Anoro®Ellipta® 22 .mu.g / 55 .mu.g of powder 30 doses for inhalation, metered

The instruction for medical use of Ellipta® Anoro® medicine the Trade name of Anoro® Ellipta® the International unlicensed name Is not present the Dosage form Powder for inhalations dosed, 22 mkg / 55 mkg Structure 1 dose soderzhit1 Streep with vilanteroly active agents: 40 mkg of a vilanterol of the trifenatat micronized (25 mkg in terms of vilanterol2) excipients: magnesium stearate, lactoses monohydrate. A strip with umeklidiniy active agents: 74.2 mkg an umeklidiniya of the bromide micronized (62.5 mkg in terms of umeklidiniy2) excipients: magnesium stearate, lactoses monohydrate. 1. For compensation of losses when filling cells by production of ready drug mix of a vilanterol and excipients can be put in ready drug much up to 8%, mix an umeklidiniya and excipients — is a lot of to 6%. 2. The nominal amount of active ingredient put in the course of production is specified, the brought quantity of a vilanterol is 22 mkg, an umeklidiniya – 55 mkg. The description the Plastic inhaler with the body of light gray color, a red cover of a mouthpiece and the counter of doses packed into the container from a foil containing the moisture absorbing bag. The container is sealed by easily opening foil. The inhaler contains two strips, each strip consists of 30 evenly distributed cells, each of which contains powder of white color. Pharmacotherapeutic group Drugs for treatment of obstructive respiratory diseases. Inhalation sympathomimetics. Adrenomimetiki in a combination from antikholinergika. Vilanterol with umeklidiny bromide. ATX R03AL03 code. The pharmacological Pharmacokinetics At properties inhalation use of a combination an umeklidiniya and a vilanterola the pharmacokinetics of each component was similar to that, observed at use of each active ingredient separately. For this reason the pharmacokinetics of each substance will be considered separately. Absorption At healthy volunteers after inhalation of a vilanterol the average maximum concentration (Cmax) was reached in 5–15 minutes. The absolute bioavailability of an inhalation vilanterol, on average, was 27% taking into account very insignificant absorption of substance in an oral cavity. After repeated inhalations of a vilanterol in 6 days the equilibrium state with 2.4-fold accumulation was reached. At healthy volunteers after inhalation the umeklidiniya of Cmax was reached in 5–15 minutes. The absolute bioavailability inhalation an umeklidiniya, on average, was 13% taking into account very insignificant absorption of substance in an oral cavity. After repeated inhalations an umeklidiniya in 7–10 days the equilibrium state with 1.5-2-fold accumulation was reached. Distribution After intravenous administration of a vilanterol to healthy volunteers the average volume of distribution in an equilibrium state was 165 l. Linking with proteins of blood plasma of the person of in vitro, on average, is equal to 94%. After intravenous administration an umeklidiniya to healthy volunteers the average volume of distribution was 86 l. Linking with proteins of blood plasma of the person of in vitro, on average, is equal to 89%. Metabolism of the Research in vitro was shown that vilanterol is metabolized mainly under the influence of an isoenzyme of CYP3A4 of a system of P450 cytochrome and that it is substrate of the carrier of the R-glycoprotein (P-gp). The main way of metabolism is O-dealkylation with formation of a number of the metabolites having significantly lower бета1st and beta2-adrenomimetichesky activity. The metabolic profile of blood plasma defined in a human body during the research with use of radioactive isotopes after oral administration of a vilanterol will be coordinated with high metabolism of the first passing. System exposure of metabolites is insignificant. The umeklidiniya is the main way of metabolism oxidation (hydroxylation, O-dealkylation) with the subsequent conjugation (a glyukuronirovaniye, etc.), leading to formation of a number of metabolites with lower pharmacological activity, or metabolites which pharmacological activity is not established. System exposure of such metabolites low. The available pharmacokinetic data obtained at a research on healthy volunteers and patients with HOBL indicate lack of changes of system exposure (Cmax and average area under pharmacokinetic curve (AUC)) and the predicted exposure when studying population pharmacokinetics of a vilanterol and an umeklidiniya at their combined use in comparison with the similar indicators received at use of both components separately. At combined use of strong inhibitor of an isoenzyme of CYP3A4 – a ketokonazola (400 mg) increase in average AUC(0-t) and Cmax of a vilanterol for 65 and 22%, respectively was observed. Increase in