Composition, form of production and packaging
The tablets covered with a film shell of white color, round, biconcave, on one side are engraved "GS NX3" and "25".
1 tab.
eltrombopag olamine 31.9 mg,
which corresponds to the content of eltrombopag 25 mg
[PRING] mannitol - 29.7 mg, microcrystalline cellulose - 14.9 mg, povidone K30 - 3.2 mg.
Extragranular components: microcrystalline cellulose - 238.8 mg, sodium carboxymethyl starch (type A) - 28 mg, magnesium stearate - 3.5 mg.
Composition of the film shell: opadray В® white YS-1-7706-G - 14 mg (hypromellose - 8.365 mg, titanium dioxide - 4.375 mg, macrogol 400 - 1.12 mg, polysorbate 80 - 0.14 mg).
7 pcs. - blisters (4) - packs of cardboard.
The tablets covered with a film membrane of brown color, round, biconcave, on one side are engraved "GS UFU" and "50".
1 tab.
elmrombopag olamine 63.8 mg,
which corresponds to the content of eltrombopag 50 mg
[PRING] mannitol - 59.5 mg, microcrystalline cellulose - 29.8 mg, povidone K30 - 6.4 mg.
Extragranular components: microcrystalline cellulose - 159.1 mg, sodium carboxymethyl starch (type A) - 28 mg, magnesium stearate - 3.5 mg.
The composition of the film shell: opadray В® brown 03B26716 - 14 mg (hypromellose - 8.75 mg, titanium dioxide - 3.09 mg, macrogol 400 - 0.875 mg, iron-oxide oxide yellow - 0.99 mg, iron-oxide red-0.3 mg).
7 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Stimulator of hemopoiesis. Thrombopoietin is the main cytokine that takes part in the regulation of megakaryopoiesis and the production of platelets. It is an endogenous ligand for the thrombopoietin receptor. Eltrombopag interacts with the transmembrane domain of the human thrombopoietin receptor and initiates a signal transfer cascade reminiscent of that for endogenous thrombopoietin, which is accompanied by induction of the proliferation and differentiation of megakaryocytes from bone marrow precursor cells.
Eltrombopag differs from thrombopoietin from the point of view of influence on platelet aggregation. Unlike thrombopoietin, the effect of eltrombopag on platelets in a healthy person does not increase aggregation by adenosine diphosphate (ADP) and does not stimulate the expression of P-selectin. Eltrombopag does not prevent the aggregation of platelets under the influence of ADP or collagen.
PHARMACOKINETICS
Parameters of pharmacokinetics of eltrombopag after its administration to patients with idiopathic thrombocytopenic purpura (ITP) are presented in the table below.
Mean geometric (confidence interval (CI) 95%) values ​​of plasma parameters of pharmacokinetics of eltrombopag in equilibrium in adult patients with ITP
Scheme of treatment with eltrombopag C max (Ојg / ml) AUC (0-t) (Ојg h / ml)
50 mg 1 time / day (n = 34) 8.01 (6.73; 9.53) 108 (88; 134)
75 mg 1 time / day (n = 26) 12.7 (11; 14.5) 168 (143, 198)
Data on the plasma concentration of eltrombopag in blood plasma versus time from 590 patients with viral hepatitis C (HCV) included in Phase III studies TPL103922 / ENABLE 1 and TPL108390 / ENABLE 2 were combined with data from patients with HCV included in Study II phase TPL102357, and healthy adult volunteers in the group for pharmacokinetics analysis. The results of measurements of C max and AUC (0-t) elthrombopag for HCV patients included in Phase III studies are presented in the table for each test dose. The highest exposure of eltrombopag was observed in patients with HCV with prescribed doses of eltrombopag (according to the table below).
