Revolade^® (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Siegfried Barbera, S.L. (Spain)

Labeled By

SIEGFRIED BARBERA, S.L. (Spain)

Packaging and Quality Control Release

SCOPINSKY PHARMACEUTICAL PLANT, CJSC (Russia)

Quality Control Release

NOVARTIS PHARMA, AG (Switzerland)

ATC Code

B02BX05 (Eltrombopag)

Active Substance

Eltrombopag (Rec.INN registered by WHO)

Dosage Forms

	Revolade®	Film-coated tablets, 25 mg: 28 pcs.
		Film-coated tablets, 50 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, engraved with “GS NX3” and “25” on one side.

Excipients : mannitol, microcrystalline cellulose PH101, povidone K30.

Extragranular components microcrystalline cellulose PH102, sodium carboxymethyl starch (type A), magnesium stearate.
Film coating composition opadry^® white YS-1-7706-G (hypromellose, titanium dioxide E171, macrogol-400, polysorbate 80).

7 pcs. – blisters (4) – cardboard packs.

Film-coated tablets brown, round, biconvex, engraved with “GS UFU” and “50” on one side.

Excipients : mannitol, microcrystalline cellulose PH101, povidone K30.

Extragranular components microcrystalline cellulose PH102, sodium carboxymethyl starch (type A), magnesium stearate.
Film coating composition opadry^® brown 03B26716 (hypromellose, titanium dioxide E171, macrogol-400, iron oxide yellow E172, iron oxide red E172).

7 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Thrombopoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant

Pharmacological Action

Hematopoiesis stimulant. Thrombopoietin is the primary cytokine involved in the regulation of megakaryopoiesis and platelet production. It is an endogenous ligand for the thrombopoietin receptor. Eltrombopag interacts with the transmembrane domain of the human thrombopoietin receptor and initiates a signaling cascade similar to that of endogenous thrombopoietin, leading to the induction of proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.

Eltrombopag differs from thrombopoietin in its effect on platelet aggregation. Unlike thrombopoietin, exposure of eltrombopag to platelets from healthy individuals does not enhance aggregation induced by adenosine diphosphate (ADP) and does not stimulate P-selectin expression. Eltrombopag does not inhibit platelet aggregation induced by ADP or collagen.

Pharmacokinetics

The pharmacokinetic parameters of eltrombopag after its administration to patients with idiopathic thrombocytopenic purpura (ITP) are presented in the table below.

Geometric mean (95% confidence interval (CI)) steady-state plasma pharmacokinetic parameters of eltrombopag in adult patients with ITP

Plasma concentration-time data from 590 patients with viral hepatitis C (HCV) enrolled in Phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were pooled with data from HCV patients enrolled in Phase II study TPL102357 and healthy adult volunteers for pharmacokinetic analysis. The C_max and AUC_(0-t) measurements of eltrombopag for HCV patients enrolled in Phase III studies are presented in the table for each study dose. The highest eltrombopag exposure was observed in HCV patients at the administered eltrombopag doses (according to the table below).

Geometric mean (95% CI) steady-state plasma parameters of eltrombopag in patients with chronic HCV

Data are presented as geometric mean (95% CI). AUC _(0-t) and C_max are based on secondary estimates of individual patient data from the high-dose pharmacokinetic group.

Absorption

Eltrombopag is absorbed and reaches C_max 2-6 hours after oral administration. Concomitant administration of eltrombopag with antacids and other products containing polyvalent cations (e.g., dairy products and mineral supplements) significantly reduces eltrombopag exposure.

The absolute bioavailability of oral eltrombopag has not been established. Based on renal excretion of the drug and analysis of metabolites eliminated via the intestine, it was shown that the estimated absorption of drug derivatives after administration of a single 75 mg dose was at least 52%.

Distribution

Binding to human plasma proteins is high (>99.9%). Eltrombopag is a substrate for BCRP (breast cancer resistance protein) but not for P-glycoprotein or OATP1B1.

