Eltrombopag-vista
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELTROMBOPAG-VISTA ELTROMBOPAG-VISTA
Composition:
Active substance: eltrombopag;
1 tablet contains 25 or 50 mg of eltrombopag (as eltrombopag olamine);
Excipients: microcrystalline cellulose, mannitol, povidone, isomalt (E 953), calcium silicate, sodium starch glycolate, magnesium stearate;
coating: hypromellose, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), triacetin.
Pharmaceutical form. Film-coated tablets.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
25 mg tablets: round, biconvex, film-coated tablets, dark pink in color, with imprint «II» on one side, approximately 8 mm in diameter;
50 mg tablets: round, biconvex, film-coated tablets, pink in color, with imprint «III» on one side, approximately 10 mm in diameter.
Pharmacotherapeutic group. Antihemorrhagics, systemic hemostatics. ATC code B02BX05.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action.
Thrombopoietin is the primary cytokine involved in the regulation of megakaryopoiesis and platelet production and is the endogenous ligand for thrombopoietin receptors. Eltrombopag binds to the transmembrane domain of human thrombopoietin receptors and initiates a signaling cascade similar, but not identical, to that triggered by endogenous thrombopoietin, thereby inducing proliferation and differentiation of megakaryocytes from precursor cells in the bone marrow.
Clinical efficacy and safety.
Studies in patients with chronic immune (idiopathic) thrombocytopenia (ITP). Two randomized, double-blind, placebo-controlled phase III studies, RAISE (TRA102537) and TRA100773B, and two open-label studies, REPEAT (TRA108057) and EXTEND (TRA105325), evaluated the safety and efficacy of eltrombopag in adult patients with previously treated chronic ITP. A clinical study comparing eltrombopag treatment with other treatment options (e.g., splenectomy) has not been conducted. The long-term safety of eltrombopag should be considered prior to initiating therapy.
Children (aged 1–17 years). The safety and efficacy of eltrombopag in pediatric patients were evaluated in two studies.
TRA115450 (PETIT2): The primary endpoint was sustained response, defined as the proportion of individuals receiving eltrombopag who achieved platelet counts ≥ 50,000/μL for at least 6 out of 8 weeks (in the absence of emergency therapy) during weeks 5 to 12 of the double-blind randomized phase. Participants had confirmed chronic ITP lasting at least 1 year and had either not responded to at least one prior ITP therapy, relapsed during such therapy, or were unable to continue other ITP treatment for medical reasons, and had platelet counts < 30,000/μL. 92% of patients were randomized in a 2:1 ratio to receive eltrombopag (n = 63) or placebo (n = 29) and were stratified into three baseline groups. The dose of eltrombopag could be adjusted based on the individual patient's platelet count.
Overall, a significantly greater proportion of patients receiving eltrombopag (40%) compared to placebo (3%) achieved the primary endpoint (odds ratio: 18.0 [95% confidence interval (CI): 2.3; 140.9], p < 0.001). This result was consistent across all three age groups (Table 1).
Table 1
Sustained platelet response in children with chronic ITP by age
| Groups |
Elthrombopag n/N (%) [95 % CI] |
Placebo n/N (%) [95 % CI] |
| Group 1 (12–17 years) |
9/23 (39 %) [20 %, 61 %] |
1/10 (10%) [0 %, 45 %] |
| Group 2 (6–11 years) |
11/26 (42 %) [23 %, 63 %] |
0/13 (0 %) [CI] |
| Group 3 (1–5 years) |
5/14 (36 %) [13 %, 65 %] |
0/6 (0 %) [CI] |
NA — not available.
A statistically smaller number of patients receiving eltrombopag required emergency therapy during the randomized period compared to the placebo group (19 % [12/63] vs. 24 % [7/29], p = 0.032).
At baseline, 71 % of individuals in the eltrombopag group and 69 % in the placebo group reported any bleeding (grade 1–4 according to WHO). After 12 weeks, the proportion of patients receiving eltrombopag who reported any bleeding decreased to half of the baseline level (36 %). In comparison, after 12 weeks, 55 % of patients receiving placebo reported any bleeding.
Participants were allowed to reduce the initial ITP therapy only during the open-label phase of the study, and 53 % (8/15) of patients were able to reduce (n = 1) or discontinue (n = 7) their initial ITP therapy, predominantly corticosteroids, without the need for emergency therapy.