Mean geometric (95% CI) values ​​of stationary parameters of eltrombopag in blood plasma in patients with chronic HCV
The dose of eltrombopag (1 time / day) N C max (Ојg / ml) AUC (0-t) (Ојg h / ml)
25 mg 330 6.40 (5.97, 6.86) 118 (109, 128)
50 mg 119 9.08 (7.96, 10.35) 166 (143, 192)
75 mg 45 16.71 (14.26, 19.58) 301 (250, 363)
100 mg 96 19.19 (16.81, 21.91) 354 (304, 411)
Data are presented as geometric mean (CI 95%). AUC (0-t) and C max are based on secondary data estimates for each patient from the high-dose pharmacokinetic group.
Suction
Eltrombopag is absorbed and reaches C max 2-6 hours after ingestion. The combined use of eltrombopag with antacids and other products containing polyvalent cations (for example, dairy products and mineral supplements) significantly reduces the exposure of the eltrombopag.
Absolute bioavailability of elthrombopag when taken orally has not been established. Based on the indices of renal excretion of the drug and the analysis of metabolites excreted through the intestine, it was shown that the calculated values ​​of absorption of the drug derivatives after administration of its single dose of 75 mg was at least 52%.
Distribution
Binding to human plasma proteins is high (> 99.9%). Eltrombopag is a substrate for BCRP (a protein of resistant breast cancer), but not for P-glycoprotein or OATP1B1.
Metabolism
The absorbed eltrombopag undergoes active metabolism. Metabolized mainly by cleavage, oxidation and conjugation, with glucuronic acid, glutathione or cysteine.According to the clinical study of the drug labeled with a radioactive isotope, it was shown that the fraction of eltrombopag accounts for about 64% of the radioactive isotope of carbon in the plasma. Minor metabolites, each accounting for less than 10% of the plasma radioactivity, are formed by glucuronidation and oxidation.
Based on the study of radio-labeled eltrombopag, it was found that approximately 20% of the drug dose is metabolized by oxidation.
In vitro studies have shown that CYP1A2 and CYP2C8 are isoenzymes responsible for oxidative metabolism, whereas uridine-diphospho-glucuronyltransferases UGT1A1 and UGT1A3 are isoenzymes responsible for glucuronization. In the process of cleavage, bacteria from the lower gastrointestinal tract can participate.
Excretion
The primary way of excretion of eltrombopagus is the excretion through the intestine (59%); with a 31% dose found in the urine in the form of metabolites. The starting substance in the urine is absent. In unchanged form with feces, about 20% of the injected drug is excreted. T 1/2 of the eltrombopag from the plasma is about 21-32 h.
Pharmacokinetics in special clinical cases
The pharmacokinetics of elthrombopag has been studied after administration of the drug to adult patients with impaired renal function. After the administration of eltrombopag in a single dose of 50 mg to patients with mild renal impairment AUC (0-?),
eltrombopag decreased by 32% (90% CI: 63% decrease and 26% increase); patients with moderate renal impairment - by 36% (90% CI: 66% decrease and 19% increase); patients with severe renal impairment - by 60% (90% CI: 18% decrease, 80% decrease) compared with healthy volunteers. In patients with impaired renal function, there was a tendency to decrease the exposure of eltrombopag in plasma, but when comparing such patients and healthy volunteers, a significant variability in the exposure indices was revealed.
After intravenous administration of eltrombopag in a single dose of 50 mg in patients with cirrhosis of the liver (a violation of liver function), AUC (0-?) Eltrombopag increased by 41% (90% CI: 13% decrease and 128% increase); patients with moderate impairment of liver function - by 93% (90% CI: 19% reduction and 213% increase); patients with severe liver damage - by 80% (90% CI: 11% decrease and 192% increase) compared with healthy volunteers. When comparing such patients and healthy individuals, a significant variability in the exposure indices was revealed.
The effect of liver function abnormalities on the pharmacokinetics of elthrombopag with the repeated administration of the drug was assessed by a group analysis of pharmacokinetics in 28 healthy adult volunteers and 79 patients with chronic liver disease. According to the results of the group analysis of pharmacokinetics, in patients with cirrhosis of the liver (a violation of the liver function), the plasma parameters of AUC (0-t) eltrombopag were higher than those of healthy volunteers, while the AUC (0-t) values ​​increased with an increase in scores for the Child-Pugh scale. Compared with healthy volunteers in patients with mild violations of liver function, the plasma parameters of AUC (0-t) eltrombopag were higher by approximately 87-110%, and in patients with moderate impairment of liver function, approximately 141-240%.