Metabolism

Absorbed Eltrombopag undergoes extensive metabolism. It is metabolized primarily by cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. According to a clinical study with a radiolabeled drug, eltrombopag accounted for approximately 64% of the carbon radiolabel in plasma. Minor metabolites, each accounting for less than 10% of plasma radioactivity, are formed by glucuronidation and oxidation.

Based on a study with radiolabeled eltrombopag, it was determined that approximately 20% of the drug dose is metabolized by oxidation.

In vitro studies have shown that CYP1A2 and CYP2C8 are the isoenzymes responsible for oxidative metabolism, while uridine diphosphate glucuronosyltransferases UGT1A1 and UGT1A3 are the isoenzymes responsible for glucuronidation. Bacteria in the lower gastrointestinal tract may be involved in the cleavage process.

Excretion

The predominant route of eltrombopag elimination is via fecal excretion (59%); with 31% of the dose found in urine as metabolites. The parent compound is not present in urine. Approximately 20% of the administered drug is excreted unchanged in feces. The T_1/2 of eltrombopag from plasma is approximately 21-32 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetics of eltrombopag were studied after administration to adult patients with renal impairment. After administration of a single 50 mg dose of eltrombopag to patients with mild renal impairment, the AUC_(0-∞)
Of eltrombopag decreased by 32% (90% CI: 63% decrease and 26% increase); in patients with moderate renal impairment – by 36% (90% CI: 66% decrease and 19% increase); in patients with severe renal impairment – by 60% (90% CI: 18% decrease, 80% decrease) compared to healthy volunteers. Patients with renal impairment showed a trend towards reduced plasma eltrombopag exposure, but significant variability in exposure parameters was identified when comparing such patients with healthy volunteers.

After oral administration of a single 50 mg dose of eltrombopag to patients with liver cirrhosis (hepatic impairment), the AUC_(0-∞) of eltrombopag increased by 41% (90% CI: 13% decrease and 128% increase); in patients with moderate hepatic impairment – by 93% (90% CI: 19% decrease and 213% increase); in patients with severe hepatic impairment – by 80% (90% CI: 11% decrease and 192% increase) compared to healthy volunteers. Significant variability in exposure parameters was identified when comparing such patients with healthy individuals.

The effect of hepatic impairment on the pharmacokinetics of eltrombopag upon repeated administration was assessed by population pharmacokinetic analysis in 28 healthy adult volunteers and 79 patients with chronic liver disease. According to the population pharmacokinetic analysis results, patients with liver cirrhosis (hepatic impairment) had higher plasma AUC_(0-t) values of eltrombopag compared to healthy volunteers, with AUC_(0-t) values increasing with higher Child-Pugh scores. Compared to healthy volunteers, patients with mild hepatic impairment had plasma AUC_(0-t) values of eltrombopag approximately 87-110% higher, and patients with moderate hepatic impairment had values approximately 141-240% higher.

Patients with ITP and liver cirrhosis (hepatic impairment) should be prescribed Eltrombopag with caution and under constant monitoring. In patients with chronic ITP and mild, moderate, and severe hepatic impairment, eltrombopag therapy should be initiated at a reduced dose of 25 mg once daily.

A similar analysis was conducted with 28 healthy adult volunteers and 635 patients with HCV. Most patients had a Child-Pugh score of 5-6 points. According to pharmacokinetic analysis, patients with HCV had higher AUC_(0-t) values of eltrombopag compared to healthy volunteers, with AUC_(0-t) values increasing with higher Child-Pugh scores. Compared to healthy volunteers, patients with HCV had plasma AUC_(0-t) values of eltrombopag approximately 100-144% higher. In patients with HCV, eltrombopag therapy should be initiated at a dose of 25 mg once daily.

The pharmacokinetics of eltrombopag in patients of East Asian race were evaluated using population pharmacokinetic analysis in 111 healthy adults (31 of East Asian origin) and 88 patients with ITP (18 of East Asian origin). Based on the pharmacokinetic analysis results in patients with ITP of East Asian origin (i.e., Japanese, Chinese, Taiwanese, and Korean), the AUC_(0-t) values of eltrombopag were approximately 87% higher than in patients not of East Asian origin (predominantly Caucasians); without body weight-based dose adjustment.

