Revoleyd
Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain
Code of automatic telephone exchange: B02BX05
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Tablets, film coated white color, round, biconvex, on one party also "25" are engraved "GS NX3".
Active ingredient: элтромбопаг olamina of 31.9 mg,
what corresponds to the maintenance of an eltrombopag of 25 mg
Excipients: Mannitolum - 29.7 mg, cellulose microcrystallic - 14.9 mg, K30 povidone - 3.2 mg.
Ekstragranulovy components: cellulose microcrystallic - 238.8 mg, sodium carboxymethylstarch (type A) - 28 mg, magnesium stearate - 3.5 mg.
Structure of a film cover: опадрай® white YS-1-7706-G - 14 mg (a gipromelloza - 8.365 mg, titanium dioxide - 4.375 mg, a macrogoal of 400 - 1.12 mg, polysorbate of 80 - 0.14 mg).
Tablets, film coated brown color, round, biconvex, on one party also "50" are engraved "GS UFU".
Active ingredient: элтромбопаг olamina of 63.8 mg,
what corresponds to the maintenance of an eltrombopag of 50 mg
Excipients: Mannitolum - 59.5 mg, cellulose microcrystallic - 29.8 mg, K30 povidone - 6.4 mg.
Ekstragranulovy components: cellulose microcrystallic - 159.1 mg, sodium carboxymethylstarch (type A) - 28 mg, magnesium stearate - 3.5 mg.
Structure of a film cover: опадрай® brown 03B26716 - 14 mg (a gipromelloza - 8.75 mg, titanium dioxide - 3.09 mg, a macrogoal of 400 - 0.875 mg, dye ferrous oxide yellow - 0.99 mg, dye ferrous oxide red - 0.3 mg).
Pharmacological properties:
Hemogenesis stimulator. Trombopoetin is the main cytokine which takes part in regulation of a megakariopoez and development of thrombocytes. It is an endogenous ligand for a receptor of a trombopoetin. Элтромбопаг interacts with a transmembrane domain of a human receptor of a trombopoetin and initiates the signal transmission cascade reminding that for an endogenous trombopoetin that is followed by induction of proliferation and a differentiation of megacaryocytes from marrow progenitors.
Элтромбопаг differs from a trombopoetin from the point of view of influence on aggregation of thrombocytes. Unlike a trombopoetin, impact of an eltrombopag on thrombocytes of the healthy person does not strengthen aggregation under the influence of adenosinediphosphate (ADF) and does not stimulate the R-selectin expression. Элтромбопаг does not interfere with aggregation of thrombocytes under the influence of ADF or collagen.
Pharmacokinetics. Parameters of pharmacokinetics of an eltrombopag after its introduction to patients with the idiopathic Werlhof's disease (IWD) are given in the table below.
Averages geometrical (the confidence interval (CI) of 95%) values of plasma parameters of pharmacokinetics of an eltrombopag in an equilibrium state at adult patients with ITP
Scheme of treatment eltrombopagy Cmax AUC(0-t)
(mkg/ml) (мкг×ч/мл)
50 mg of 1 times / 8.01 108
(n=34) (6.73; 9.53) (88; 134)
75 mg of 1 times / 12.7 168
(n=26) (11; 14.5) (143; 198)
These dependences of concentration of an eltrombopag in a blood plasma from time received at 590 patients with the viral hepatitis With (VH) included in researches III of the phase TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data at patients from VGS included in a research II of the phase TPL102357 and healthy adult volunteers in group for the analysis of pharmacokinetics. Results of measurements of Cmax and AUC(0-t) of an eltrombopag for patients from VGS included in phase researches III are presented in the table for each studied dose. The highest exposure of an eltrombopag was observed at patients with VGS at the appointed doses of an eltrombopag (according to the table below).
Averages geometrical (DI of 95%) values of stationary parameters of an eltrombopag in a blood plasma at patients with chronic VGS
Dose of an eltrombopag of N Cmax AUC(0-t)
(1 time/) (mkg/ml) (мкг×ч/мл)
25 mg 330 6.40 118
(5.97; 6.86) (109, 128)
50 mg 119 9.08 166
(7.96; 10:35) (143, 192)
75 mg 45 16.71 301
(14:26; 19:58) (250, 363)
100 mg 96 19.19 354
(16.81; 21.91) (304, 411)
Data are presented in the form of an average geometrical (DI of 95%). (0-t) and Cmax are founded by AUC on secondary estimates of data for each patient from pharmacokinetic group in a high dose.