Patients with ITP and liver cirrhosis (a violation of liver function) should be prescribed eltrombopag with caution and in the presence of continuous monitoring . In patients with chronic ITP and mild, moderate and severe impairment of liver function, therapy with eltrombopag should be started with a reduced dose of 25 mg once daily.
A similar analysis was conducted with the participation of 28 healthy adult volunteers and 635 patients with HCV. In most patients, the Child-Pugh score was 5-6.According to the pharmacokinetic analysis, patients with HCV had higher AUC (0-t) eltrombopag values ​​than healthy volunteers, with AUC (0-t) increasing with the Child-Pugh score. Compared with healthy volunteers, plasma parameters of AUC (0-t) eltrombopagus were higher by approximately 100-144% in patients with HCV.In patients with HCV, treatment with eltrombopag should be started at a dose of 25 mg once daily.
In patients of the East Asian race, the pharmacokinetics of elthrombopag were evaluated by the analysis of population pharmacokinetics in 111 healthy adults (31 from East Asia) and 88 from ITP (18 from East Asia). Based on the results of the pharmacokinetic analysis, the AUC (0-t) elthrombopag values ​​in patients with ITP of East Asian origin (ie Japanese, Chinese, Taiwanese and Koreans) were approximately 87% higher than those of patients not of East Asian origin (mainly Caucasoids);with the correction of the dose by body weight was not carried out.
A study of the influence of ethnicity on East African pharmacokinetics on the pharmacokinetics of elthrombopag was carried out using a population-based pharmacokinetics analysis involving 635 patients with HCV (145 East Asian and 69 Southeast Asian patients). Based on the results of a population analysis of pharmacokinetics, it was found that the pharmacokinetics of elthrombopag were similar in patients of East Asian and South-East Asian descent. On average, the AUC(0-t) eltrombopag in blood plasma in the patients of East Asian and South Asian origin was approximately 55% higher in comparison with patients of other races (predominantly Caucasoid).
The effect of sex on the pharmacokinetics of elthrombopag was assessed using a population pharmacokinetics assay in 111 healthy volunteers (14 of them are female) and 88 patients with ITP (57 of them are female). According to population pharmacokinetic analysis, the plasma index of AUC (0-t) elthrombopag in patients with ITP was approximately 50% higher than in male patients; with the correction of doses by body weight was not carried out.
The effect of sex on the pharmacokinetics of elthrombopag was evaluated using a population-based pharmacokinetics analysis involving 635 patients with HCV (260 women). Based on the results of the model evaluation, in women with hepatitis C virus, the AUC (0-t) eltrombopag values ​​in plasma were 41% higher than in men.
Age differences in the pharmacokinetics of elthrombopag were evaluated using a population-based pharmacokinetics analysis involving 28 healthy volunteers and 635 patients with HCV aged 19 to 74 years. Based on the model evaluation in elderly patients (> 60 years of age), the AUC (0-t) eltrombopag values ​​in plasma were 36% higher than in younger patients.
INDICATIONS
- in order to reduce the risk of bleeding in the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) with insufficient effectiveness of corticosteroids, immunoglobulins or splenectomy;
- in order to ensure the possibility of carrying out or optimizing the antiviral therapy, including interferon, in the treatment of thrombocytopenia in patients with chronic viral hepatitis C (HCV).
DOSING MODE
The dosage regimen is set individually based on the number of platelets.
In most patients, an increase in the number of platelets occurs after 1-2 weeks of treatment.
The drug Revolide should be taken four hours before or four hours after taking antacids, dairy products or mineral supplements containing polyvalent cations (for example, aluminum, calcium, iron, magnesium, selenium and zinc).
The drug can be taken with food containing a small amount of calcium (50 mg) or, preferably, not containing calcium.