TRA108062 (PETIT): The primary endpoint was the proportion of participants who achieved a platelet count ≥ 50,000/µL at least once between weeks 1 and 6 of the randomized period. Patients had either failed to respond to at least one prior ITP therapy or experienced a relapse during such therapy, and had platelet counts < 30,000/µL (n = 67). During the randomized study period, participants were randomized in a 2:1 ratio to receive eltrombopag (n = 45) or placebo (n = 22) and stratified into three baseline groups. The dose of eltrombopag could be adjusted based on the individual patient's platelet count.
Overall, a significantly higher proportion of patients receiving eltrombopag (62 %) compared to the placebo group (32 %) achieved the primary endpoint (odds ratio: 4.3 [95 % CI: 1.4; 13.3], p = 0.011).
Sustained response was observed in 50 % of those who initially responded during 20 out of 24 weeks in the PETIT 2 study and during 15 out of 24 weeks in the PETIT study.
Studies in patients with thrombocytopenia associated with chronic hepatitis C. The efficacy and safety of eltrombopag in the treatment of thrombocytopenia in patients with chronic hepatitis C (HCV) were evaluated in two randomized, double-blind, placebo-controlled studies. In the ENABLE 1 study, pegylated interferon alfa-2a plus ribavirin was used for antiviral treatment, while in the ENABLE 2 study, pegylated interferon alfa-2b and ribavirin were used. Patients did not receive direct-acting antiviral agents.
Severe aplastic anemia. Eltrombopag was studied in a single-center, open-label, single-group trial involving 43 patients with severe aplastic anemia and refractory thrombocytopenia after at least one course of immunosuppressive therapy (IST), who had platelet counts ≤ 30,000/µL.
The majority of participants, 33 (77 %), were considered to have primary refractory disease, defined as an inadequate response to prior IST in any parameter. In the other 10 participants, there was an inadequate platelet response to prior treatment. All 10 had received at least 2 prior IST regimens, and 50 % had received at least 3 prior IST regimens. Patients with Fanconi anemia, infection unresponsive to appropriate therapy, presence of ≥ 50 % PNH clone in neutrophils, were excluded from the study. At baseline, the median platelet count was 20,000/µL, hemoglobin levels were 8.4 g/dL, absolute neutrophil count (ANC) was 0.58 × 10⁹/L, and absolute reticulocyte count was 24.3 × 10⁹/L. 86 % of patients were dependent on red blood cell transfusions, and 91 % on platelet transfusions. The majority of patients (84 %) had received at least 2 prior courses of IST. Three patients had cytogenetic abnormalities at baseline.
The primary endpoint was hematologic response assessed after 12 weeks of eltrombopag treatment. Hematologic response was defined as meeting one or more of the following criteria: an increase in platelet count to 20,000/µL from baseline or stabilization of platelet count with transfusion independence for at least 8 weeks; an increase in hemoglobin levels by > 1.5 g/dL or a reduction of ≥ 4 units of red blood cell transfusions over 8 consecutive weeks; an increase in absolute neutrophil count (ANC) by 100 % or an increase in ANC > 0.5 × 10⁹/L.
The rate of hematologic response was 40 % (17 out of 43 patients; 95 % CI 25, 56), with most responding in one parameter (13/17, 76 %), while 3 responses in two parameters and 1 response in three parameters were observed at 12 weeks. Eltrombopag treatment was discontinued at 16 weeks if hematologic response or transfusion independence was not achieved. Patients who responded continued treatment in the extension phase of the study. A total of 14 patients entered this phase. Nine of these patients achieved responses in multiple parameters, four of the nine continued therapy, and five reduced their eltrombopag treatment while maintaining response (median follow-up: 20.6 months, range: 5.7 to 22.5 months). The other five patients discontinued therapy: three due to relapse during the 3-month extension phase. During eltrombopag treatment, 59 % (23/39) of patients achieved platelet transfusion independence (28 days without transfusion), and 27 % (10/37) achieved red blood cell transfusion independence (56 days without transfusion). The longest period of platelet transfusion independence for non-responders was 27 days (median). The longest period of platelet transfusion independence for responders was 287 days (median). The longest period of red blood cell transfusion independence for non-responders was 29 days (median). The longest period of red blood cell transfusion independence for responders was 266 days (median).
Over 50 % of responders who were transfusion-dependent at baseline achieved a reduction of > 80 % in the need for both platelet and red blood cell transfusions compared to baseline.
Preliminary data from a confirmatory study (study ELT116826), a non-randomized, open-label, phase II single-group study in patients with refractory severe aplastic anemia (SAA), demonstrated consistent results. Data are limited to 21 out of the planned 60 patients with hematologic response, reported in 52 % of patients at 6 months. Multilineage response was observed in 45 % of patients.
