were similar to those observed when using each active substance separately (see subsection "Metabolism"). For this reason, the pharmacokinetics of each substance will be considered separately. Absorption In healthy volunteers, after inhalation of vilanterol, the average maximum concentration (Cmax) was reached within 5–15 minutes. The absolute bioavailability of inhaled vilanterol was 27.%, taking into account the insignificant absorption of the substance in the oral cavity. After repeated inhalations of vilanterol, after 6 days, an equilibrium state was reached with a 2.4-fold accumulation. In healthy volunteers, after inhalation of umeclidinium, Cmax was achieved within 5–15 minutes. The absolute bioavailability of inhaled umeclidinium averaged 13.%, taking into account the insignificant absorption of the substance in the oral cavity. After repeated inhalations of umeclidinium, after 7–10 days, an equilibrium state was reached with a 1.5–2-fold accumulation. Distribution Following intravenous administration of vilanterol to healthy volunteers, the mean volume of distribution at steady state was 165.L. Binding to human plasma proteins in vitro averaged 94%. Following intravenous administration of umeclidinium to healthy volunteers, the mean volume of distribution was 86.L. Binding to human plasma proteins in vitro averaged 89%. Metabolism In vitro studies have shown that vilanterol is metabolized primarily by the cytochrome P450 isoenzyme CYP3A4 and that it is a substrate of the P-glycoprotein (P-gp) transporter. The main route of metabolism is O-dealkylation with the formation of a number of metabolites with significantly lower beta 1 and beta 2 adrenomimetic activity. The plasma metabolic profile determined in humans in a radioisotope study following oral administration of vilanterol is consistent with high first-pass metabolism. Systemic exposure of metabolites is low. In vitro studies have shown that umeclidinium is metabolized primarily by the cytochrome P450 isoenzyme CYP2D6 and that it is a substrate of the P-gp transporter. The main route of metabolism of umeclidinium is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc.), leading to the formation of a number of metabolites with lower pharmacological activity, or metabolites whose pharmacological activity has not been established. The systemic exposure of such metabolites is low. Available pharmacokinetic data obtained from studies in healthy volunteers and patients with COPD indicate no changes in systemic exposure (Cmax and mean area under the curve (AUC)) and predicted exposure when studying the population pharmacokinetics of vilanterol and umeclidinium when they were coadministered according to compared with similar indicators obtained when using both components separately. When co-administered with a strong inhibitor of the CYP3A4 isoenzyme, ketoconazole (400 mg), an increase in the average AUC (0-t) and Cmax of vilanterol was observed by 65 and 22%, respectively. Increased exposure to vilanterol did not increase the systemic effects associated with beta-agonists on heart rate, blood potassium, or QT interval (Frederick's method). Both umeclidinium and vilanterol are P-gp substrates. In healthy volunteers, the effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the pharmacokinetics of vilanterol and umeclidinium at steady state was determined. There was no effect of verapamil on Cmax, vilanterol or umeclidinium. There was an approximately 1.4-fold increase in the AUC of umeclidinium, while the AUC of vilanterol remained unchanged. Elimination Plasma clearance of vilanterol after intravenous administration was 108.l/h. After oral administration of vilanterol, labeled with a radioactive isotope, the mass balance showed that 70% of the radioactive substance was excreted by the kidneys and 30% by the intestines. Elimination of vilanterol mainly occurred through the metabolic route, followed by excretion of metabolites by the kidneys and intestines. After inhalation of vilanterol for 10 days, the plasma half-life averaged 11 hours. Plasma clearance of umeclidinium after intravenous administration was 151.l/h. 192 hours after intravenous administration, approximately 58% of the dose of radiolabeled substance (or 73% of the radioactive substance released) was excreted by the intestines, indicating secretion of this compound into bile. The kidneys excreted 22% of the dose of the substance labeled with a radioactive isotope (27% of the isolated radioactive substance) after 168 hours. 168 hours after oral administration of the drug to healthy men, the bulk of the radioactive substance was excreted mainly by the intestines (92% of the ingested dose of the radiolabeled substance, or 99% of the excreted radioactive substance). When taken orally, less than 1% of the dose of the substance (1% of the released radioactive substance) is excreted by the kidneys, which indicates negligible absorption with this route of drug administration. After inhalation of umeclidinium for 10 days, the plasma half-life averaged 19 hours, with 3 to 4% of the unchanged substance excreted by the kidneys at steady state. Special groups of patients Elderly patients Population pharmacokinetic analysis showed similarity in the pharmacokinetics of vilanterol and umeclidinium determined in patients with COPD in the age group 65 years and older