Adults
Patients with chronic immune (idiopathic) thrombocytopenia
To achieve and maintain a number of platelets? 50 000 / ОјL it is necessary to use the minimally effective dose of the drug Revolide. The choice of doses is based on the change in the number of platelets. In clinical studies, an increase in the number of platelets was observed within 1-2 weeks after the initiation of therapy with the drug Revolide and the decline occurred within 1-2 weeks after discontinuation of the drug.
Initial dosing regimen
The recommended initial dose of the drug Revolide is 50 mg 1 time / day.
For patients of East Asian origin (for example, Chinese, Japanese, Taiwan, Koreans or Thais), the drug Revolide should be taken with a reduced dose of 25 mg 1 time / day.
Monitoring and correction of dose
After initial therapy with the drug Revolide, you need to adjust the dose to maintain a platelet count of? 50,000 / Ојl, which is necessary to reduce the risk of bleeding.Do not exceed the dose of 75 mg / day.
During therapy with the drug, Revolide should regularly monitor hematological indicators and liver function. The dose of eltrombopag should be adjusted in accordance with Table 1, depending on the number of platelets. During therapy with eltrombopag, a full blood test should be performed weekly until a stable platelet count is reached? 50 000 / ОјL for at least 4 weeks. After stabilizing the content of platelets, a complete blood test should be done monthly.
Use the lowest dose of the drug, which allows to maintain the content of platelets at a clinically necessary level.
Table 1. Correction of the dose of eltrombopag for patients with MRI
The content of platelets Correction of dose or response
<50 000 / ОјL for at least 2 weeks of therapy. Increase the daily dose by 25 mg to a maximum dose of 75 mg / day.
? 200 000 / mkl, but? 400 000 / ОјL Reduce the daily dose to 25 mg. After 2 weeks, evaluate the effect of a new dose and decide on a further dose adjustment.
> 400 000 / Ојl Stop the reception of the elethrombopag; Increase the frequency of study of platelet count to 2 times / week. If the platelet count is <150,000 / ОјL, then the therapy should be resumed at the lowest daily dose.
The standard dose adjustment to the side of reduction or increase should be 25 mg / day. However, some patients may require a combination of different doses on different days.
After any correction of the dose of the drug, Revolide, the platelet content should be monitored at least weekly for 2-3 weeks. After at least 2 weeks, the platelet count should be evaluated in patients to consider the need for further dose adjustment.
In patients with cirrhosis of the liver (a violation of the function of the liver), the dose should be raised no earlier than 3 weeks later.
Abolition of the drug
Treatment with Revolide should be discontinued if the platelet count does not increase to a value sufficient to reduce the risk of bleeding after 4 weeks of treatment with eltrombopag at a dose of 75 mg / day.
Patients with chronic HCV accompanied by thrombocytopenia
When taking the drug Revolide in combination with antiviral therapy must take into account the full information on the joint medical use of these drugs.
To maintain and achieve the required number of platelets use the minimum effective dose of the drug necessary to start and optimize antiviral therapy. The choice of doses is based on the restoration of the number of platelets.
The drug Revolide is not used to normalize the number of platelets. In clinical studies, an increase in the number of platelets was observed within 1 week after the initiation of therapy with the drug Revolide.
Initial dosing regimen
The initial dose of the drug Revolide is 25 mg 1 time / day. No dose adjustment is required for patients with HCV of East Asian origin (eg, Chinese, Japanese, Taiwan, Koreans or Thais) or patients with mild hepatic impairment.
Monitoring and dose selection
The dose of eltrombopag is increased by 25 mg every 2 weeks until the blood platelet count is reached, which is optimal for the initiation of antiviral therapy and in accordance with Table 2. Monitor platelet counts every week during the onset of antiviral therapy.
During antiviral therapy, the dose of eltrombopag should be adjusted in such a way as to avoid a reduction in the dose of peginterferon. Platelet counts should be monitored weekly until they achieve a stable level. Further it is necessary to monitor blood count, platelet count including research and peripheral blood smear. Dose should not exceed 100 mg / day. Information on recommended doses penginterferona alpha and ribavirin are obtained from the instructions for use of these drugs.