Pharmacokinetics.
Pharmacokinetic parameters of eltrombopag when used for the treatment of adults with idiopathic thrombocytopenic purpura (ITP) are as follows: when administered at a dose of 50 mg once daily, the maximum concentration of the drug (Cmax) is 8.01 µg/mL (6.73; 9.53), and the area under the concentration-time curve (AUC) is 108 µg·h/mL (88; 134). When administered at a dose of 75 mg once daily, Cmax is 12.7 µg/mL (11.0; 14.5), and AUC is 168 µg·h/mL (143; 198).
Pharmacokinetic parameters of eltrombopag when used for the treatment of adults with chronic hepatitis C (HCV) are as follows: when administered at a dose of 50 mg once daily, the maximum concentration of the drug (Cmax) is 9.08 µg/mL (7.96; 10.35), and the area under the concentration-time curve (AUC) is 166 µg·h/mL (143; 192). When administered at a dose of 75 mg once daily, Cmax is 16.71 µg/mL (14.26; 19.58), and AUC is 301 µg·h/mL (250; 363). When administered at a dose of 100 mg once daily, Cmax is 19.19 µg/mL (16.81; 21.91), and AUC is 354 µg·h/mL (304; 411). Thus, when the same doses of eltrombopag are administered, its exposure during treatment of patients with chronic HCV is higher than its exposure during treatment of patients with ITP.
Absorption and bioavailability. Peak concentrations of eltrombopag are reached within 2–6 hours after oral administration. Concomitant administration with antacids and other substances containing polyvalent cations, such as dairy products and mineral supplements, significantly reduces eltrombopag concentrations. In a relative bioavailability study in adults, administration of eltrombopag as an oral suspension powder resulted in an AUC(0–∞) value 22 % higher than that achieved with tablets. The absolute bioavailability of eltrombopag when administered to humans has not been established. Based on urinary excretion and fecal metabolite elimination, the oral absorption of eltrombopag-related substances after a single 75 mg dose is approximately 52 %.
Distribution. Eltrombopag is highly bound to human plasma proteins (> 99.9 %), primarily to albumin. Eltrombopag is a substrate of the breast cancer resistance protein (BCRP), but not a substrate of P-glycoprotein or organic anion transporting polypeptides.
Metabolism. Eltrombopag is primarily metabolized via cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In a radiolabeled study, eltrombopag accounted for approximately 64 % of the plasma radioactivity AUC. Minor metabolites resulting from glucuronidation and oxidation, each accounting for less than 10 % of plasma radioactivity, were also detected. Based on data from human studies with radiolabeled eltrombopag, approximately 20 % of the dose is metabolized via oxidation. In vitro studies identified that the isoenzymes CYP1A2 and CYP2C8 are responsible for oxidative metabolism, the uridine diphosphate glucuronosyltransferase isoenzymes UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage process of the drug.
Elimination. Absorbed eltrombopag is extensively metabolized. Eltrombopag is primarily eliminated in feces (59 %), with 31 % of the dose appearing in urine as metabolites. Unchanged eltrombopag was not detected in urine. Unchanged eltrombopag excreted in feces accounts for approximately 20 % of the dose. The plasma half-life of eltrombopag is approximately 21–32 hours.
Pharmacokinetic interactions. Based on results from studies with radiolabeled eltrombopag, glucuronidation plays a minor role in its metabolism. Studies using human liver microsomes showed that UGT1A1 and UGT1A3 enzymes are responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of several UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not expected due to the limited impact of UGT enzymes on eltrombopag glucuronidation and potential concomitant medications. Approximately 21 % of the eltrombopag dose may be metabolized via oxidation. Studies using human liver microsomes showed that CYP1A2 and CYP2C8 enzymes are responsible for eltrombopag oxidation. In vitro and in vivo studies showed that eltrombopag is not an inhibitor of CYP enzymes.
In vitro studies demonstrated that eltrombopag is an inhibitor of OATP1B1 and breast cancer resistance protein (BCRP) transporters; eltrombopag increased exposure to the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study. In clinical studies with eltrombopag, a 50 % dose reduction of statins was recommended. Concomitant administration of 200 mg cyclosporine (a BCRP inhibitor) reduced Cmax and AUCinf of eltrombopag by 25 % and 18 %, respectively. Concomitant administration of 600 mg cyclosporine reduced Cmax and AUCinf of eltrombopag by 39 % and 24 %, respectively.