and in the age group under 65 years. Patients with Renal Impairment: In a study of patients with severe renal impairment, no data were obtained indicating an increase in the systemic exposure of vilanterol or umeclidinium (Cmax and AUC). There is no evidence of changes in protein binding in patients with renal impairment compared with healthy volunteers. Patients with Hepatic Impairment In a study of patients with moderate hepatic impairment, no data were obtained indicating an increase in the systemic exposure of vilanterol or umeclidinium (Cmax and AUC). There is no evidence of changes in protein binding in patients with moderate hepatic impairment compared with healthy volunteers. The combination of vilanterol and umeclidinium has not been studied in patients with severe hepatic impairment. Other Patient Populations Population pharmacokinetic analysis data showed no need for dose adjustment of vilanterol or umeclidinium based on age, race, gender, use of inhaled corticosteroids, or body weight. In a study of patients with weak metabolic activity of the CYP2D6 isoenzyme, no data were obtained indicating a clinically significant effect of the genetic polymorphism of the CYP2D6 isoenzyme on the systemic exposure of umeclidinium. INDICATIONS FOR USE Anoro Ellipta is used as a maintenance bronchodilator therapy aimed at alleviating the symptoms of chronic obstructive pulmonary disease (COPD). CONTRAINDICATIONS The drug Anoro Ellipta is contraindicated in: • patients with a history of severe allergic reactions to milk protein or hypersensitivity to the active substances or any other component included in the drug, • children under 18 years of age. WITH CAUTION After using sympathomimetics and muscarinic receptor antagonists, including the drug Anoro Ellipta, undesirable reactions such as arrhythmia (for example, atrial fibrillation and tachycardia) may be observed in the cardiovascular system. In this regard, patients with severe forms of cardiovascular disease should prescribe Anoro Ellipta with caution. Given the antimuscarinic activity of this drug, it should be used with caution in patients with angle-closure glaucoma or urinary retention. USE IN PREGNANCY AND BREASTFEEDING Fertility There are no data on the effect of Anoro Ellipta on human fertility. Preclinical studies have not shown any effects of vilanterol or umeclidinium on fertility. Pregnancy There are no or limited data on the use of the combination of vilanterol and umeclidinium in pregnant women. Preclinical studies have shown reproductive toxicity with inhaled use of vilanterol. The use of Anoro Ellipta in pregnant women is permissible only if the potential benefit to the mother outweighs the possible risk to the fetus. Breastfeeding There are no data on the excretion of vilanterol or umeclidinium into human breast milk. However, other beta 2 agonists are detected in breast milk. The risk of the drug entering the body of a newborn or child along with milk cannot be excluded. Taking into account the ratio of the benefits of therapy for the mother and breastfeeding for the child, it is necessary to make a decision either to discontinue the drug or to stop breastfeeding. DOSAGE AND ADMINISTRATION The drug Anoro Ellipta is intended for inhalation use only. The recommended and maximum dose of Anoro Ellipta is one inhalation of 22 mcg + 55 mcg/dose once a day at the same time. Special groups of patients Children This drug is not used to treat patients under 18 years of age, taking into account the indications for its use. Elderly patients Patients over 65 years of age do not require dose adjustment (see section “Pharmacological properties”, subsection “Pharmacokinetics”). Patients with impaired renal function: Patients with impaired renal function do not require dose adjustment (see section “Pharmacological properties”, subsection “Pharmacokinetics”). Patients with impaired liver function: Patients with mild or moderate hepatic impairment do not require dose adjustment. Studies on the use of the combination of vilanterol and umeclidinium in patients with severe liver dysfunction have not been conducted (see section “Pharmacological properties”, subsection “Pharmacokinetics”). Recommendations for use When using the Ellipta inhaler for the first time, there is no need to check the correct operation of the inhaler or specially prepare the inhaler for use. Simply follow the directions for use below consistently. The cardboard pack of the Ellipta inhaler contains Container lid Inhaler Bag with desiccant Container Cardboard pack Instructions for use The inhaler is packed in a container. Do not open the container until you are ready to inhale the medication. When you are ready to use the inhaler, remove the cap from the container. The container contains a sachet of desiccant to reduce humidity. Do not open this sachet; it is not intended for food or inhalation and should be thrown away. When you remove the inhaler from the container, the cap is in the closed position. Do not open it until you are ready to inhale the medication. In the designated “Use By” field on the inhaler label, write the date that corresponds to the opening date plus 6 weeks. Do not use the inhaler after this date. Below are detailed step -by -step instructions for using the Ellipt inhaler: I. Read the following information before use when opening and closing