exposure of a vilanterol did not lead to strengthening of the system effects characteristic of beta-agonists: influence on heart rate, potassium content in blood or an interval of QT (korrigirovanny by Frederik's method). As umeklidiniya, and vilanterol are P-gp substrates. At healthy volunteers defined influence of moderate inhibitor of the carrier of P-gp of verapamil (240 mg once a day) on pharmacokinetics of a vilanterol and an umeklidiniya in an equilibrium state. Influences of verapamil on Cmax of a vilanterol or an umeklidiniya it was not observed. Approximately 1.4-fold increase in AUC an umeklidiniya was noted, at this AUC the vilanterola did not change. Removal the Plasma clearance of a vilanterol after intravenous administration was 108 l/h. After oral administration of a vilanterol, marked radioactive isotope, the balance of masses showed that 70% of radioactive material were removed by kidneys and 30% — intestines. Removal of a vilanterol mainly happened in the metabolic way to the subsequent excretion of metabolites kidneys and intestines. After inhalations of a vilanterol within 10 days the plasma elimination half-life made, on average, 11 h. The plasma clearance an umeklidiniya after intravenous administration was 151 l/h. In 192 hours after intravenous administration about 58% of a dose of substance, marked radioactive isotope (or 73% of the emitted radioactive material) were removed by intestines that indicates secretion of this connection in bile. Kidneys removed 22% of a dose of substance, marked by radioactive isotope (27% of the emitted radioactive material) in 168 hours. In 168 hours after oral administration of drug by healthy men the bulk of radioactive material was removed mainly by intestines (92% of the accepted dose of substance, marked radioactive isotope, or 99% of the emitted radioactive material). At oral administration the kidneys remove less than 1% of a dose of substance (1% of the emitted radioactive material) that indicates very insignificant absorption at this way of administration of drug. After repeated inhalations an umeklidiniya within 10 days the plasma elimination half-life made, on average, 19 h, at the same time from 3 to 4% of not changed substance were removed by kidneys in an equilibrium state. Patients of advanced age the Population pharmacokinetic analysis showed special groups of patients similarity of the pharmacokinetics of a vilanterol and an umeklidiniya defined at patients with HOBL in an age group of 65 years and is more senior and in an age group 65 years are younger. Patients with a renal failure At a research of patients with a heavy renal failure the data indicating increase in system exposure of a vilanterol or an umeklidiniya were not obtained (Cmax and AUC). There are no signs of changes of linking with proteins at patients with a renal failure in comparison with healthy volunteers. The abnormal liver function At a research of patients with a moderate abnormal liver function was not obtained the data indicating increase in system exposure of a vilanterol or an umeklidiniya (Cmax and AUC). There are no signs of changes of linking with proteins at patients with an abnormal liver function in comparison with healthy volunteers. Researches of a combination of a vilanterol and an umeklidiniya at patients with a heavy abnormal liver function were not conducted. Other groups of patients Data of the population analysis of pharmacokinetics the lack of need of dose adjustment of a vilanterol or an umeklidiniya depending on age, racial and sex showed, uses of inhalation glucocorticosteroids or body weight. At a research of patients with weak metabolic activity of an isoenzyme of CYP2D6 the data indicating clinically significant influence of genetic polymorphism of an isoenzyme of CYP2D6 on system exposure an umeklidiniya were not obtained. The pharmacodynamics the action Mechanism the Drug Anoro® Ellipta® represents a combination of the inhalation antagonist of muskarinovy holinoretseptor of long action and an inhalation beta2-adrenomimetik of long action (AHDD/BADD). After oral inhalation both connections make local impact on airways, causing a bronkhodilatation at the expense of various mechanisms of action. Vilanterol belongs to the class of selection agonists of beta2-adrenergic receptors of long action (beta2-agonists). Pharmacological effects of agonists of beta2-adrenoceptors, including vilanterol, at least, are partially connected with stimulation of intracellular adenylatecyclase — enzyme which catalyzes transformation of adenosine triphosphate (ATP) into cyclic 3’, 5 ’-adenosinemonophosphate (cyclic AMF). Increase in level of cyclic AMF leads to relaxation of smooth muscles of bronchial tubes and oppression of release from cells (first of all from mast cells) mediators of