Eltrombopag forms chelate complexes with polyvalent cations such as iron, calcium, magnesium, aluminum, selenium, and zinc.
In vitro studies demonstrated that eltrombopag is not a substrate for organic anion transporting polypeptides, OATP1B1, but is an inhibitor of this transporter (IC50 value 2.7 µM [1.2 µg/mL]). In vitro studies also demonstrated that eltrombopag is an inhibitor and substrate of breast cancer resistance protein (BCRP) transporters (IC50 value 2.7 µM [1.2 µg/mL]).
Special patient populations.
Renal impairment. The pharmacokinetics of eltrombopag were studied after administration of the drug to adult patients with renal impairment. After a single 50 mg dose, AUC of eltrombopag decreased by 32 % in patients with mild renal impairment, by 36 % in patients with moderate renal impairment, and by 60 % in patients with severe renal impairment compared to healthy volunteers. Although plasma concentrations of eltrombopag are generally lower in patients with renal impairment, there is substantial variability in exposure levels when comparing patients with renal impairment to healthy volunteers. Patients with renal impairment should be treated with caution and under continuous monitoring, such as by measuring serum creatinine and/or urine analysis. The efficacy and safety of eltrombopag in patients with moderate or severe renal impairment and hepatic dysfunction have not been established.
Hepatic impairment. The pharmacokinetics of eltrombopag were studied after administration of the drug to adult patients with hepatic impairment. After a single 50 mg dose, AUC of eltrombopag increased by 41 % in patients with mild hepatic impairment, by 80 % in patients with moderate hepatic impairment, and by 93 % in patients with severe hepatic impairment compared to healthy volunteers. There is substantial variability in exposure levels when comparing patients with hepatic impairment to healthy volunteers.
The effect of hepatic impairment on the pharmacokinetics of eltrombopag after repeated administration was studied using population pharmacokinetic analysis of data from 28 healthy volunteers and 714 patients with hepatic dysfunction (673 patients with HCV and 41 patients with chronic liver disease of other etiology). Of these 714 patients, 642 had mild hepatic dysfunction, 67 had moderate hepatic dysfunction, and 2 had severe hepatic dysfunction. Patients with mild hepatic impairment had approximately 111 % higher (95 % CI: 45 % to 283 %) eltrombopag AUC in plasma, and patients with moderate hepatic impairment had 183 % higher (95 % CI: 90 % to 459 %) eltrombopag AUC in plasma compared to healthy volunteers.
Therefore, eltrombopag should not be used for the treatment of ITP patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the risk of portal vein thrombosis (see sections "Dosage and administration" and "Special warnings and precautions").
Patients with hepatic impairment should be treated with caution. Patients with chronic ITP and mild, moderate, or severe hepatic impairment should initiate treatment with eltrombopag at a reduced dose of 25 mg once daily.
Race. The effect of East Asian origin on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy adults (31 East Asian subjects) and 88 ITP patients (18 East Asian subjects). According to population pharmacokinetic analysis in East Asian ITP patients, eltrombopag AUC values were approximately 49 % higher than in patients of other races, primarily Caucasian (see section "Dosage and administration").
The effect of East/Southeast Asian origin (e.g., Chinese, Japanese, Taiwanese, Korean, or Thai) on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 635 HCV patients (145 East Asian and 69 Southeast Asian subjects). Based on population pharmacokinetic analysis estimates, eltrombopag AUC values in East/Southeast Asian patients were approximately 55 % higher compared to patients of other races, primarily Caucasian (see section "Dosage and administration").
Gender. The effect of gender on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy adults (14 women) and 88 ITP patients (57 women). According to population pharmacokinetic analysis, eltrombopag AUC values in female ITP patients were approximately 23 % higher than in male patients, without body weight adjustment.
The effect of gender on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 635 HCV patients (260 women). According to modeling results, eltrombopag AUC values in women with HCV were approximately 41 % higher compared to men.
Age. The effect of age on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 28 healthy individuals, 673 HCV patients, and 41 patients with chronic liver disease of other etiology aged 19 to 74 years. Pharmacokinetic data in patients aged 75 years and older are lacking. According to population pharmacokinetic analysis, eltrombopag AUC values in elderly patients (> 65 years) were 41 % higher compared to younger patients.
Pediatrics (1 to 17 years of age). Clinical study data indicate that eltrombopag clearance from plasma after oral administration increases with increasing body weight. The effects of race and gender on eltrombopag pharmacokinetic parameters in pediatric and adult patients are similar. Eltrombopag AUC values in East/Southeast Asian patients were approximately 43 % higher compared to patients of other races. Eltrombopag AUC values in female ITP patients were approximately 25 % higher compared to male patients.
Pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are presented in Table 2.
Table 2
Mean plasma pharmacokinetic parameters of eltrombopag at steady state in pediatric patients with ITP (50 mg once daily).
| Age |
Cmax (μg/mL) |
AUC(0–τ) (μg×h/mL) |
| 12–17 years (n = 62) |
6.80 (6.17; 7.50) |
103 (91.1; 116) |
| 6–11 years (n = 68) |
10.3 (9.42; 11.2) |
153 (137; 170) |
| 1–5 years (n = 38) |
11.6 (10.4; 12.9) |
162 (139; 187) |
Clinical characteristics.
Indications.
Treatment of adult patients with chronic immune (idiopathic) thrombocytopenic purpura who are refractory to other medicinal products (e.g., corticosteroids, immunoglobulins).
Treatment of children aged one year and older with chronic immune (idiopathic) thrombocytopenic purpura with a disease duration of 6 months or longer since diagnosis, who are refractory to other medicinal products (e.g., corticosteroids, immunoglobulins).
Treatment of thrombocytopenia in adult patients with chronic hepatitis C, when the degree of thrombocytopenia is the main factor preventing initiation or limiting the ability to continue optimal interferon-based therapy.
Treatment of adult patients with severe acquired aplastic anemia (SAA) who have not been previously treated with immunosuppressive therapy or have responded poorly to prior treatment and are not suitable candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to eltrombopag or to any other component of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Effect of eltrombopag on other medicinal products.
HMG-CoA reductase inhibitors (hydroxymethylglutaryl-coenzyme A reductase). In vitro studies have demonstrated that eltrombopag is not a substrate for organic anion transporting polypeptides (OATP1B1), but is an inhibitor of these transporters. In vitro studies also showed that eltrombopag is a substrate and inhibitor of BCRP. Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin in 39 healthy adult volunteers resulted in a 103% increase in rosuvastatin plasma Cmax (90% confidence interval [CI]: 82%, 126%) and a 55% increase in AUC0–∞ (90% CI: 42%, 69%). Interaction with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, is also expected. When co-administered with eltrombopag, statin doses should be reduced and statin-related adverse reactions should be closely monitored.
OATP1B1 and BCRP substrates.
Eltrombopag should be used with caution when co-administered with other OATP1B1 substrates (e.g., methotrexate) and BCRP substrates (e.g., topotecan and methotrexate). Cytochrome P450 substrates.
Studies using human liver microsomes showed that eltrombopag (at concentrations up to 100 µM) did not inhibit CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 4A4/5, and 4A9/11 in vitro, and inhibited CYP2C8 and CYP2C9 when paclitaxel and diclofenac were used as test substrates. Administration of 75 mg eltrombopag to 24 healthy male volunteers did not inhibit or induce metabolism of test substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam). Clinically significant interactions with CYP450 substrates are not expected when co-administered with eltrombopag.
HCV protease inhibitors.
Dose adjustment is not required when eltrombopag is co-administered with telaprevir or boceprevir. Concomitant administration of a single 200 mg dose of eltrombopag with 750 mg telaprevir every 8 hours did not alter telaprevir plasma concentrations.
Concomitant administration of a single 200 mg dose of eltrombopag with 800 mg boceprevir every 8 hours did not change AUC(0–τ), but increased Cmax by 20% and decreased Cmin by 32%. The clinical significance of the Cmin reduction has not been established; careful clinical and laboratory monitoring of HCV suppression is recommended.
Effect of other medicinal products on eltrombopag.
Cyclosporine.
In vitro studies have shown that eltrombopag is a substrate and inhibitor of breast cancer resistance protein (BCRP). Reduced eltrombopag exposure was observed when co-administered with 200 mg and 600 mg cyclosporine (a BCRP inhibitor). Concomitant administration of 200 mg cyclosporine reduced eltrombopag Cmax and AUC0–∞ by 25% and 18%, respectively. Concomitant administration of 600 mg cyclosporine reduced eltrombopag Cmax and AUC0–∞ by 39% and 24%, respectively. Dose adjustment of eltrombopag during treatment should be based on the patient's platelet count. Platelet counts should be monitored at least once weekly for 2–3 weeks after initiating concomitant use of eltrombopag with cyclosporine. Dose increases of eltrombopag may be required based on platelet counts.
Polyvalent cations (chelation).