Absorption
Элтромбопаг it is soaked up and reaches Cmax in 2-6 h after intake. Joint reception of an eltrombopag with the antacids and other products containing polyvalent cations (for example, dairy products and mineral additives), considerably reduces exposure of an eltrombopag.
Absolute bioavailability of an eltrombopag at intake was not established. On the basis of indicators of renal excretion of drug and the analysis of the metabolites removed through intestines it was shown that calculated values of absorption of derivatives of drug after introduction of its single dose of 75 mg were made by, at least, 52%.
Distribution
Linkng with proteins of plasma of the person high (> 99.9%). Элтромбопаг is substrate for BCRP (protein of a resistant breast cancer), but not for the R-glycoprotein or OATP1B1.
Metabolism
Soaked up элтромбопаг is exposed to active metabolism. It is metabolized preferential by splitting, oxidation and conjugation, with glucuronic acid, glutathione or cysteine. According to clinical trial of drug, marked radioactive isotope, it was shown that about 64% of radioactive isotope of carbon in plasma fall to the share of an eltrombopag. Minor metabolites, less than 10% of radioactivity of plasma fall to the share of each of which, are formed by a glyukuronidation and oxidation.
Based on a research marked radioactive isotope of an eltrombopag, it was established that about 20% of a dose of drug are metabolized by oxidation.
The researches in vitro showed that CYP1A2 and CYP2C8 are the isoenzymes which are responsible for oxidizing metabolism whereas UGT1A1 and UGT1A3 uridine-diphospho-glyukuroniltransferazy - the isoenzymes which are responsible for a glyukuronization. In the course of splitting bacteria from lower parts of a GIT can take part.
Removal
Preferential way of removal of an eltrombopag is intestinal elimination (59%); at the same time 31% of a dose are found in urine in the form of metabolites. Initial substance in urine is absent. In an invariable view with a stake about 20% of the administered drug are removed. T1/2 of an eltrombopag makes about 21-32 h of plasma.
Pharmacokinetics in special clinical cases
The pharmacokinetics of an eltrombopag was studied after purpose of drug to adult patients with disturbance of functions of kidneys. After introduction of an eltrombopag in a single dose of 50 mg to patients with easy renal failures of AUC(0-∞)
the eltrombopaga decreased by 32% (90% of DI: 63% decrease and 26% increase); to patients with moderate renal failures - for 36% (90% of DI:-66% decrease and 19% increase); to patients with heavy renal failures - for 60% (90% of DI: 18% decrease, 80% decrease) in comparison with healthy volunteers. At patients with a renal failure the tendency to decrease in exposure of an eltrombopag in plasma was noted, however when comparing such patients and healthy volunteers essential variability of indicators of exposure was revealed.
After introduction in an eltrombopag in a single dose of 50 mg to patients with cirrhosis (abnormal liver function) of AUC(0-∞) the eltrombopaga increased by 41% (90% of DI: 13% decrease and 128% increase); to patients with moderate abnormal liver functions - for 93% (90% of DI: 19% decrease and 213% increase); to patients with severe defeats of function of a liver - for 80% (90% of DI: 11% decrease and 192% increase) in comparison with healthy volunteers. When comparing such patients and healthy faces essential variability of indicators of exposure was revealed.
Influence of an abnormal liver function on pharmacokinetics of an eltrombopag at repeated purpose of drug was estimated by means of the group analysis of pharmacokinetics at 28 healthy adult volunteers and 79 patients with chronic diseases of a liver. According to results of the group analysis of pharmacokinetics, at patients with cirrhosis (abnormal liver function) higher plasma rates of AUC(0-t) of an eltrombopag in comparison with indicators of healthy volunteers were noted, at the same time AUC(0-t) values increased with increase in score indicators on a scale of Chayld-Pyyu. In comparison with healthy volunteers at patients with easy abnormal liver functions plasma indicators of AUC(0-t) of an eltrombopag were about 87 - 110% higher, and at patients with moderate abnormal liver functions — approximately for 141–240%.
Patients with ITP and cirrhosis (abnormal liver function) should appoint элтромбопаг with care and in the presence of constant observation. At patients with chronic ITP and easy, moderate and heavy abnormal liver functions therapy eltrombopagy should be begun with a reduced dose — 25 mg once a day.