Table 2. Correction eltrombopaga dose for patients with HCV during antiviral therapy
Platelet dose adjustment or response
<50,000 / ul for at least 2 weeks of therapy Increase daily dose of 25 mg, but not higher than 100 mg / day.
from? 200 000 / ml up to? 400 000 / ml Decrease daily dose of 25 mg. After 2 weeks to evaluate the effect of a new dose and decide on further dose adjustment.
> 400,000 / ul stop reception eltrombopaga; increase the frequency content of the platelet number studies to 2 times / week. If the content of the platelet count <150,000 / microliter, resume therapy lowest daily dose *.
* For patients who are taking eltrombopag 25 mg 1 time / day, you should consider taking a dose of 12.5 mg 1 time / day or 25 mg a day.
removal of the drug
Patients with HCV genotype 1/4/6, regardless of the decision on the continuation of interferon therapy should consider the abolition eltrombopaga if the effect of antiviral treatment is not achieved within 12 weeks. Discontinue treatment with Revoleyd, if after 24 weeks of treatment will be detected HCV RNA. After the abolition of the antiviral therapy should be discontinued Revoleyd drug.
It should stop using the product Revoleyd in case of an excessive increase of the number of platelets, as described in Table 2, or clinically significant deviations from normal liver function tests.
Children
Safety and effectiveness of eltrombopaga in children have not been established.
Elderly patients
There are limited data on the use eltrombopaga in patients aged 65 years and older. In clinical studies eltrombapaga there were no clinically relevant differences in the safety of the drug in patients aged 65 years or older, compared with younger patients. However, not excluded hypersensitivity to the drug in some elderly patients.
Patients with impaired hepatic function
should be careful in appointing eltrombopaga patients with ITP, and impaired liver function (index> 5 on the scale of Child-Pugh). If the use eltrombopaga ITP patients having impaired liver function is necessary, it is recommended to begin treatment eltrombopagom 25 mg 1 time / day.
Increase dose Revoleyd patients with hepatic failure should not earlier than 3 weeks after initiation of therapy.
In patients with chronic HCV, and impaired liver function should be administered the drug Revoleyd 25 mg 1 time / day.
Immigrants from East Asia
in patients with ITP East Asian origin and their descendants (eg, Chinese, Japanese, Taiwanese people, Koreans and Thais) appoint a drug in a reduced initial dose of 25 mg 1 time / day.
Thrombocytopenia in patients with chronic HCV and East Asian descent should begin treatment eltrombopagom at a dose of 25 mg 1 time / day.
It is necessary to continue to monitor platelet count in patients.
In patients with ITP or HCV East Asian origin with hepatic impairment, treatment should be started eltrombopagom a dose of 25 mg 1 time / day.
SIDE EFFECT
Safety and efficacy eltrombopaga was shown in 2 randomized, double-blind, placebo-controlled studies in adults with chronic ITP patients previously treated.
Studies ENABLE 1 (TPL103922 N = 716) and ENABLE 2 (TPL108390 N = 805) were randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of eltrombopaga patients with thrombocytopenia and hepatitis C, which shows antiviral therapy .
In studies of patients with HCV sample for safety evaluation consisted of all randomized patients who received trial medication according to the double blind method in Part 2 studies ENABLE 1 (treatment group eltrombopagom N = 449 Placebo N = 232) and ENABLE 2 (treatment group eltrombopagom n = 506, placebo n = 252).
Patients were analyzed in accordance with EU received therapy eltrombopagom (total sample security assessment under double-blind treatment group eltrombopagom n = 955, placebo n = 484).
Most adverse reactions associated with eltrombopagom, had mild to moderate severity, early onset, and, in rare cases a reason to change treatment.
Determining the frequency of adverse reactions: very common (1/10?), Common (1/100 and <1/10?), Rare (1/1000 and <1/100?), Rarely (1/10 000 and <1? / 1000), very rare (<1/10 000, including isolated cases).
