Revolade
The effectiveness and safety of eltrombopag for the treatment of other diseases and conditions associated with thrombocytopenia, including post-chemotherapy thrombocytopenia and myelodysplastic syndromes, have not been established at this time.
Liver dysfunction
When using eltrombopag, disturbances in laboratory parameters of liver function are possible. In clinical studies, an increase in the activity of ALT, AST and the concentration of indirect bilirubin was noted. These phenomena were mostly mild (grade 1-2) and reversible, without clinically significant symptoms that would indicate liver dysfunction. According to 2 placebo-controlled studies, adverse events in the form of increased ALT activity were noted in 5.7% and 4% of patients treated with eltrombopag and placebo, respectively.
In 2 controlled clinical trials in patients with thrombocytopenia and HCV, ≥3-fold increases in the upper limit of normal (ULN) of ALT or AST were reported in 34% and 38% in the eltrombopag group and placebo group, respectively. The administration of eltrombopag in combination with peginterferon/ribavirin was indirectly associated with hyperbilirubinemia. Cases of ≥1.5-fold increases in total bilirubin above ULN of 76% and 50% were reported in the eltrombopag group and placebo group, respectively.
ALT, AST, and serum bilirubin concentrations should be assessed prior to initiation of eltrombopag treatment, then monitored every 2 weeks during dose titration, and monthly after a stable dose is established. A repeat study after detecting abnormalities in liver function tests is carried out within 3-5 days. If the serum concentration of total bilirubin is increased, the concentrations of its individual fractions should be determined. If a deviation is confirmed, monitoring continues until the indicators stabilize or the indicators return to the original level.
Treatment with eltrombopag is discontinued if ALT increases, with a ≥3-fold increase in ULN in patients with normal liver function or a ≥3-fold increase from baseline in patients with elevated pre-treatment ALT and the following:
— progression of the deviation, or
— deviation persists for ≥4 weeks, or
- its combination with an increase in the concentration of direct bilirubin, or
- its combination with clinical symptoms of liver damage or signs of decompensation of liver function.
Eltrombopag should be administered with caution in patients with ITP and liver disease. The minimum starting dose of eltrombopag should be used when administered to patients with hepatic impairment.
Decompensation of liver function (use with interferons)
In patients with chronic HCV and cirrhosis, there may be a risk of liver decompensation, in some cases fatal, when treated with alpha interferons. In two controlled clinical trials in patients with thrombocytopenia and HCV, in which eltrombopag was used as needed to achieve target platelet counts for antiviral therapy, safety outcomes indicative of liver decompensation were more frequently reported in the eltrombopag group (13 %) than in the placebo group (7%). Patients with low albumin levels (<3.5 g/dL) or MELD (Model for End-Stage Liver Disease) score ≥10 at baseline had a higher risk of liver decompensation. Patients with these characteristics should be closely monitored for signs and symptoms of decompensated liver failure. To obtain information about withdrawal criteria, use the instructions for use of the corresponding interferon preparations. Revolade should be discontinued if antiviral therapy is discontinued due to decompensated liver failure.
Thrombotic and/or thromboembolic complications
Platelet counts higher than normal pose a theoretical risk of thrombotic and/or thromboembolic complications. In clinical trials of eltrombopag in patients with ITP, thromboembolic complications were observed with low and normal platelet counts.
Patients with known risk factors for thrombotic and/or thromboembolic complications (such as factor V Leiden mutation, antithrombin III deficiency, antiphospholipid syndrome, etc.) require special monitoring when prescribing eltrombopag.
Platelet counts should be monitored closely and consideration should be given to dose reduction or discontinuation of eltrombopag if platelet counts exceed target values.
In ITP studies, 17 of 446 patients (3.8%) had 21 thrombotic and/or thromboembolic episodes. Thromboembolism included: embolism, incl. pulmonary embolism, deep vein thrombosis, transient ischemic attack, myocardial infarction, ischemic stroke and suspected prolonged reversible ischemic neurological deficit.
In two controlled studies of thrombocytopenic patients with HCV treated with interferon, 31 of 955 patients (3%) receiving eltrombopag and 5 of 484 patients (1%) receiving placebo experienced thrombotic and/or thromboembolic events. Portal vein thrombosis was the most common thrombotic and/or thromboembolic event in both groups (1% of patients receiving eltrombopag and 1% of patients receiving placebo). There was no temporal relationship between the start of treatment and the development of thrombotic and/or thromboembolic complications. Most cases of thrombotic and/or thromboembolic complications did not lead to cessation of antiviral therapy.