The similar analysis was carried out with participation of 28 healthy adult volunteers and 635 patients with VGS. At most of patients the indicator on a scale of Chayld-Pyyu made 5-6 points. According to the pharmacokinetic analysis, patients with VGS had higher rates of AUC(0-t) of an eltrombopag in comparison with indicators of healthy volunteers, at the same time AUC(0-t) values increased with increase in score indicators on a scale of Chayld-Pyyu. In comparison with healthy volunteers at patients with VGS plasma indicators of AUC(0-t) of an eltrombopag were about 100-144% higher. At patients with VGS therapy eltrombopagy it is necessary to begin with a dose 25 mg once a day.
At patients of east Asian race the pharmacokinetics of an eltrombopag was estimated by means of the analysis of population pharmacokinetics at 111 healthy adults (31 - natives of East Asia) and 88 patients with ITP (18 - natives of East Asia). On the basis of results of the pharmacokinetic analysis at patients with ITP of an east Asian origin (i.e. Japanese, Chinese, inhabitants of Taiwan and Koreans) indicators of AUC(0-t) of an eltrombopag were about 87% higher, than at patients not of an east Asian origin (preferential Caucasians); at the same time dose adjustment on body weight was not carried out.
Studying of influence of an ethnic origin to natives of East Asia on pharmacokinetics of an eltrombopag was carried out by means of the population analysis of pharmacokinetics with participation of 635 patients with VGS (145 patients of an East Asian origin and 69 patients of a South East Asian origin). On the basis of results of the population analysis of pharmacokinetics it is established that at patients of an east Asian and South East Asian origin the similar pharmacokinetics of an eltrombopag was observed. On average at patients of an east Asian and southern Asian origin of AUC(0-t) value of an eltrombopag in a blood plasma were about 55% higher in comparison with patients of other races (preferential Caucasian).
Influence of a floor on pharmacokinetics of an eltrombopag was estimated by means of the analysis of population pharmacokinetics at 111 healthy volunteers (from them 14 - a female) and 88 patients with ITP (from them 57 - a female). According to the population pharmacokinetic analysis, the plasma indicator of AUC(0-t) of an eltrombopag at patients with ITP was about 50% higher in comparison with patients of a male; at the same time correction of doses on body weight was not carried out.
Influence of a floor on pharmacokinetics of an eltrombopag was estimated by means of the population analysis of pharmacokinetics with participation of 635 patients with VGS (260 women). By results of assessment by means of model at women with a hepatitis virus From AUC(0-t) value of an eltrombopag in a blood plasma were 41% higher in comparison with men.
Age distinctions on pharmacokinetics of an eltrombopag estimated by means of the population analysis of pharmacokinetics with participation of 28 healthy volunteers and 635 patients with VGS aged from 19 up to 74 years. By results of assessment by means of model at elderly patients (> 60 years) AUC(0-t) values of an eltrombopag in a blood plasma were 36% higher in comparison with younger patients.
Indications to use:
— for the purpose of reduction of risk of bleeding at treatment of thrombocytopenia at patients with a chronic immune (idiopathic) Werlhof's disease (ITP) at insufficient efficiency of corticosteroids, immunoglobulins or a splenectomy;
— for the purpose of a possibility of carrying out or optimization of the performed antiviral therapy including interferon at treatment of thrombocytopenia at patients with the chronic viral hepatitis With (VH).
Route of administration and doses:
The mode of dosing is set individually on the basis of quantity of thrombocytes.
At most of patients increase in quantity of thrombocytes happens in 1–2 weeks of treatment.
Drug Revoleyd should be accepted in four hours prior to or in four hours after reception of the antacids, dairy products or mineral additives containing polyvalent cations (for example, aluminum, calcium, iron, magnesium, selenium and zinc).
Drug can be accepted with the food containing a small amount of calcium (50 mg) or that is preferable, not so calciferous.
Adults
Patients with chronic immune (idiopathic) thrombocytopenia
For achievement and maintenance of quantity of thrombocytes ≥ 50 000/mkl it is necessary to use minimum effective dose of drug Revoleyd. Selection of doses is based on change of quantity of thrombocytes. In clinical trials increase in quantity of thrombocytes was observed within 1–2 weeks after the beginning of therapy by drug Revoleyd and decrease happened within 1–2 weeks after the termination of administration of drug.