reactions of immediate hypersensitivity. Umeklidiny is an antagonist of muskarinovy receptors of long action (also called antikholinergiky). He represents derivative a hinuklidin, being the antagonist of muskarinovy receptors who affects muskarinovy cholinergic receptors of various subtypes. Umeklidiny has bronchodilatory effect by competitive inhibition of linking of acetylcholine with muskarinovy atsetilkholinovy receptors of smooth muscles of airways. When performing preclinical trials on in the vitro models this connection shows slow reversibility of action on human muskarinovy receptors of M3 subtype, and on in the Vivo models duration of influence of drug after introduction directly to lungs was shown. Pharmakodinamichesky effects In placebo - controlled clinical trial of efficiency of a combination of vilanterol/umeklidiniya increase in volume of the forced exhalation for the first second (OFV1) after the first dose in the first day was observed. This indicator increased by 0.11 l (р<, 0.001) in 15 minutes after drug use. The difference between an initial indicator and peak OFV1 defined within 6 hours after drug use in the first day and on the 24th week of an experiment made 0.27 and 0.32 l, respectively. At placebo use the similar rates were 0.11 l (Day of I) and 0.10 l (24th week). Influence of a combination of a vilanterol and an umeklidiniya on duration of an interval of QT estimated at placebo and moxifloxacin - a controlled research. 103 healthy volunteers applied a combination of a vilanterol and an umeklidiniya for 10 days in a dosage of 22 mkg / 113 mkg or 88 mkg / 452 mkg once a day. After repeated use of this drug clinically significant influence on QT interval duration (Frederik, korrigirovanny by a method) was not observed. Besides, clinically significant influence of a combination of a vilanterol and an umeklidiniya on a warm rhythm was not observed at 24-hour holterovsky monitoring of the ECG at 281 patients receiving this drug for 12 months in a dosage of 22 mkg / 113 mkg once a day. Clinical performance of single use a vilanterola/umeklidiniya was estimated in the clinical trials conducted at 6835 patients with the diagnosis of HOBL. Use of Anoro® Ellipta® showed statistically reliable improvement of pulmonary function by means of increase in OFV1. Anoro® Ellipta® showed statistical and clinically significant decrease in the tranzitorny index of an asthma on the 24th week. Drug also showed significant improvement of the quality of life defined with use of the Respiratory Questionnaire of Hospital of Saint George. As shown in a number of researches, 12 weeks use of Anoro® Ellipta® allows to reduce the number of aggravations of HOBL, (salbutamol) reduces the need for use of means of the emergency therapy, increases resistance of patients to physical activities and increases pulmonary volume. Indications - the supporting bronchodilatory therapy directed to relief of symptoms of the chronic obstructive pulmonary disease (COPD). The route of administration and doses the Drug Anoro® Ellipta® is intended only for inhalation use. The drug Anoro® Ellipta® should be used daily at the same time once a day. The recommended dose of the drug Anoro® Ellipta®: one inhalation of 22 mkg / 55 mkg/dose once a day. The maximum dose makes one inhalation of drug Аноро® 22 of mkg / 55 mkg once a day. Special groups of patients Children This drug is not used for treatment of patients 18 years are younger, accepting in attention of the indication for its appointment. Patients of advanced age to Patients are more senior than 65 years of dose adjustment it is not required. Patients with a renal failure with a renal failure of dose adjustment it is not required to Patients. Patients with an abnormal liver function with an abnormal liver function of light or moderate severity of dose adjustment it is not required to Patients. Researches on use of a combination of a vilanterol and an umeklidiniya on patients with a heavy abnormal liver function were not conducted. Recommendations about use the Inhaler of Ellipta® contains previously measured doses and is ready to use. At the first use of an inhaler of Ellipta® there is no need for check of correctness of its work or special preparation of an inhaler for operation. Just follow the recommendations about use provided below. The inhaler of Ellipta® is packed into the container containing the moisture absorbing bag of silica gel which is not intended for food or inhalations. This bag should be utilized. When you for the first time get an inhaler from the sealed container, its cover is in a closed position. Do not open it until you are not ready to administration of drug. On the label of an inhaler Ellipta®, in the place allocated for this purpose To use to, it is necessary to write expiration date of