the lid of the Ellipt inhaler without taking the drug, one dose is lost. This dose remains closed inside the inhaler, but it will be inaccessible to receive. It is impossible to accidentally get a greater dose or double dose for one inhalation. The dose counter shows how many doses of the drug are left in the inhale. Before using the inhaler, the dose counter shows the number 30. With each opening of the lid, the number of doses decreases by 1. When less than 10 doses remain, half of the meter becomes red. After the last dose of the drug is spent, half the meter is highlighted in red, the counter shows the number 0. This means that the inhaler is empty. If you open the lid after that, the dose counter will become completely red. The dose counter is one dose of the drug is ready for inhalation after each opening of the lid. II. Dose preparation do not open the lid until you are ready to take the drug. Do not shake the inhaler. 1. Lower the lid down to the click. 2. The dose of the drug is ready for inhalation, and in confirmation of this dose counter reduces the number of doses per unit. 3. If the dose meter has not reduced the number of doses after you have heard a click, then the inhaler is not ready to supply the dose of the drug. In this case, you should contact the phone or address indicated in the subsection “Contact for additional information”. 4. Never shake the inhaler. The mouthpiece of the III Click III. Inhalation of the drug 5. Holding the inhaler at a certain distance from the mouth, make an exhalation of maximum depth. Do not exhale into the inhaler. 6. Place the mouthpiece between the lips and grab it tightly with your lips. Do not cover the ventilation hole with your fingers. 7. Make one long, uniform, deep breath through your mouth. Hold your breath as much as possible (at least 3-4 seconds). 8. Remove the inhaler from the mouth. 9. Slowly and calmly exhale. Even with the proper use of the inhaler, you cannot feel the taste or feel the intake of the drug. If you want to wipe the mouthpiece before closing the cover, use a dry napkin. IV. Closing the inhaler lift the lid to the stop, having achieved the complete closure of the mouthpiece. When stored in the refrigerator, the inhaler should be kept at at least one hour before use. Side effects of clinical studies of the safety profile of the combination of vilanterol and training is based on data from clinical studies, in which approximately 3, 000, patients with COPD received the drug in dosage 22,+, 55, μg/dose or more for up to 1, year During research. Of these, about 1, 600, patients received a drug in a dosage of 22,+, 55, mcg/dose once a day and about 1, 300, patients - in a dosage of 22,+, 113, μg/dose once a day. The adverse reactions presented below are listed according to the damage to organs and organ systems and the frequency of occurrence. The frequency of occurrence is determined as follows: very often (≥, 1/10), often (≥, 1/100 and <, 1/10), infrequently (≥, 1/1, 000 and <,, 1/100), rarely (≥, 1/10, 000 and <, 1/1, 000), very rarely (<,, 1/10, 000, including individual cases). The incidence of unwanted reactions infectious and parasitic diseases is often: urinary tract infections, sinusitis, nasopharyngitis, pharyngitis, and infection of the upper respiratory tract. Violations from the heart are infrequent: atrial fibrillation, supraventricular tachycardia, tachycardia. Violations of the respiratory system, the organs of the chest and mediastinum are often: cough, pain in the oropharynx. Violations from the gastrointestinal tract are often: constipation, dry mouth. District observation data violations by the immune system of the hypersensitivity reaction, including: infrequently: rash. Rarely: anaphylaxia, angioedema, urticaria. Mental disorders infrequently: anxiety. Violations of the nervous system are rare: tremor, a violation of taste. Violations of the organ of vision are rarely: visibility of vision, glaucoma, an increase in intraocular pressure. Violations from the heart are rare: a rapid heartbeat. Violations of the respiratory system, the organs of the chest and mediastinum are rare: paradoxical bronchospasm, dysphony. Violations from the skeletal-muscular and connective tissue infrequently: muscle cramps. Violations of the kidneys and urinary tract rarely: delayed urine, dysuria. An overdose of symptoms an overdose of the drug Ellipto can cause the development of symptoms and signs caused by the action of individual components of the drug, including known undesirable reactions that develop when exposed to antagonists of muscarin receptors (for example, dry mouth, accommodation disorders and tachycardia) and signs observed during an overdose 2 -agonists (for example, tremor, headache and tachycardia). Treatment in case of an overdose requires symptomatic therapy and, if necessary, the patient is provided with appropriate observation. Further care of patients in case of an overdose must be carried out in accordance with clinical indications. Interaction with other drugs of beta -blockers can weaken the effects of beta 2 -agonists or act as antagonists of the drugs of this group, including vilanterol. The simultaneous use of non-election or selective beta-blockers should be avoided, excluding cases of good reason for their joint use. Vilantherol,-the component of the drug ANoro Ellipt, is