Initial mode of dosing
The recommended initial dose of drug Revoleyd makes 50 mg of 1 times /
For patients of an East Asian origin (for example, Chinese, Japanese, inhabitants of Taiwan, Koreans or Thais) administration of drug Revoleyd should be begun with a reduced dose - 25 mg of 1 times /
Monitoring and dose adjustment
After initial therapy by drug Revoleyd it is necessary to adjust a dose for maintenance of quantity of thrombocytes ≥50 000/mkl that is necessary for reduction of risk of bleeding. It is not necessary to exceed a dose of 75 mg /
During therapy by drug Revoleyd it is regularly necessary to control hematologic indicators and indicators of function of a liver. The dose of an eltrombopag should be adjusted according to Table 1 depending on quantity of thrombocytes. During therapy eltrombopagy it is weekly necessary to carry out an integrated analysis of blood until the stable maintenance of thrombocytes ≥ 50 000/mkl, at least, within 4 weeks is reached. After stabilization of maintenance of thrombocytes the integrated analysis of blood needs to be carried out monthly.
It is necessary to use the smallest dose of drug allowing to support the maintenance of thrombocytes at the level, necessary from the clinical point of view.
Table 1. Dose adjustment of an eltrombopag for patients with ITR
Contents Dose adjustment or answer
thrombocytes
<50 000/mkl during to Increase a daily dose by 25 mg
at least, to the maximum dose of 75 mg/days
2 weeks of therapy
≥ 200 000/mkl,
but ≤ 400 000/mkl to Reduce a daily dose to 25 mg. 2 weeks later
to estimate effect of a new dose and to make the decision
about further dose adjustment.
> 400 000/mkl to Stop reception of an eltrombopag; to increase frequency
researches of maintenance of thrombocytes to 2 times/weeks.
If soderazhny thrombocytes <150 000/mkl, then follows
to resume therapy in the smallest daily dose.
Standard dose adjustment towards decrease or increase has to make 25 mg / However at some patients the combination of various doses in different days can be required.
After any dose adjustment of drug Revoleyd the maintenance of thrombocytes should be controlled, at least, weekly within 2-3 weeks. At least, 2 weeks later it is necessary to estimate the maintenance of thrombocytes at patients for consideration of need of further dose adjustment.
At patients with cirrhosis (abnormal liver function) it is necessary to raise a dose not earlier than in 3 weeks.
Drug withdrawal
Treatment by drug Revoleyd should be stopped if the maintenance of thrombocytes does not increase to the value sufficient for reduction of risk of bleedings, after 4 weeks of therapy eltrombopagy in a dose of 75 mg /
Patients with the chronic VGS which is followed by thrombocytopenia
At administration of drug Revoleyd in combination with antiviral therapy it is necessary to consider the complete information about a combined medical use of these drugs.
For maintenance and achievement of necessary quantity of thrombocytes use minimum effective dose of drug necessary for a start and optimization of antiviral therapy. Selection of doses is based on recovery of quantity of thrombocytes.
Drug Revoleyd is not used for normalization of quantity of thrombocytes. In clinical trials increase in quantity of thrombocytes was observed within 1 week after the beginning of therapy by drug Revoleyd.
Initial mode of dosing
The initial dose of drug Revoleyd makes 25 mg of 1 times / dose adjustment for patients with VGS of an east Asian origin (for example, Chinese, Japanese, inhabitants of Taiwan, Koreans or Thais) or patients with an easy abnormal liver function is not required.
Monitoring and selection of a dose
The dose of an eltrombopag is increased by 25 mg by each 2 weeks before achievement of maintenance of thrombocytes in blood, optimum to start antiviral therapy and according to Table 2. It is necessary to control quantity of thrombocytes every week in the period of the beginning of antiviral therapy.
During antiviral therapy it is necessary to adjust a dose of an eltrombopag so that to avoid a peginterferon dose decline. The quantity of thrombocytes should be monitorirovat weekly before achievement of their stable level. Further it is necessary to carry out monitoring of the general blood test, including researches of quantity of thrombocytes and a smear of peripheral blood. It is not necessary to exceed a dose of 100 mg / Information on the recommended doses of a penginterferon the alpha and a ribavirina receive from the application instruction of these drugs.
Table 2. Dose adjustment of an eltrombopag for patients with VGS during antiviral therapy
Quantity Dose adjustment or answer
thrombocytes
50 000/mkl during, on
to last resort, 2 weeks of therapy to Increase a daily dose by 25 mg, but it is not higher than 100 mg /
from ≥200 000/mkl to ≤400 000/mkl to Reduce a daily dose to 25 mg. 2 weeks later
to estimate effect of a new dose and to make the decision
about further dose adjustment.
> 400 000/mkl to Stop reception of an eltrombopag; to increase frequency
researches of content of quantity of thrombocytes
to 2 times/weeks. If content of quantity of thrombocytes
<150 000/mkl to resume therapy in the smallest daily дозе*.