use of drug. Date To use to makes 6 weeks from the moment of opening of a container. After this date the inhaler of Ellipta® should not be used, the container can be utilized. Detailed instructions of use of an inhaler of Ellipta® are given below: I. Read the following information before use When opening and closing a cover of an inhaler of Ellipta® without intake of medicine there is a loss of one dose. This dose remains closed in an inhaler, but it will be inaccessible for reception. It is impossible to receive accidentally a high dose or a double dose for one inhalation. The counter of doses shows how many doses of medicine remained in an inhaler. Before use of an inhaler the counter of doses shows number 30. At each opening of a cover the quantity of doses decreases by 1. When there are less than 10 doses, a half of the counter becomes red. After the last dose of drug is spent, a half of the counter is highlighted in red color, the counter shows figure 0. It means that the inhaler is empty. If you open a cover after that, the counter of doses will become completely red. The counter of doses One dose of medicine is ready to inhalation after each opening of a cover the Cover of II. Preparation of a dose do not open a cover until you are ready to administration of drug. Do not stir up an inhaler. 1. Lower a cover down to click. Mouthpiece Click Air vent 2. The dose of drug is ready to inhalation, and in confirmation of it the counter of doses reduces number of doses by unit. 3. If about
an etchik of doses did not reduce number of doses after you heard click, then the inhaler is not ready to giving of a dose of medicine. In this case it is necessary to address by phone or the address specified in the subsection The Address of the Organization Accepting in the territory of the Republic of Kazakhstan Claims from Consumers on Quality of Products (Goods). 4. Never stir up an inhaler. III. Inhalation of medicine 1. Holding an inhaler at some distance from a mouth, make an exhalation of the maximum depth. Do not exhale in an inhaler. 2. Place a mouthpiece between lips and densely clasp it with lips. Do not close fingers an air vent. 3. Make one deep, long, uniform breath. Hold the breath as far as possible (at least, for 3–4 seconds). 4. Remove an inhaler from a mouth. 5. Slowly and quietly exhale. Lips have to repeat an inhaler mouthpiece form precisely. Do not close an air vent fingers. At the correct use of an inhaler you can not feel taste or not feel intake of medicine. IV. Closing of an inhaler If you want to wipe a mouthpiece before closing of a cover, use a dry tissue. Lift a cover against the stop, having achieved full closing of a mouthpiece. Side effects the Profile of safety of a combination of a vilanterol and an umeklidiniya is based on data of clinical trials as in a combination, and separate components in which 6855 patients with HOBL, and from spontaneous messages participated. The program of clinical trials included 2354 patients who received the drug Anoro® Ellipta® within clinical trials of a phase with an III duration of 24 weeks or more once a day, from whom 1296 patients received the recommended dose of 22 mkg / 55 mkg within 24nedelnykh researches, 832 patients received the increased dose of 22 mkg / 113 mkg within 24nedelnykh researches and 226 patients received a dose of 22 mkg / 113 mkg within the 12-month research. The undesirable reactions given below are listed according to defeat of bodies and the systems of bodies and occurrence frequency. Frequency of occurrence is defined as follows: very often (≥ 1/10), it is frequent (≥ 1/100 and & lt, 1/10), infrequently (≥ 1/1000 and & lt, 1/100), is rare (≥ 1/10,000 and & lt, 1/1000), is very rare (& lt, 1/10,000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug. Very often - a nasopharyngitis Often - a headache - dryness in a mouth - pain in a stomatopharynx - sinusitis - a nasopharyngitis - pharyngitis - cough - upper respiratory tract infections - infections of urinary tract - a constipation Infrequently - tachycardia - supraventricular tachycardia - atrial fibrillation - an idioventricular rhythm - supraventricular premature ventricular contraction - fibrillation of auricles - rash - a tremor - a food faddism - heartbeat - a muscular spasm - the concern Is rare - an anaphylaxis, a Quincke's disease, a small tortoiseshell - illegibility of sight - glaucoma - increase in intraocular pressure - a paradoxical bronchospasm - an ischuria - a dysuria - the syndrome of infravezikalny obstruction Providing data on expected side reactions of drug is very important point allowing to carry out continuous monitoring of a ratio risk/advantage of medicine. Health workers should provide information on any expected adverse reactions, through the national system of collection of