The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was studied using population pharmacokinetic analysis involving 635 patients with HCV (145 patients of East Asian origin and 69 patients of Southeast Asian origin). Based on the population pharmacokinetic analysis results, it was found that patients of East Asian and Southeast Asian origin had similar eltrombopag pharmacokinetics. On average, patients of East Asian and South Asian origin had plasma AUC_(0-t) values of eltrombopag approximately 55% higher compared to patients of other races (predominantly Caucasian).

The influence of gender on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy volunteers (14 of whom were female) and 88 patients with ITP (57 of whom were female). According to population pharmacokinetic analysis, the plasma AUC_(0-t) of eltrombopag in female patients with ITP was approximately 50% higher compared to male patients; without body weight-based dose adjustment.

The influence of gender on the pharmacokinetics of eltrombopag was assessed using population pharmacokinetic analysis involving 635 patients with HCV (260 women). According to the model-based assessment, female patients with hepatitis C virus had plasma AUC_(0-t) values of eltrombopag 41% higher compared to men.

Age-related differences in the pharmacokinetics of eltrombopag were assessed using population pharmacokinetic analysis involving 28 healthy volunteers and 635 patients with HCV aged from 19 to 74 years. According to the model-based assessment, elderly patients (> 60 years) had plasma AUC_(0-t) values of eltrombopag 36% higher compared to younger patients.

Indications

• To reduce the risk of bleeding in the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) when corticosteroids, immunoglobulins, or splenectomy are insufficiently effective;
• To enable the initiation or optimization of interferon-based antiviral therapy in the treatment of thrombocytopenia in patients with chronic viral hepatitis C (HCV).

ICD codes

Dosage Regimen

The dosage regimen is established individually based on the platelet count.

In most patients, an increase in platelet count occurs within 1-2 weeks of treatment.

Revolade^® should be taken four hours before or four hours after taking antacids, dairy products, or mineral supplements containing polyvalent cations (e.g., aluminum, calcium, iron, magnesium, selenium, and zinc).

The drug can be taken with food containing a small amount of calcium (50 mg) or, preferably, with food containing 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 adjustment is based on changes in platelet count. In clinical studies, an increase in platelet count was observed within 1-2 weeks after starting therapy with Revolade^® and a decrease occurred within 1-2 weeks after discontinuation of the drug.

Initial dosing regimen

The recommended starting dose of Revolade^® is 50 mg once daily.

For patients of East Asian origin (e.g., 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^®, the dose should be adjusted to maintain a platelet count ≥50,000/µL, which is necessary to reduce the risk of bleeding. The dose should not exceed 75 mg/day.

During therapy with Revolade^®, hematological parameters and liver function should be regularly monitored. The dose of eltrombopag should be adjusted according to Table 1 based on 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. After platelet count stabilization, a complete blood count should be performed monthly.

The lowest dose of the drug that maintains the platelet count at a clinically necessary level should be used.

Table 1. Dose adjustment of eltrombopag for patients with ITP

The standard dose adjustment, either decrease or increase, should be 25 mg/day. However, some patients may require a combination of different doses on different days.

After any adjustment of the Revolade^® dose, the platelet count should be monitored at least weekly for 2-3 weeks. After at least 2 weeks, the patient’s platelet count should be assessed to consider the need for further dose adjustment.

In patients with liver cirrhosis (hepatic impairment), the dose should not be increased earlier than 3 weeks.

Discontinuation of the drug

Treatment with Revolade^® should be discontinued if the platelet count does not increase to a level sufficient to reduce the risk of bleeding after 4 weeks of therapy with eltrombopag at a dose of 75 mg/day.

Patients with chronic HCV accompanied by thrombocytopenia

When taking Revolade^® in combination with antiviral therapy, the complete information on the combined medical use of these drugs must be taken into account.