* For patients who accept элтромбопаг 25 mg of 1 times/, it is necessary to consider a question of reception of a dose of 12,5 mg of 1 times / or 25 mg every other day.
Drug withdrawal
At patients with VGS of a genotype 1/4/6, irrespective of the decision on continuation of therapy of an interferonama, it is necessary to consider cancellation of an eltrombopag if the effect of treatment is not reached by antiviral drugs in 12 weeks. It is necessary to stop treatment by drug Revoleyd if after 24 weeks therapy VGS RNA is found. After cancellation of antiviral therapy it is necessary to stop drug use Revoleyd.
It is necessary to stop drug use Revoleyd in case of excessive increase in quantity of thrombocytes as it is described in table 2, or clinically significant aberrations of functional trials of a liver.
Children
Safety and efficiency of use of an eltrombopag for children are not established.
Patients of advanced age
There are limited data on use of an eltrombopag for patients at the age of 65 years and are more senior. During clinical trials of an eltrombapag clinically significant distinctions of safety of drug at patients at the age of 65 years were not noted and is more senior, in comparison with younger patients. However hypersensitivity to drug at some patients of advanced age is not excluded.
Patients with an abnormal liver function
It is necessary to be careful at purpose of an eltrombopag to patients with ITP and an abnormal liver function (an index> 5 on a scale of Chayld-Pyyu). If use of an eltrombopag at patients from ITP having an abnormal liver function nevertheless is necessary, it is recommended to begin treatment eltrombopagy in a dose of 25 mg of 1 times /
It is necessary to increase a drug dose Revoleyd to patients with a liver failure not earlier than in 3 weeks after the beginning of therapy.
At patients with chronic VGS and disturbance of functions of a liver it is necessary to appoint drug Revoleyd in a dose of 25 mg of 1 times /
Natives of East Asia
At patients with ITP of an east Asian origin and their descendants (for example, Chinese, Japanese, inhabitants of Taiwan, Koreans and Thais) drug in a reduced initial dose of 25 mg of 1 times / is recommended to appoint
Patients with thrombocytopenia and chronic VGS of an east Asian origin should begin treatment eltrombopagy in a dose of 25 mg of 1 times /
It is necessary to continue to carry out monitoring of maintenance of thrombocytes at patients.
At patients with ITP or VGS of an east Asian origin with an abnormal liver function, it is necessary to begin treatment eltrombopagy with a dose of 25 mg of 1 times /
Features of use:
Efficiency and safety of use of an eltrombopag for treatment of other diseases and states which are followed by thrombocytopenia including thrombocytopenia after chemotherapy and miyelodisplastichesky syndromes, are not established now.
Abnormal liver functions
At use of an eltrombopag disturbances of laboratory indicators of function of a liver are possible. In clinical trials increase in activity of ALT, ACT and concentration of an indirect bilirubin is noted. These phenomena carried mostly easy (the 1-2nd degree) and reversible character without clinically significant symptoms which would testify to an abnormal liver function. According to 2 placebos - controlled researches the undesirable phenomena in the form of increase in activity of ALT were noted at 5.7% and 4% of the patients receiving treatment eltrombopagy and placebo respectively.
In 2 controlled clinical trials with participation of patients with thrombocytopenia and VGS cases of ≥3-fold increase in value of the upper bound of norm (UBN) of ALT or nuclear heating plant in 34% and 38% at reception in group of an eltrombopag were registered and in group of placebo, respectively. Purpose of an eltrombopag in a combination with peginterferonom/ribaviriny was indirectly connected with a hyperbilirubinemia. Cases of ≥1.5-fold increase in the general bilirubin above VGN value in 76% and 50% at reception in group of an eltrombopag were registered and in group of placebo, respectively.
Activity of ALT, ACT and concentration of bilirubin in serum need to be estimated prior to treatment eltrombopagy, then to control each 2 weeks during titration of a dose, and also monthly after purpose of a stable dose. The repeated research after identification of disturbances of functional tests of a liver is conducted within 3-5 days. If serumal concentration of the general bilirubin is increased, it is necessary to define concentration of its separate fractions. In case of confirmation of a deviation monitoring is continued until stabilization of indicators, or by returns of indicators to initial level.
Treatment eltrombopagy is stopped in case of increase in activity of ALT at ≥3-fold increase in VGN value at patients with normal function of a liver or ≥3-fold increase in rather initial level at patients with a superactivity of ALT prior to treatment and the following signs:
— progressing of a deviation, or
— preservation of a deviation of ≥4 weeks, or
— its combination to increase in concentration of direct bilirubin, or
— its combination to clinical symptoms of damage of a liver or signs of a decompensation of function of a liver.