In a controlled study of thrombocytopenic patients with chronic liver disease (n=288) undergoing elective invasive procedures, the risk of portal thrombosis was increased in patients receiving eltrombopag 75 mg once daily for 14 days. There were 6 episodes of thromboembolism (all in the portal vein system) in the group of patients receiving eltrombopag, and 2 in the placebo group (the first in the portal vein system, the second myocardial infarction).
Revolade should not be used to treat thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
Bleeding after stopping treatment with eltrombopag
After stopping treatment with eltrombopag, most patients return to baseline platelet counts within 2 weeks, increasing the risk of bleeding and in some cases may cause bleeding. Platelet counts should be monitored weekly for 4 weeks after discontinuation of eltrombopag.
Reticulin formation in bone marrow and the risk of bone marrow fibrosis
Thrombopoietin receptor agonists, including eltrombopag, may increase the risk of formation or proliferation of reticulin fibers in the bone marrow. Before initiating treatment with eltrombopag, peripheral blood smears should be assessed to determine the baseline level of cellular morphological changes. After achieving a stable dose of eltrombopag, a complete clinical blood test with a leukocyte count is performed monthly. If immature or dysplastic cells are detected, a peripheral blood smear should be examined for the appearance of new or intensification of existing morphological changes (for example, the appearance of teardrop-shaped and nuclear red blood cells, immature leukocytes), or to detect cytopenia. If the patient develops new or worsening morphological abnormalities or cytopenias, treatment with eltrombopag should be discontinued and a bone marrow biopsy, including staining the smear to detect fibrosis, should be considered.
Malignant neoplasms and progression of malignant neoplasms
There is a theoretical possibility that thrombopoietin receptor agonists may stimulate the progression of existing hematologic malignancies, such as myelodysplastic syndrome. In clinical trials, there was no difference in the incidence of malignancies or hematologic malignancies between patients receiving placebo and patients receiving eltrombopag.
Cataract
In toxicological studies of eltrombopag in rodents, cataracts were detected. The clinical significance of these data is unknown. Routine monitoring of patients for the development of cataracts is recommended.
In controlled trials in patients with thrombocytopenia and HCV who received interferon-based treatment (n=1439), progression of pre-existing cataracts or the appearance of cataracts was reported in 8% in the eltrombopag group and 5% in the placebo group.
Impact on the ability to drive vehicles and operate machinery
Studies on the effect of eltrombopag on the ability to drive vehicles or operate machinery have not been conducted. Based on the pharmacological properties of eltrombopag, adverse effects on such activities are not expected. However, when assessing a patient's ability to perform activities that require quick thinking, motor and cognitive skills, the patient's clinical condition and the adverse effect profile of eltrombopag should be taken into account.
Release form, composition and packaging
Film-coated tablets
white, round, biconvex, with “GS NX3” and “25” engraved on one side.
1 tablet contains:
active substance:
eltrombopag olamine - 31.9 mg, which corresponds to the content of eltrombopag - 25 mg;
Excipients:
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:
opadry 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) - cardboard packs.
Film-coated tablets
brown, round, biconvex, with “GS UFU” and “50” engraved on one side.
1 tablet contains:
active substance:
eltrombopag olamine - 63.8 mg, which corresponds to the content of eltrombopag - 50 mg;
Excipients:
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;
composition of the film shell:
opadry brown 03B26716 - 14 mg (hypromellose - 8.75 mg, titanium dioxide - 3.09 mg, macrogol 400 - 0.875 mg, yellow iron oxide dye - 0.99 mg, red iron oxide dye - 0.3 mg).
7 pcs. - blisters (4) - cardboard packs.
Side effects
Adverse events in patients with chronic ITP
Infections and infestations: pharyngitis, urinary tract infections.
From the digestive system: nausea, diarrhea, dry mouth, vomiting.
From the liver and biliary tract: increased activity of AST, ALT.
Dermatological reactions: alopecia, rash.
From the musculoskeletal system: back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia.
Adverse events in patients with chronic viral hepatitis C
From the hematopoietic system: anemia.
Metabolism: decreased appetite.
From the side of the central nervous system: insomnia, headache.
From the respiratory system: cough.
From the digestive system: nausea, diarrhea.
From the liver and biliary tract: hyperbilirubinemia.
Dermatological reactions: itching, alopecia.
From the musculoskeletal system: myalgia.
Other: fatigue, hyperthermia, fever, asthenia, peripheral edema, influenza-like illness.
Dosage
The dosage regimen is set individually based on the platelet count.
In most patients, an increase in platelet counts occurs after 1–2 weeks of treatment.