The minimum effective dose of the drug necessary to initiate and optimize antiviral therapy is used to maintain and achieve the required platelet count. Dose selection is based on the restoration of the platelet count.

Revolade^® is not used to normalize the platelet count. In clinical studies, an increase in platelet count was observed within 1 week after starting therapy with Revolade^®.

Initial dosing regimen

The initial dose of Revolade^® is 25 mg once daily. No dose adjustment is required for patients of East Asian HCV origin (e.g., Chinese, Japanese, Taiwanese, Korean, or Thai) or patients with mild hepatic impairment.

Monitoring and dose selection

The dose of eltrombopag is increased by 25 mg every 2 weeks until a platelet count optimal for initiating antiviral therapy is achieved, in accordance with Table 2. Platelet count should be monitored weekly during the initiation of antiviral therapy.

During antiviral therapy, the dose of eltrombopag should be adjusted to avoid a reduction in the dose of peginterferon. Platelet count should be monitored weekly until a stable level is reached. Subsequently, monitoring of a complete blood count, including platelet count and peripheral blood smear, should be performed. The dose should not exceed 100 mg/day. Information on the recommended doses of peginterferon alfa and ribavirin is obtained from the prescribing information for these drugs.

Table 2. Dose adjustment of eltrombopag for HCV patients during antiviral therapy

*For patients taking Eltrombopag 25 mg once daily, consideration should be given to a dose of 12.5 mg once daily or 25 mg every other day.

Drug discontinuation

In patients with HCV genotype 1/4/6, regardless of the decision to continue interferon therapy, discontinuation of eltrombopag should be considered if the antiviral treatment effect 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, the use of Revolade^® should be discontinued.

The use of Revolade^® should be discontinued in case of an excessive increase in platelet count, as described in Table 2, or clinically significant abnormalities in liver function tests.

Children

The safety and efficacy 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. In clinical studies of eltrombopag, no clinically significant differences in the safety of the drug were observed in patients aged 65 years and older compared to younger patients. However, increased sensitivity to the drug in some elderly patients cannot be ruled out.

Patients with hepatic impairment

Caution should be exercised when prescribing eltrombopag to patients with ITP and hepatic impairment (Child-Pugh score >5). If the use of eltrombopag in patients with ITP and hepatic impairment is necessary, it is recommended to start treatment with eltrombopag at a dose of 25 mg once daily.

The dose of Revolade^® should not be increased in patients with hepatic insufficiency earlier than 3 weeks after starting therapy.

In patients with chronic HCV and hepatic impairment, Revolade^® should be prescribed at a dose of 25 mg once daily.

Patients of East Asian origin

In patients of East Asian origin and their descendants (e.g., Chinese, Japanese, Taiwanese, Korean, and Thai) with ITP, it is recommended to prescribe the drug at a reduced initial dose of 25 mg once daily.

Patients of East Asian origin with thrombocytopenia and chronic HCV should start treatment with eltrombopag at a dose of 25 mg once daily.

Platelet count monitoring should be continued in patients.

In patients of East Asian origin with ITP or HCV and hepatic impairment, treatment with eltrombopag should be started at a dose of 25 mg once daily.

Adverse Reactions

The safety and efficacy of eltrombopag were demonstrated in 2 double-blind, randomized, placebo-controlled studies in adult patients with chronic ITP who had been previously treated.

Studies ENABLE 1 (TPL103922 N=716) and ENABLE 2 (TPL108390 N=805) were randomized, double-blind, placebo-controlled, multicenter studies to evaluate the efficacy and safety of eltrombopag in patients with thrombocytopenia and viral hepatitis C who required antiviral therapy.

In the HCV patient studies, the safety analysis set consisted of all randomized patients who received the study drug according to the double-blind method in part 2 of the ENABLE 1 study (eltrombopag treatment group N=449, placebo N=232) and the ENABLE 2 study (eltrombopag treatment group n=506, placebo n=252).

Patients were analyzed according to the therapy received with eltrombopag (total safety analysis set according to the double-blind method, eltrombopag treatment group n=955 and placebo n=484).