At patients with ITP and diseases of a liver элтромбопаг it is necessary to appoint with care. It is necessary to use the minimum initial dose of an eltrombopag at appointment to patients with a liver failure.
Decompensation of function of a liver (use from interferona)
At patients with chronic VGS and cirrhosis at treatment of an interferonama the alpha can exist risk of a decompensation of function of a liver, in certain cases with a lethal outcome. In two controlled clinical trials with participation of patients with thrombocytopenia and VGS in which элтромбопаг used as required for achievement of the target quantity of thrombocytes necessary for performing antiviral therapy reported about the results on safety testimonial of a decompensation of function of a liver, a thicket in group of an eltrombopag (13%), than in group of placebo (7%). At patients with the low level of albumine (g/dl <3,5) or point ≥10 on MELD scale (model of a final stage of a disease of a liver) at the initial level was higher risk of a decompensation of function of a liver. Patients with such characteristics should be observed carefully on existence of signs and symptoms of a decompensation of a liver failure. For obtaining information on criteria of cancellation the application instruction of the corresponding drugs of interferon is used. Administration of drug Revoleyd should be stopped if antiviral therapy was cancelled in connection with a decompensation of a liver failure.
Trombotichesky and/or tromboembolic episodes
The maintenance of thrombocytes of norm gives theoretical risk of trombotichesky and/or tromboembolic episodes above. In clinical trials of an eltrombopag at patients with ITP tromboembolic episodes were observed at the low and normal maintenance of thrombocytes.
Patients with the known risk factors of trombotichesky and/or tromboembolic episodes (such as mutation of the V factor of Leiden, deficit of antithrombin III, anti-phospholipidic syndrome, etc.) need special control at purpose of an eltrombopag.
It is necessary to control carefully the maintenance of thrombocytes and to consider a question of a dose decline or cancellation of an eltrombopag if the maintenance of thrombocytes exceeds target values.
At researches ITP at 17 of 446 patients (3.8%) 21 trombotichesky and/or thromboembolic episodes were noted. Thromboembolisms included: an embolism, including a pulmonary embolism, a deep vein thrombosis, the tranzitorny ischemic attacks, a myocardial infarction, an ischemic stroke and the suspected prolonged reversible ischemic neurologic deficit.
In two controlled researches with participation of the patients with thrombocytopenia and VGS receiving therapy by interferon at 31 of 955 patients (3%) receiving элтромбопаг and at 5 of 484 patients (1%) receiving placebo trombotichesky and/or tromboembolic episodes were noted. Thrombosis of a portal vein was the most widespread of trombotichesky and/or tromboembolic episodes in both groups (at 1% of the patients receiving элтромбопаг and 1% of the patients receiving placebo). Temporary communication between an initiation of treatment and development of trombotichesky and/or tromboembolic episodes was not observed. The majority of cases of trombotichesky and/or tromboembolic episodes did not lead to the termination of antiviral therapy.
In a controlled research with participation of the patients with thrombocytopenia and chronic diseases of a liver (n=288) who transferred elective invasive interventions, the risk of thrombosis in system of a portal vein was increased at the patients receiving элтромбопаг in a dose of 75 mg of 1 times / within 14 days. 6 episodes of a thromboembolism (all - in system of a portal vein) in group of the patients receiving элтромбопаг, and 2 - in group of placebo were noted (the first - in system of a portal vein, the second - a myocardial infarction).
Drug Revoleyd should not be used for treatment of thrombocytopenia at patients with a chronic disease of a liver within preparation for invasive procedures.
Bleeding after the treatment termination eltrombopagy
After the treatment termination eltrombopagy at most of patients the maintenance of thrombocytes within 2 weeks is returned to a reference value that increases risk of development of bleeding, and in certain cases can cause bleeding. The maintenance of thrombocytes should be controlled weekly for 4 weeks after cancellation of an eltrombopag.
Formation of reticuline in marrow and risk of fibrosis of marrow
Agonists of a receptor of a trombopoetin, including элтромбопаг, can increase risk of education or growth of reticulin fibers in marrow. Before an initiation of treatment eltrombopagy it is necessary to estimate smears of peripheral blood for determination of initial level of morphological changes of cells. After achievement of a stable dose of an eltrombopag monthly make the general clinical blood test with calculation of a leukocytic formula. At identification of unripe or dysplastic cells it is necessary to conduct a research of a smear of peripheral blood regarding emergence new, or strengthenings of the existing morphological changes (for example, emergence of tear-shaped and nuclear erythrocytes, unripe leukocytes), or identifications of a cytopenia. At emergence in the patient new, or strengthening of the existing morphological deviations or a cytopenia it is necessary to stop treatment eltrombopagy and to consider a question of a marrow biopsy, including coloring of a smear for the purpose of detection of fibrosis.