Revolade should be taken four hours before or four hours after taking antacids, dairy products, or mineral supplements that contain polyvalent cations (such as aluminum, calcium, iron, magnesium, selenium, and zinc).
The drug can be taken with food containing a small amount of calcium (50 mg) or, preferably, no calcium at all.
Adults
Patients with chronic immune (idiopathic) thrombocytopenia
To achieve and maintain a platelet count ≥ 50,000/µL, the minimum effective dose of Revolade should be used. Dose selection is based on changes in platelet counts. In clinical studies, an increase in platelet count was observed within 1-2 weeks after initiation of therapy with Revolade and a decrease occurred within 1-2 weeks after discontinuation of the drug.
Initial dosage regimen
The recommended starting dose of Revolade is 50 mg 1 time / day.
For patients of East Asian origin (eg, Chinese, Japanese, Taiwanese, Korean, or Thai), Revolade should be started at a reduced dose of 25 mg once daily.
Monitoring and dose adjustment
After initial therapy with Revolade, dose adjustments should be made to maintain platelet counts ≥50,000/mcL to reduce the risk of bleeding. The dose should not exceed 75 mg/day.
During therapy with Revolade, hematological and liver function parameters should be regularly monitored. The dose of eltrombopag should be adjusted according to Table 1 depending on the platelet count. During eltrombopag therapy, a complete blood count should be performed weekly until a stable platelet count of ≥ 50,000/μL is achieved for at least 4 weeks. Once the platelet count has stabilized, a complete blood count should be performed monthly.
The lowest dose of the drug should be used to maintain the platelet count at the level required from a clinical point of view.
The standard dose adjustment down or up should be 25 mg/day. However, some patients may require a combination of different doses on different days.
After any dose adjustment of Revolade, platelet counts should be monitored at least weekly for 2-3 weeks. After at least 2 weeks, patients' platelet counts should be assessed to consider the need for further dose adjustment.
In patients with liver cirrhosis (impaired liver function)
The dose should be increased no earlier than after 3 weeks.
Withdrawal of the drug
Treatment with Revolade should be discontinued if platelet counts do not increase sufficiently to reduce the risk of bleeding after 4 weeks of treatment with eltrombopag 75 mg/day.
Patients with chronic HCV accompanied by thrombocytopenia
When taking Revolade in combination with antiviral therapy, it is necessary to take into account complete information about the joint medical use of these drugs.
To maintain and achieve the required platelet count, use the minimum effective dose of the drug necessary to initiate and optimize antiviral therapy. Dose selection is based on platelet count recovery.
Revolade is not used to normalize platelet counts. In clinical studies, an increase in platelet count was observed within 1 week after initiation of therapy with Revolade.
Initial dosage regimen
The initial dose of Revolade is 25 mg 1 time / day. No dosage adjustment is required for HCV patients of East Asian origin (eg, Chinese, Japanese, Taiwanese, 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 platelet count in the blood is optimal for initiating antiviral therapy. The platelet count must be monitored every week during the period of initiation of antiviral therapy.
During antiviral therapy, it is necessary to adjust the dose of eltrombopag in such a way as to avoid a reduction in the dose of peginterferon. Platelet counts should be monitored weekly until stable levels are achieved. Further monitoring of a complete blood count, including platelet count studies and peripheral blood smear, is necessary. The dose should not exceed 100 mg/day. Information on the recommended doses of penginterferon alfa and ribavirin is obtained from the instructions for use of these drugs.
Withdrawal of the drug
In patients with HCV genotype 1/4/6, regardless of the decision to continue interferon therapy, discontinuation of eltrombopag should be considered if the effect of antiviral treatment is not achieved after 12 weeks. Treatment with Revolade should be discontinued if HCV RNA is detected after 24 weeks of therapy. After discontinuation of antiviral therapy, use of Revolade should be discontinued.
Revolade should be discontinued if the platelet count is excessively elevated or if clinically significant abnormal liver function tests occur.
Children
The safety and effectiveness of eltrombopag in children have not been established.
Elderly patients
There are limited data on the use of eltrombopag in patients aged 65 years and older. During clinical trials of eltrombopag, there were no clinically significant differences in the safety of the drug in patients aged 65 years and older compared with younger patients. However, increased sensitivity to the drug in some elderly patients cannot be ruled out.
Patients with liver dysfunction
Caution should be exercised when prescribing eltrombopag to patients with ITP and impaired liver function (Child-Pugh index >5). If the use of eltrombopag in patients with ITP with impaired liver function is still necessary, it is recommended to begin treatment with eltrombopag at a dose of 25 mg 1 time / day.