information (see at the end of the instruction a contact information of the organization accepting claims from consumers in the territory of the Republic of Kazakhstan). Contraindications - hypersensitivity to active ingredients or any component which is a part of drug - the significant intolerance of milk protein. Medicinal interactions Blockers of beta adrenoceptors Beta blockers can weaken effects of beta2-agonists or work as antagonists of drugs of this group including a vilanterola. It is necessary to avoid simultaneous use of non-selective and selection beta-blockers, excepting cases of existence of strong reasons for their combined use. Interactions on the basis of metabolites and Vilanterol conveyors is substrate of P450 3A4 cytochrome (CYP3A4). At co-administration of drug (for example, ketokonazoly, klaritromitsiny, itrakonazoly, ritonaviry, telitromitsiny) it is necessary to be careful with strong inhibitors of an isoenzyme CYP3A4 as there is a possibility of increase in system exposure of a vilanterol that in turn can lead to increase in risk of development of undesirable reactions. It is necessary to be careful at simultaneous use of the drug Anoro® Ellipta® with ketokonazoly and also other known strong inhibitors of an isoenzyme CYP3A4 as it can lead to increase in system exposure of a vilanterol that in turn can lead to increase in risk of development of undesirable reactions. Verapamil which is moderate CYP3A4 inhibitor has no considerable impact on pharmacokinetics of a vilanterol. Umeklidiniya bromide is substrate of P450 2D6 cytochrome (CYP2D6). The pharmacokinetics a bromide umeklidiniya in an equilibrium state was estimated on healthy volunteers with a lack of CYP2D6 (slow metabolizator). At use an umeklidiniya in the dose exceeding usual by 8 times the influence on its AUC or Cmax was not observed. After use of drug in the dose exceeding usual by 16 times the increase in AUC an umeklidiniya approximately by 1.3 times without influence on its Cmax was observed. On the basis of the magnitude of these changes no clinically significant medicinal interaction is expected at joint appointment an umeklidiniya with CYP2D6 inhibitors or when it is applied at subjects with genetic insufficiency of CYP2D6 (slow metabolizator). Other antimuskarinovy drugs and sympathomimetics Simultaneous use of a combination umeklidiny/vilanterol with other antagonists of muskarinovy receptors of long action, the agonists of beta2-adreneoretseptor of long action or medicines containing any of these substances is not studied and is not recommended as it can lead to strengthening of the known undesirable reactions of antagonists of muskarinovy receptors or agonists of beta2-adrenoceptors at use in the form of inhalations. The hypopotassemia the Accompanying gipokaliyemichesky therapy by methylxanthine derivatives, steroids or nekaliysberegayushchy diuretics can enhance potential gipokaliyemichesky effect of agonists of beta2-adrenoceptors therefore it should be applied with care. Other medicines for treatment of HOBL In spite of the fact that official researches of medicinal interaction in vivo not provodios, the combination umeklidiny/vilanterol in an inhalation form was applied along with other medicines to treatment of HOBL, including sympathomimetic bronchodilators of short action and inhalation corticosteroids. At the same time clinical signs of medicinal interaction were absent. Special instructions Bronchial asthma of Researches on use of the drug Anoro® Ellipta® for patients with bronchial asthma it was not carried out therefore it is not recommended to use the specified drug for therapy in this group of patients. It is not used for stopping of acute symptoms of a bronchospasm the Drug Anoro® Ellipta® is intended for use as maintenance therapy of HOBL. It is not necessary to use this drug for stopping of acute symptoms, i.e. as therapy of emergency aid at a sharp episode of a bronchospasm. For stopping of acute symptoms it is necessary to use bronchodilator of short action. Increase in frequency of use of bronchodilators of short action for the purpose of stopping of symptoms demonstrates deterioration in control over a disease, in this case the patient needs consultation of the doctor. The paradoxical bronchospasm As well as at other types of inhalation therapy, use of the drug Anoro® Ellipta® can cause a paradoxical bronchospasm which can be life-threatening. At development of a paradoxical bronchospasm it is necessary to stop drug treatment, and if necessary alternative therapy can be appointed. Influence on a cardiovascular system After use of sympathomimetics and antagonists of muskarinovy receptors including the drug Anoro® Ellipta®, from a cardiovascular system such undesirable reactions as arrhythmia can be observed (for example, fibrillation