Malignant new growths and progressing of malignant new growths
There is a theoretical opportunity that agonists of a receptor of a trombopoetin are capable to stimulate progressing of the existing hematologic new growths, for example, of a miyelodisplastichesky syndrome. During clinical trials distinctions in the frequency of malignant new growths or malignant new growths of blood between the patients receiving placebo and the patients receiving элтромбопаг were not shown.
Cataract
In toxicological researches of an eltrombopag at rodents the cataract came to light. Clinical value of these data is unknown. Planned control of patients regarding development of a cataract is recommended.
In controlled researches with participation of patients with thrombocytopenia and VGS which received treatment on the basis of interferon (n=1439), reported about progressing of the cataract existing initially or about emergence of a cataract in 8% in group of an eltrombopag and 5% in group of placebo.
Influence on ability to driving of motor transport and to control of mechanisms
Researches on influence of an eltrombopag on ability to control of motor transport or work with mechanisms were not conducted. On the basis of pharmacological properties of an eltrombopag negative influence on such types of activity is not expected. However at assessment of ability of the patient to perform operations which demand speed of thinking, movement and cognitive skills it is necessary to consider a clinical condition of the patient and a profile of undesirable effects of an eltrombopag.
Side effects:
Safety and efficiency of an eltrombopag was shown during 2 double blind randomized placebos - controlled researches at the adult patients from chronic ITP who were earlier receiving treatment.
The researches ENABLE 1 (TPL103922 N=716) and ENABLE 2 (TPL108390 N=805) were randomized, double blind people, placebo - controlled, multicenter researches for assessment of efficiency and safety of use of an eltrombopag for patients with thrombocytopenia and a viral hepatitis With to which antiviral therapy is shown.
In researches of patients with VGS selection for assessment of safety consisted of all randomized patients who received the studied drug according to a double blind method regarding 2 researches ENABLE 1 (group of treatment eltrombopagy N=449, N=232 placebo) and ENABLE 2 (group of treatment eltrombopagy n=506, n=252 placebo).
Patients analyzed in соответствиис the received therapy eltrombopagy (the general selection for safety assessment according to a double blind method, group of treatment eltrombopagy n=955 and n=484 placebo).
The majority of the undesirable reactions connected with eltrombopagy had easy or moderate expressiveness, the early beginning, and in rare instances served as the reason for treatment change.
Determination of frequency of side reactions: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1000), is very rare (<1/10 000, including separate cases).
The undesirable phenomena at patients from chronic ITP
Infections and invasions: often - pharyngitis, infections of urinary tract.
From the alimentary system: very often - nausea, diarrhea; often - dryness in a mouth, vomiting.
From a liver and biliary tract: often - increase in activity of nuclear heating plant, ALT.
Dermatological reactions: often - an alopecia, rash.
From a musculoskeletal system: often - a dorsodynia, pain in a thorax of musculoskeletal character, musculoskeletal pain, a mialgiya.
The undesirable phenomena at patients with chronic virus hepatitis C
From system of a hemopoiesis: very often - anemia.
From a metabolism: very often - a loss of appetite.
From TsNS: very often - sleeplessness, a headache.
From respiratory system: very often - cough.
From the alimentary system: very often - nausea, diarrhea.
From a liver and biliary tract: often - a hyperbilirubinemia.
Dermatological reactions: very often - an itch, an alopecia.
From a musculoskeletal system: very often - mialgiya.
Others: very often - fatigue, a hyperthermia, fever, an adynamy, peripheral hypostasis, a grippopodobny disease.
Interaction with other medicines:
Rozuvastatin: the researches in vitro showed what элтромбопаг is not substrate for transport polypeptide of organic OATP1B1 anions, but acts as inhibitor of this transporter. Results of the researches in vitro also allowed to establish what элтромбопаг is substrate and BCRP inhibitor. At combined use of an eltrompopag and rozuvastatin within clinical trial of medicinal interaction observed increase in concentration of a rozuvastatin in a blood plasma. At combined use with eltrombopagy it is necessary to consider a question of a dose decline of a rozuvastatin, also to carry out by a careful monitoring. In clinical trials of an eltrombopag at the accompanying therapy rozuvastatiny the dose decline of the last for 50% was recommended. Combined use of an eltrombopag and other substrates of polypeptide conveyors of organic anions (OATP1B1) and BCRP demands care.