The dose of Revolade should be increased in patients with liver failure no earlier than 3 weeks after the start of therapy.
In patients with chronic HCV and impaired liver function, Revolade should be prescribed at a dose of 25 mg 1 time / day.
East Asians
In patients with ITP of East Asian origin and their descendants (for example, Chinese, Japanese, Taiwanese, Koreans and Thais), it is recommended to prescribe the drug at a reduced initial dose of 25 mg 1 time / day.
Patients with thrombocytopenia and chronic HCV of East Asian origin should begin treatment with eltrombopag at a dose of 25 mg once a day.
Overdose
During clinical studies, one case of overdose was reported when a patient ingested 500 mg of eltrombopag.
Symptoms:
non-spread rash, transient bradycardia, fatigue, increased transaminase activity. These changes were reversible. There may be a significant increase in platelet count, which can lead to thrombotic and/or thromboembolic complications.
Treatment:
Oral medications containing metal cations, such as calcium, aluminum or magnesium, should be considered to reduce the absorption of eltrombolag. Platelet counts should be carefully monitored. Treatment with eltrombopag is restarted according to dosing recommendations.
Since renal excretion is not the primary route of elimination of eltrombopag, which is actively bound to plasma proteins, it is likely that hemodialysis is not an effective method to significantly accelerate the elimination of eltrombopag from the body.
Pregnancy and lactation
There are no data on the effectiveness and safety of eltrombopag during pregnancy.
The use of the drug during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether eltrombopag is excreted in breast milk. During breastfeeding, treatment with eltrombopag is not recommended, unless the expected benefit of therapy to the mother outweighs the potential risk to the infant.
Drug interactions
Rosuvastatin:
In vitro
studies have shown that eltrombopag is not a substrate for the organic anion transport polypeptide OATP1B1, but acts as an inhibitor of this transporter.
in vitro
studies also revealed that eltrombopag is a substrate and inhibitor of BCRP. When eltrompopag and rosuvastatin were co-administered in a clinical drug interaction study, an increase in rosuvastatin plasma concentrations was observed. When used concomitantly with eltrombopag, a dose reduction of rosuvastatin should be considered and close monitoring should be performed. In clinical trials of eltrombopag with concomitant therapy with rosuvastatin, a 50% dose reduction of the latter was recommended. Concomitant use of eltrombopag and other organic anion transporter polypeptide (OATP1B1) and BCRP substrates requires caution.
Polyvalent cations (formation of chelate complexes):
To avoid significant reduction in absorption of eltrombopag, the drug should be taken at least 4 hours before or after taking antacids, dairy products and other substances containing polyvalent cations (for example, mineral supplements containing aluminum, calcium, iron, magnesium, selenium and zinc ).
Interaction with food:
Administration of a single dose of eltrombopag 50 mg with a standard high-calorie, high-fat, high-dairy breakfast reduced AUC(0-∞) by 59% (90% CI: 54%, 64%) and Cmax by 65%. (90% CI: 59%, 70%). Low calcium foods (<50 mg calcium), including fruit, lean ham, beef, fruit juice, soy milk, and cereals without added calcium, iron, and magnesium, did not have a significant effect. influence on plasma exposure of eltrombopag, regardless of calorie and fat content of food
.
Lopinavir/ritonavir
(LPV/RTV) combination:
Concomitant use of eltrombopag and LPV/RTV may result in decreased eltrombopag concentrations. In a study of 40 healthy volunteers, co-administration of a single dose of 100 mg eltrombopag and repeated administration of LPV/RTV 400 mg/100 mg twice daily resulted in a decrease in plasma eltrombopag AUC(0-∞) by 17% (90% CI: 6.6%, 26.6%). Therefore, increased caution should be exercised when eltrombopag and LPV/RTV are used concomitantly. Platelet counts should be carefully monitored to ensure an appropriate dose of eltrombopag when initiating or discontinuing LPV/RTV therapy.
Contraindications
There are no known contraindications for the use of the drug as indicated in recommended doses.
Carefully _
The drug should be used in patients with impaired renal function, liver function, in the presence of risk factors for thromboembolism (for example, deficiency of factor V Leiden, antithrombin III, antiphospholipid syndrome), during pregnancy, and lactation.
Revolade is not recommended for use in patients with liver failure ≥5 on the Child-Pugh scale unless the expected benefit outweighs the risk of portal vein thrombosis. If treatment is appropriate, caution should be exercised when using Revolade in patients with hepatic impairment.