Most adverse reactions associated with eltrombopag were mild or moderate in severity, had an early onset, and rarely led to a change in treatment.

Definition of frequency of adverse reactions: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000, including isolated cases).

Adverse events in patients with chronic ITP

Infections and infestations: common – pharyngitis, urinary tract infections.

Gastrointestinal system: very common – nausea, diarrhea; common – dry mouth, vomiting.

Hepatobiliary system: common – increased AST, ALT.

Dermatological reactions: common – alopecia, rash.

Musculoskeletal system: common – back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia.

Adverse events in patients with chronic viral hepatitis C

Hematopoietic system: very common – anemia.

Metabolism: very common – decreased appetite.

Central nervous system: very common – insomnia, headache.

Respiratory system: very common – cough.

Gastrointestinal system: very common – nausea, diarrhea.

Hepatobiliary system: common – hyperbilirubinemia.

Dermatological reactions: very common – pruritus, alopecia.

Musculoskeletal system: very common – myalgia.

General disorders: very common – fatigue, hyperthermia, pyrexia, asthenia, peripheral edema, influenza-like illness.

Contraindications

There are no known contraindications for the use of the drug for the indications in the recommended doses.

Caution should be exercised when using the drug in patients with renal impairment, hepatic impairment, in the presence of risk factors for thromboembolism (e.g., Factor V Leiden deficiency, antithrombin III deficiency, antiphospholipid syndrome), during pregnancy, and during lactation.

Revolade^® is not recommended for use in patients with hepatic insufficiency ≥5 points on the Child-Pugh scale, unless the expected benefit outweighs the risk of portal vein thrombosis. If treatment is deemed appropriate, caution should be exercised when using Revolade^® in patients with hepatic insufficiency.

Use in Pregnancy and Lactation

There are no data on the efficacy and safety of eltrombopag during pregnancy.

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. Treatment with eltrombopag is not recommended during breastfeeding, unless the expected therapeutic benefit to the mother outweighs the potential risk to the breastfed infant.

Use in Hepatic Impairment

Caution should be exercised when using the drug in patients with hepatic impairment.

Use in Renal Impairment

Caution should be exercised when using the drug in patients with renal impairment.

Pediatric Use

The safety and efficacy of eltrombopag in children have not been established.

Geriatric Use

There are limited data on the use of eltrombopag in patients aged 65 years and older. In clinical studies of eltrombopag, no clinically significant differences in the safety of the drug were observed in patients aged 65 years and older compared to younger patients. However, increased sensitivity to the drug in some elderly patients cannot be ruled out.

Special Precautions

The efficacy and safety of eltrombopag for the treatment of other diseases and conditions accompanied by thrombocytopenia, including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes, have not been established to date.

Hepatic impairment

Abnormalities in liver function laboratory parameters may occur with the use of eltrombopag. Clinical studies have noted increases in ALT, AST, and indirect bilirubin concentrations. These phenomena were mostly mild (grade 1-2) and reversible, without clinically significant symptoms indicative of hepatic impairment. According to 2 placebo-controlled studies, adverse events in the form of increased ALT were noted in 5.7% and 4% of patients receiving eltrombopag and placebo, respectively.

In 2 controlled clinical studies involving patients with thrombocytopenia and HCV, cases of ≥3-fold increase in the upper limit of normal (ULN) for ALT or AST were reported in 34% and 38% in the eltrombopag and placebo groups, respectively. The administration of eltrombopag in combination with peginterferon/ribavirin was indirectly associated with hyperbilirubinemia. Cases of ≥1.5-fold increase in total bilirubin above the ULN were reported in 76% and 50% in the eltrombopag and placebo groups, respectively.

ALT, AST activity and serum bilirubin concentration should be assessed before starting treatment with eltrombopag, then monitored every 2 weeks during dose titration, and monthly after a stable dose is established. Repeat testing after detection of abnormal liver function tests should be performed within 3-5 days. If the serum total bilirubin concentration is increased, the concentrations of its individual fractions should be determined. If the deviation is confirmed, monitoring should be continued until the parameters stabilize or return to baseline levels.