Polyvalent cations (formation of chelate complexes): in order to avoid considerable decrease in absorption of an eltrombopag drug should be taken, at least, for 4 h to or after reception of the antacids, dairy products and other substances containing polyvalent cations (for example, the mineral additives containing aluminum, calcium, iron, magnesium, selenium and zinc).
Interaction with food: introduction of a single dose eltrombopaga 50 mg with the standard high-calorific breakfast containing a large amount of fat and dairy products lowers an area indicator under pharmacokinetic curve AUC(0-∞) by 59% (90% of DI: 54%, 64%) and Cmax for 65% (90% of DI: 59%, 70%). Food with the small content of calcium (<50 mg of calcium), including fruit, fast ham, beef, fruit juice, soy milk and grain without additives of calcium, iron and magnesium, has no significant effect on plasma exposure of an eltrombopag regardless of caloric content and the content of fat in food.
Combination lopinavir/ritonavir (LPV/RTV): simultaneous use of an eltrombopag and LPV/RTV can lead to decrease in concentration of an eltrombopag. In a research with participation of 40 healthy volunteers it was established that simultaneous single use of an eltrombopag in a dose of 100 mg and repeated use of LPV/RTV in a dose of 400 mg / 100 two times a day led mg to decrease in value of AUC(0-∞) an eltrombopaga in a blood plasma for 17% (90% of DI: 6.6%, 26.6%). Therefore, at simultaneous use of an eltrombopag and LPV/RTV it is necessary to show the increased care. It is necessary to control carefully quantity of thrombocytes for providing the corresponding dose of an eltrombopag at appointment or the termination of therapy of LPV/RTV.
Contraindications:
There are no known contraindications for use of drug according to indications in the recommended doses.
With care it is necessary to use drug at patients with a renal failure, a liver, with risk factors of a thromboembolism (for example, deficit of the V factor of Leiden, antithrombin III, an anti-phospholipidic syndrome), at pregnancy, in the period of a lactation.
Drug Revoleyd is not recommended to a primenyat of patients with a liver failure of ≥5 points on a scale of Chayld-Pyyu if the expected advantage does not exceed risk of thrombosis of a portal vein. If treatment is reasonable, it is necessary to show care at drug use Revoleyd at patients with a liver failure.
Use of drug REVOLEYD at pregnancy and feeding by a breast
Data on efficiency and safety of an eltrombopag at pregnancy are not available.
Use of drug at pregnancy is possible only in that case when the estimated advantage for mother surpasses potential risk for a fruit.
It is unknown whether it is allocated элтромбопаг with breast milk. During breastfeeding treatment eltrombopagy is not recommended, except for cases when the expected advantage of therapy for mother exceeds potential risk for the baby.
Use at abnormal liver functions
With care it is necessary to use drug at patients with an abnormal liver function.
Use at renal failures
With care it is necessary to use drug at patients with a renal failure.
Use for elderly patients
There are limited data on use of an eltrombopag for patients at the age of 65 years and are more senior. During clinical trials of an eltrombapag clinically significant distinctions of safety of drug at patients at the age of 65 years were not noted and is more senior, in comparison with younger patients. However hypersensitivity to drug at some patients of advanced age is not excluded.
Use for children
Safety and efficiency of use of an eltrombopag for children are not established.
Overdose:
During clinical trials one case of overdose when the patient accepted in 500 mg of an eltrombopag is registered.
Symptoms: not widespread rash, passing bradycardia, fatigue, in increase in activity of transaminases. These changes were reversible. Perhaps significant increase in maintenance of thrombocytes which can lead to trombotichesky and/or tromboembolic episodes.
Treatment: it is necessary to consider a question of intake of the drugs containing cations of metals, for example, of calcium, aluminum or magnesium for reduction of absorption of an eltrombolag. It is necessary to control the maintenance of thrombocytes carefully. Treatment eltrombopagy is resumed according to recommendations about the dosing mode.
As renal excretion is not the main way of removal of an eltrombopag which actively contacts proteins of a blood plasma, most likely, the hemodialysis is not an effective method of essential acceleration of removal of an eltrombopag from an organism.
Storage conditions:
Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 3 years.
Issue conditions:
According to the recipe
Packaging:
• tablets, film cover, 25 mg: 28
• tablets, film cover, 50 mg: 28