subjected to rapid metabolism of the first passage in the gastrointestinal tract and liver using the CyP3A4 isoenzyme cytochrome P450. With the simultaneous prescription of the drug with strong inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole), caution should be observed, since there is the possibility of increasing the systemic exposition of vilanterol, which in turn can lead to an increase in the risk of undesirable reactions (see, the “pharmacological properties” section). Special instructions of studies on the use of anoro ellipte drug in patients with bronchial asthma were not carried out, so it is not recommended to use the specified drug for therapy in this group of patients. Anoro Ellipta is designed for use as supportive COPD therapy. This drug should not be used to stop acute symptoms, i.e. as the therapy of emergency care in an acute episode of bronchospasm. To stop acute symptoms, you must use a short -acting bronchiger. An increase in the frequency of the use of short -action bronchodilators in order to relieve symptoms indicates a deterioration in control over the disease, in this case the patient needs a doctor’s consultation. As with other types of inhalation therapy, the use of anoro ellipte can cause paradoxical bronchospasm, which can be life -threatening. With the development of paradoxical bronchospasm, it is necessary to stop treatment with the drug, and if necessary, alternative therapy can be prescribed. Anoro Ellipta is designed to support the treatment of patients with COPD. Due to the fact that patients over 40 years old, when prescribing the drug under 40 years of age, require a spiritualistic confirmation of the diagnosis of COPD, in the total population of the COPD. The impact on the ability to drive vehicles, mechanisms for the study of the effect of the drug ANoro Ellipt on the ability to drive vehicles and work with mechanisms were not carried out. Form of release powder for inhalations dosed, 22, mcg,+, 55, mcg/dose. 30, doses in a plastic inhaler with a light gray body, a red lid of a mouthpiece and a dose counter. The inhaler contains two aluminum laminated strips, each of which consists of 30 cells that contain white powder. The inhaler is placed in a multi -layer container made of aluminum foil containing a bag of drainage. The container is sealed with an easily opening lid. 1, container, along with instructions for the use of cardboard in a pack. The shelf life is an unknown aluminum container: 2, year. Opened aluminum container: 6, weeks. In a specially designated field “use before” on the inhaler label, write the date. The date should be indicated immediately after the opening of the aluminum container. Do not use after the expiration date stated on the package. Storage conditions are stored at a temperature of not higher than 30 ° C. Keep out of the reach of children. Vacation conditions are released according to the recipe. / GLAXO Operations UK Limited SG12 0DJ, Hertfordshire, VEA, Priori Street, Great Britain / Priory Street, Ware, Hertfordshire, SG12 0DJ, United Kingdom Name or owner of the registration certificate TKLYAN TRARADING ", Russia 125167, G. Moscow, Leningradsky Prospekt, 37a, building 4, floor 3, room XV, room 1 Organization receiving claims for the quality of the drug and reports of unwanted reactions: JSC Glaxosmitklyain Trading, Russia 125167, Moscow, Leningradsky Prospekt, Leningradsky Prospekt. d. 37a, building 4, floor 3, room XV, room 1 tel., Fax tightly wrap with your lips the mouthpiece for inhalation. Do not cover the ventilation hole with your fingers. Sange with a drainage
Vilanterol + Umeclidinium bromide (Vilanterolum + Umeclidinii bromidum)
When administered in combination with umeclidinium and vilanterol by inhalation, the pharmacokinetics of each compound were similar to those observed when each active substance was administered separately. For this reason, the pharmacokinetics of each substance will be considered separately.
Suction
In healthy volunteers, after inhalation of vilanterol, the average maximum concentration of the substance in the blood plasma was reached within 5-15 minutes. The absolute bioavailability of inhaled vilanterol averaged 27%, taking into account very little absorption of the substance in the oral cavity. After repeated inhalations of vilanterol after 6 days, a steady state was reached with a 2.4-fold accumulation.
In healthy volunteers, after inhalation of umeclidinium, the maximum concentration of the substance in the blood plasma was reached within 5-15 minutes. The absolute bioavailability of inhaled umeclidinium averaged 13%, taking into account very little absorption of the substance in the oral cavity. After repeated inhalations of umeclidinium, after 7-10 days an equilibrium state was reached with a 1.5-2-fold accumulation. After inhalation of 113 mcg of umeclidinium, systemic exposure was approximately twice that observed after inhalation of the drug at a dosage of 55 mcg.
Distribution
Following intravenous administration of vilanterol to healthy volunteers, the mean volume of distribution at steady state was 165 L. Binding to human plasma proteins in vitro
the average is 94%.
Following intravenous administration of umeclidinium to healthy volunteers, the mean volume of distribution was 86 L. Binding to human plasma proteins in vitro
the average is 89%.