of auricles and tachycardia). Patients with clinically significant uncontrollable cardiovascular diseases were excluded from clinical trials. In this regard, patients with severe forms of cardiovascular diseases should appoint the drug Anoro® Ellipta® with care. Antimuskarinovy activity Considering antimuskarinovy activity of this drug, patients should appoint it with care with closed-angle glaucoma or an ischuria. A hypopotassemia At some patients beta 2-adrenergic agonists can lead to development of the expressed hypopotassemia which can potentially cause undesirable reactions from a cardiovascular system. Decrease in potassium in blood serum, usually quickly, does not demand its additional reception. Clinically significant effects of a hypopotassemia in clinical trials of the drug Anoro® Ellipta®, in the recommended therapeutic dose, were not observed. It is necessary to show care, at simultaneous use of the drug Anoro® Ellipta® and drugs which can cause a hypopotassemia. A hyperglycemia At some patients, beta 2-adrenergic agonists can lead to development of a temporary hyperglycemia. Increases in level of glucose in blood at clinical trials of the drug Anoro® Ellipta® in the recommended therapeutic dose, it was not observed. At patients with diabetes from an initiation of treatment with the drug Anoro® Ellipta® glucose level in blood has to be controlled regularly. The accompanying states the Drug Anoro® Ellipta® should be used with care the patient with convulsive disorders or a thyrotoxicosis and also to patients who are sensitive to beta 2 - to agonists. Excipients Drug contains lactose. Drug is not recommended to be used to patients with rare hereditary diseases, such as: galaktozny intolerance, deficiency of lactase or glyukozo-galaktozny Lapp-malabsorption. Fertility Data on influence of the drug Anoro® Ellipta® on fertility of the person are absent. In preclinical trials of influence of a vilanterol or an umeklidiniya on fertility it is not revealed. Pregnancy the combinations of a vilanterol Given on use and an umeklidiniya at pregnant women are absent. In preclinical trials the reproductive toxicity at inhalation use of a vilanterol which are not clinically significant was revealed. Use of the drug Anoro® Ellipta® for pregnant women is admissible only if the potential advantage for mother exceeds possible risk for a fruit. A lactation Data on excretion of a vilanterol or an umeklidiniya in breast milk of the person are absent. However other beta2-agonists are defined in breast milk. The risk of penetration of drug together with milk in an organism of the newborn or child cannot be excluded. In view of a ratio of advantage of therapy for mother and breastfeeding for the child, it is necessary to make the decision either on drug withdrawal, or on the breastfeeding termination. The Drug Anoro® Ellipta® has no feature of influence of medicine on ability to run the vehicle or potentially dangerous mechanisms or has insignificant impact on ability to run vehicles and to work with mechanisms. Overdose Symptoms: the overdose by the drug Anoro® Ellipta® can cause development of the symptoms and signs caused by action of separate components of drug including the known effects of antagonists of muskarinovy receptors (for example, dryness in a mouth, disturbances of accommodation and tachycardia) and the signs observed at overdose by other beta2-agonists (for example, arrhythmias, a tremor, a headache, heartbeat, nausea, a hyperglycemia and a hypopotassemia). Treatment: in case of overdose the symptomatic therapy is required and, if necessary, for the patient the corresponding observation is provided. A form of release and packing Powder for inhalations dosed, 22 mkg + 55 mkg / a dose. On 30 doses place in a plastic inhaler with the body of light gray color, a red cover of a mouthpiece and the counter of doses. The inhaler contains two aluminum laminated strips, each of which consists of 30 cells which contain powder of white color. The inhaler is placed in the multilayered container from aluminum foil containing the moisture absorbing bag. The container is sealed by easily opening foil. On 1 container together with the instruction for medical use on state and Russian place in a cardboard pack. To Store storage conditions at a temperature not over 30 ºС. To store out of children's reach! If the drug Anoro® Ellipta® was stored in the fridge, it is necessary to leave before use an inhaler at the room temperature for one hour. To store an inhaler of Ellipta® in a tight container for protection against moisture. It is recommended to open a container just before the first use. On an inhaler of Ellipta®, in the place allocated for this purpose, it is necessary to write date okonch
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