Treatment with eltrombopag should be discontinued in case of an increase in ALT activity with a ≥3-fold increase in the ULN in patients with normal liver function or a ≥3-fold increase relative to baseline in patients with elevated ALT before starting treatment and the following signs:

• Progression of the deviation, or
• Persistence of the deviation for ≥4 weeks, or
• Its combination with an increase in direct bilirubin concentration, or
• Its combination with clinical symptoms of liver damage or signs of hepatic decompensation.

Eltrombopag should be prescribed with caution in patients with ITP and liver disease. The minimum initial dose of eltrombopag should be used when prescribing to patients with hepatic insufficiency.

Hepatic decompensation (use with interferons)

In patients with chronic HCV and liver cirrhosis treated with interferon alfa, there may be a risk of hepatic decompensation, in some cases fatal. In two controlled clinical studies involving patients with thrombocytopenia and HCV, in which Eltrombopag was used as needed to achieve the target platelet count required for antiviral therapy, safety outcomes indicative of hepatic decompensation were reported more frequently in the eltrombopag group (13%) than in the placebo group (7%). Patients with low albumin levels (<3.5 g/dL) or a MELD (Model for End-Stage Liver Disease) score ≥10 at baseline had a higher risk of hepatic decompensation. Patients with such characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The prescribing information for the respective interferon drugs should be used for information on discontinuation criteria. Revolade^® should be discontinued if antiviral therapy is discontinued due to hepatic decompensation.

Thrombotic and/or thromboembolic complications

A platelet count above normal carries a theoretical risk of thrombotic and/or thromboembolic complications. In clinical studies of eltrombopag in patients with ITP, thromboembolic complications were observed at 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 count should be carefully monitored and a dose reduction or discontinuation of eltrombopag should be considered if the platelet count exceeds target values.

In ITP studies, 21 thrombotic and/or thromboembolic episodes were noted in 17 out of 446 patients (3.8%). Thromboembolisms included: embolism, including pulmonary embolism, deep vein thrombosis, transient ischemic attacks, myocardial infarction, ischemic stroke, and suspected prolonged reversible ischemic neurological deficit.

In two controlled studies involving patients with thrombocytopenia and HCV receiving interferon therapy, thrombotic and/or thromboembolic complications were noted in 31 out of 955 patients (3%) receiving Eltrombopag and in 5 out of 484 patients (1%) receiving placebo. Portal vein thrombosis was the most common thrombotic and/or thromboembolic complication in both groups (in 1% of patients receiving Eltrombopag and 1% of patients receiving placebo). No temporal relationship was observed 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 discontinuation of antiviral therapy.

In a controlled study involving patients with thrombocytopenia and chronic liver disease (n=288) who underwent elective invasive procedures, the risk of portal system thrombosis was increased in patients receiving Eltrombopag 75 mg once daily for 14 days. Six thromboembolic episodes (all in the portal system) were noted in the group of patients receiving Eltrombopag, and two in the placebo group (the first in the portal 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 discontinuation of eltrombopag treatment

After discontinuation of eltrombopag treatment, the platelet count in most patients returns to baseline within 2 weeks, which increases the risk of bleeding, and in some cases may cause bleeding. Platelet count should be monitored weekly for 4 weeks after discontinuation of eltrombopag.

Reticulin formation in the bone marrow and risk of bone marrow fibrosis

Thrombopoietin receptor agonists, including Eltrombopag, may increase the risk of development or progression of reticulin fiber deposition in the bone marrow. Before starting treatment with eltrombopag, peripheral blood smears should be evaluated to determine the baseline level of cellular morphological changes. After a stable dose of eltrombopag is reached, a complete blood count with differential should be performed monthly. If immature or dysplastic cells are detected, a peripheral blood smear should be examined for the appearance of new or worsening of existing morphological changes (e.g., appearance of teardrop and nucleated red blood cells, immature white blood cells), or for the detection of cytopenia. If the patient develops new or worsening existing morphological abnormalities or cytopenia, treatment with eltrombopag should be discontinued and a bone marrow biopsy, including staining for fibrosis, should be considered.