Metabolism
In vitro studies
showed that vilanterol is metabolized primarily by the cytochrome P450 isoenzyme CYP3A4 and that it is a substrate of the P-glycoprotein (P-gp) transporter. The main route of metabolism is O-dealkylation with the formation of a number of metabolites with significantly lower beta1- and beta2-adrenomimetic activity. The plasma metabolic profile determined in humans in a radioisotope study following oral administration of vilanterol is consistent with high first-pass metabolism. Systemic exposure to metabolites is negligible.
In vitro studies
showed that umeclidinium is metabolized primarily by the cytochrome P450 isoenzyme CYP2D6 and that it is a substrate of the P-gp transporter. The main route of metabolism of umeclidinium is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc.), leading to the formation of a number of metabolites with lower pharmacological activity or metabolites whose pharmacological activity has not been established. The systemic exposure of such metabolites is low.
Available pharmacokinetic data from studies in healthy volunteers and patients with chronic obstructive pulmonary disease indicate no change in systemic exposure (maximum plasma concentration and mean area under the curve (AUC)) and predicted exposure in population pharmacokinetics studies of vilanterol and umeclidinium when used together compared to similar indicators obtained when both components were used separately. When co-administered with a strong inhibitor of the CYP3A4 isoenzyme, ketoconazole (400 mg), an increase in mean AUC (0-1) and maximum plasma concentration of vilanterol was observed by 65 and 22%, respectively. Increased exposure to vilanterol did not increase the systemic effects associated with beta-agonists on heart rate, blood potassium, or QT interval (Frederick's method).
Both umeclidinium and vilanterol are P-gp substrates. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of vilanterol and umeclidinium was determined in healthy volunteers. There was no effect of verapamil on the maximum plasma concentrations of vilanterol or umeclidinium. There was an approximately 1.4-fold increase in the area under the pharmacokinetic curve of umeclidinium, while the area under the pharmacokinetic curve of vilanterol did not change.
Removal
Plasma clearance of vilanterol after intravenous administration was 108 L per hour. After oral administration of radiolabeled vilanterol, mass balance showed that 70% of the radioactive substance was excreted by the kidneys and 30% by the intestines. Elimination of vilanterol mainly occurred through the metabolic route, followed by excretion of metabolites by the kidneys and intestines. After inhalation of vilanterol for 10 days, the plasma half-life averaged 11 hours.
Plasma clearance of umeclidinium after intravenous administration was 151 L per hour. At 192 hours after intravenous administration, approximately 58% of the radiolabeled dose (or 73% of the radioactive substance released) was excreted by the intestine, indicating secretion of the compound into bile. The kidneys excreted 22% of the radiolabeled dose (27% of the excreted radioactive substance) after 168 hours. 168 hours after oral administration of the drug to healthy men, the bulk of the radioactive substance was excreted mainly by the intestines (92% of the ingested dose of the radiolabeled substance or 99% of the excreted radioactive substance). When administered orally, less than 1% of the dose is excreted by the kidneys (1% of the radioactive substance released), indicating very little absorption by this route of administration. After repeated inhalations of umeclidinium for 10 days, the plasma half-life averaged 19 hours, with 3 to 4% of unchanged drug excreted by the kidneys at steady state.
Special patient groups
Elderly patients
Population pharmacokinetic analysis showed similarity in the pharmacokinetics of vilanterol and umeclidinium determined in patients with chronic obstructive pulmonary disease in the age group 65 years and older and in the age group under 65 years.
Patients with impaired renal function
In a study of patients with severe renal impairment, there was no data indicating an increase in the systemic exposure of vilanterol or umeclidinium (maximum plasma concentration and area under the pharmacokinetic curve). There is no evidence of changes in protein binding in patients with renal impairment compared with healthy volunteers.
Liver dysfunction
In a study of patients with moderate hepatic impairment, there was no data indicating an increase in the systemic exposure of vilanterol or umeclidinium (maximum plasma concentration and area under the pharmacokinetic curve). There is no evidence of changes in protein binding in patients with hepatic impairment compared with healthy volunteers. The combination of vilanterol and umeclidinium has not been studied in patients with severe hepatic impairment.
Other patient groups
Data from a population pharmacokinetic analysis showed no need for dose adjustment of vilanterol or umeclidinium depending on age, race, gender, use of inhaled corticosteroids, or body weight. In a study of patients with weak metabolic activity of the CYP2D6 isoenzyme, no data were obtained indicating a clinically significant effect of the genetic polymorphism of the CYP2D6 isoenzyme on systemic exposure to umeclidinium.