Adverse events in patients with chronic ITP
Infections and infestations: often - pharyngitis, urinary tract infection.
From the digestive system: very often - nausea, diarrhea; often - dry mouth, vomiting.
Of the liver and biliary tract: often - increased activity of AST, ALT.
Dermatological reactions: often - alopecia, rash.
On the part of the musculoskeletal system: often - back pain, chest pain, musculoskeletal nature, musculoskeletal pain, myalgia.
Adverse events in patients with chronic viral hepatitis C
From hemopoiesis system: very often - anemia.
From a metabolism: often - loss of appetite.
On the part of the central nervous system: very often - insomnia, headache.
The respiratory system: very often - cough.
From the digestive system: very often - nausea, diarrhea.
Of the liver and biliary tract: often - hyperbilirubinemia.
Dermatological reactions: very often - itching, alopecia.
On the part of the musculoskeletal system: very often - myalgia.
Other:very often - fatigue, pyrexia, fever, asthenia, peripheral edema, influenza-like illness .
CONTRAINDICATIONS
No known contraindications for use of the preparation according to indications in the recommended doses.
With caution should be used on patients with impaired kidney function, liver, the presence of risk factors for thromboembolic events (e.g., a deficiency of factor V Leiden, antithrombin III, antiphospholipid syndrome) during pregnancy, during lactation.
The drug is not recommended Revoleyd primenyatu patients with hepatic insufficiency? 5 points on a scale Child-Pugh, if the expected benefit does not exceed the risk of thrombosis of the portal vein. If treatment is appropriate, caution should be exercised when using the drug in Revoleyd with liver failure patients.
PREGNANCY AND LACTATION
Data on efficacy and safety eltrombopaga during pregnancy are not available.
Use of the drug during pregnancy is possible only when the intended benefits to the mother outweighs the potential risk to the fetus.
It is not known whether eltrombopag excreted in breast milk. During the period of breastfeeding eltrombopagom treatment is not recommended, except in cases where the expected benefit of therapy to the mother outweighs the potential risk to the infant.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should be used on patients with impaired renal function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should be used on patients with impaired liver function.
APPLICATION FOR CHILDREN
Safety and effectiveness of eltrombopaga in children have not been established.
APPLICATION IN ELDERLY PATIENTS
There are limited data on the use eltrombopaga in patients aged 65 years and older. In clinical studies eltrombapaga there were no clinically relevant differences in the safety of the drug in patients aged 65 years or older, compared with younger patients. However, not excluded hypersensitivity to the drug in some elderly patients.
SPECIAL INSTRUCTIONS
Efficacy and safety of eltrombopaga for treating other diseases and conditions accompanied by thrombocytopenia, including thrombocytopenia after chemotherapy and myelodysplastic syndromes are not currently installed.
Liver function abnormalities
In applying eltrombopaga possible violations of liver function laboratory parameters. In clinical studies was an increase in ALT, ACT, and the concentration of indirect bilirubin. These effects were mostly easy (grade 1-2) and reversible without clinically significant symptoms that would indicate impaired liver function. According 2 placebo-controlled studies of undesired phenomena in the form of increased ALT activity was observed in 5.7% and 4% of treated patients and placebo eltrombopagom respectively.
In 2 controlled clinical trials involving patients with thrombocytopenia and HCV have been reported cases of? 3-fold increase in value of the upper limit of normal (ULN) ALT or AST in 34% and 38% when taking into eltrombopaga group and the placebo group, respectively. Appointment eltrombopaga in combination with peginterferon / ribavirin was indirectly related to hyperbilirubinemia. cases of? 1.5-fold increase in total bilirubin above ULN values ​​of 76% and 50% for admission to eltrombopaga group and in the placebo group, respectively, were recorded.
ALT activity, ACT, and the concentration of bilirubin in the serum must be evaluated before starting treatment eltrombopagom then monitored every 2 weeks during titration, and month after administration of a stable dose. Re-study after detecting violations of liver function test was carried out for 3-5 days. If serum total bilirubin concentration is increased, it is necessary to determine the concentration of the individual fractions. In case of confirmation deviation monitoring continues until stabilization indicators or indicators returns to baseline.