Malignancies and progression of malignancies

There is a theoretical possibility that thrombopoietin receptor agonists may stimulate the progression of existing hematological malignancies, e.g., myelodysplastic syndrome. Clinical studies have shown no difference in the incidence of malignancies or hematological malignancies between patients receiving placebo and patients receiving Eltrombopag.

Cataracts

In toxicological studies of eltrombopag in rodents, cataracts were detected. The clinical significance of these data is unknown. Routine monitoring of patients for cataract development is recommended.

In controlled studies involving patients with thrombocytopenia and HCV who received interferon-based therapy (n=1439), progression of pre-existing cataracts or development of new cataracts was reported in 8% in the eltrombopag group and 5% in the placebo group.

Effect on ability to drive 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, a negative impact on such activities is not expected. However, when assessing a patient’s ability to perform activities requiring quick thinking, motor and cognitive skills, the patient’s clinical condition and the profile of adverse effects of eltrombopag should be taken into account.

Overdose

One case of overdose was recorded during clinical studies, where a patient took 500 mg of eltrombopag orally.

Symptoms non-widespread rash, transient bradycardia, fatigue, and increased transaminase activity. These changes were reversible. A significant increase in platelet count is possible, which may lead to thrombotic and/or thromboembolic complications.

Treatment the administration of oral preparations containing metal cations, such as calcium, aluminum, or magnesium, should be considered to reduce the absorption of eltrombopag. Platelet count should be carefully monitored. Eltrombopag treatment is resumed in accordance with the dosing regimen recommendations.

Since renal excretion is not the primary route of elimination for eltrombopag, which is highly bound to plasma proteins, hemodialysis is unlikely to be an effective method for significantly accelerating the removal of eltrombopag from the body.

Drug Interactions

Rosuvastatin:in vitro studies have shown that Eltrombopag is not a substrate for the organic anion transporting polypeptide OATP1B1 but acts as an inhibitor of this transporter. In vitro study results have also established that Eltrombopag is a substrate and inhibitor of BCRP. When eltrombopag and rosuvastatin were co-administered in a clinical drug interaction study, an increase in rosuvastatin plasma concentration was observed. A dose reduction of rosuvastatin should be considered when co-administered with eltrombopag, and careful monitoring should be conducted. In clinical studies of eltrombopag with concomitant rosuvastatin therapy, a 50% reduction in the latter’s dose was recommended. Co-administration of eltrombopag with other substrates of organic anion transporting polypeptides (OATP1B1) and BCRP requires caution.

Polyvalent cations (chelate formation): to avoid a significant reduction in the 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 50 mg dose of eltrombopag with a standard high-calorie, high-fat breakfast containing dairy products reduced the area under the pharmacokinetic curve AUC_(0-∞) by 59% (90% CI: 54%, 64%) and C_max by 65% (90% CI: 59%, 70%). Food with low calcium content (<50 mg calcium), including fruit, lean ham, beef, fruit juice, soy milk, and cereal without added calcium, iron, and magnesium, does not significantly affect eltrombopag plasma exposure, regardless of the calorie and fat content of the food.

Lopinavir/ritonavir combination (LPV/RTV) simultaneous use of eltrombopag and LPV/RTV may lead to a decrease in eltrombopag concentration. In a study involving 40 healthy volunteers, it was found that simultaneous single-dose administration of 100 mg eltrombopag and multiple-dose administration of 400 mg/100 mg LPV/RTV twice daily led to a 17% (90% CI: 6.6%, 26.6%) decrease in the plasma AUC_(0-∞) of eltrombopag. Therefore, increased caution is necessary when eltrombopag and LPV/RTV are used concomitantly. Platelet count should be carefully monitored to ensure the appropriate dose of eltrombopag when initiating or discontinuing LPV/RTV therapy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.