Eltrombopagom Treatment stopped in case of increase of ALT activity at 3-fold higher values CAH patients with normal liver function or 3-fold increase from baseline in patients with elevated ALT before treatment and the following features:?
- progression deviation or
- ? saving deviation 4 weeks, or
- its combination with an increase in the concentration of direct bilirubin, or
- its combination with clinical symptoms of liver injury or signs of hepatic decompensation.
In patients with ITP, and liver disease eltrombopag should be used with caution. It is necessary to use the minimum eltrombopaga initial dose when administered to patients with liver failure.
Decompensation of liver function (application with interferons)
In patients with chronic HCV and cirrhosis of the liver in the treatment of interferon alpha may be a risk of hepatic decompensation, in some cases fatal. In two controlled clinical trials involving patients with thrombocytopenia and HCV, which eltrombopag used as necessary to achieve the desired amount of platelets needed for antiviral therapy on safety results testifying decompensation of liver function, often reported in eltrombopaga group (13 %) than in the placebo group (7%). In patients with low levels of albumin (<3.5 g / dl) or a score ≥ 10 on a scale MELD (model end-stage liver disease) at baseline was a higher risk of hepatic decompensation.Patients with these characteristics should be carefully monitored for signs and symptoms of decompensated liver disease. For information on the criteria used cancel instruction on the respective interferon preparations. Admission Revoleyd drug should be discontinued if antiviral therapy was canceled due to decompensation of liver failure.
Thrombotic and / or embolic complications
platelet count above normal is a theoretical risk of thrombotic and / or thromboembolic complications. In clinical studies eltrombopaga in patients with ITP thromboembolic events were observed at low and normal platelet counts.
Patients with known risk factors for a thrombotic and / or thromboembolic complications (such as the factor V Leiden mutation, antithrombin III deficiency, antiphospholipid syndrome, etc.) Require special control when assigning eltrombopaga.
It is necessary to carefully monitor the platelet count and consider dose reduction or cancellation eltrombopaga if the platelet count exceeds the target value.
In studies of ITP in 17 of 446 patients (3.8%) was recorded 21 thrombotic and / or thromboembolic episode. Thromboembolism included: embolism, including pulmonary embolism, deep vein thrombosis, transient ischemic attack, myocardial infarction, ischemic stroke and suspected prolonged reversible ischemic neurological deficit.
In two controlled studies in patients with thrombocytopenia and HCV receiving interferon therapy, in 31 of 955 patients (3%) treated eltrombopag, and 5 out of 484 patients (1%) in the placebo group were observed thrombotic and / or embolic complications. Portal vein thrombosis was the most common of thrombotic and / or thromboembolic complications in both groups (1% of patients treated with eltrombopag and 1% of patients receiving placebo). The temporal association between the onset of the treatment and the development of thrombotic and / or thromboembolic complications. Most cases of thrombotic and / or thromboembolic complications have led to discontinuation of antiviral therapy.
In a controlled study of patients with chronic diseases, and thrombocytopenia (n = 288) liver undergoing elective invasive intervention, the risk of thrombosis of the portal vein system was elevated in patients receiving eltrombopag 75 mg 1 time / day for 14 days. It was observed 6 thromboembolic episodes (all - in the portal vein) in patients receiving eltrombopag and 2 - in the placebo group (the first - in the portal vein, a second - a myocardial infarction).
Revoleyd The drug should not be used for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
Bleeding after cessation of treatment eltrombopagom
After stopping treatment eltrombopagom most patients platelet within 2 weeks back to the original value, which increases the risk of bleeding, and in some cases can cause bleeding. Platelet count should be monitored on a weekly basis for 4 weeks after discontinuation of eltrombopaga.
Reticulin formation in the bone marrow and the risk of bone marrow fibrosis
receptor agonists thrombopoietin, including e-mail,