Eltrombopag forms chelates with polyvalent cations such as aluminium, calcium, iron, magnesium, selenium, and zinc. Administration of a single 75 mg dose of eltrombopag with a polyvalent antacid containing cations (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) reduced eltrombopag plasma AUC0–∞ and Cmax by 70%. Antacids, dairy products, and other substances containing polyvalent cations, such as mineral supplements, should be taken at least 2 hours before or 4 hours after eltrombopag administration to prevent significant reduction in eltrombopag absorption due to chelation.
Interaction with food.
Administration of eltrombopag tablets with food high in calcium (e.g., food containing dairy products) significantly reduced AUC0–∞ and Cmax. Conversely, administration of eltrombopag 2 hours before or 4 hours after meals with high or low calcium content (< 50 mg calcium) did not alter eltrombopag plasma exposure to a clinically significant extent.
Administration of a single 50 mg dose of eltrombopag tablet with a high-calorie, high-fat standard breakfast including dairy products reduced eltrombopag plasma AUC by 59% and Cmax by 65%.
Administration of a single 25 mg dose of eltrombopag oral suspension powder with a medium-calorie meal high in calcium and medium in fat reduced mean plasma AUC0–∞ by 75% and mean Cmax by 79%. This reduction in exposure was attenuated when a single 25 mg dose of eltrombopag oral suspension powder was administered 2 hours before a high-calcium meal (mean AUC0–∞ decreased by 20%, mean Cmax decreased by 14%).
Foods low in calcium (< 50 mg calcium), including fruits, lean ham, beef, unfortified (without added calcium, magnesium, or iron) fruit juice, unfortified soy milk, and unfortified cereals, did not significantly affect eltrombopag plasma exposure regardless of caloric content or fat content.
Atazanavir/ritonavir.
Concomitant administration of eltrombopag with atazanavir/ritonavir (ATV/RTV) may reduce eltrombopag concentrations. A study in 40 healthy volunteers showed that co-administration of a single 100 mg dose of eltrombopag with ATV/RTV 400/100 mg twice daily reduced eltrombopag plasma AUC0–∞ by 17%. Therefore, eltrombopag should be used with caution when co-administered with atazanavir/ritonavir. Platelet counts should be carefully monitored when initiating or discontinuing concomitant atazanavir/ritonavir therapy to ensure appropriate eltrombopag dosing.
Inhibitors and inducers of CYP1A2 and CYP2C8.
Eltrombopag is metabolized through multiple pathways, including CYP1A2, CYP2C8, UGT1A1, and UGT1A3. Medicinal products affecting inhibition or induction of a single enzyme are unlikely to have a significant effect on eltrombopag plasma concentrations; however, medicinal products affecting inhibition or induction of multiple enzymes have the potential to increase (e.g., fluvoxamine) or decrease (e.g., rifampicin) eltrombopag concentrations.
HCV protease inhibitors.
Results from drug interaction pharmacokinetic studies indicate that co-administration of repeated doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single 200 mg dose of eltrombopag does not alter eltrombopag plasma concentrations to a clinically significant extent.
Medicinal products for the treatment of ITP.
Medicinal products used in combination with eltrombopag in clinical studies for the treatment of ITP include corticosteroids, danazol and/or azathioprine, intravenous immunoglobulin, and anti-D immunoglobulin. Platelet counts should be monitored when eltrombopag is used concomitantly with other medicinal products for the treatment of ITP to maintain platelet counts within the recommended range (see section "Dosage and administration").
Special precautions for use.
In patients with chronic hepatitis C virus (HCV) infection and thrombocytopenia with advanced chronic liver disease, there is an increased risk of adverse reactions, including potentially fatal hepatic failure and thromboembolic complications. This increased risk is associated with low albumin levels ≤ 35 g/L or a Model for End-Stage Liver Disease (MELD) score ≥ 10 during treatment with eltrombopag in combination with interferon therapy. Furthermore, the benefits of treatment in terms of achieving sustained virological response (SVR) compared to placebo in these patients were minimal (particularly in patients with baseline albumin levels ≤ 35 g/L). Treatment of such patients with eltrombopag should only be initiated by physicians experienced in managing patients with advanced chronic HCV and only when there is a risk of developing thrombocytopenia or when antiviral therapy support is required. If treatment is clinically indicated, careful monitoring of these patients is necessary.
Interaction with direct-acting antiviral agents.
The safety and efficacy of combining eltrombopag with direct-acting antiviral agents approved for the treatment of chronic hepatitis C have not been established.
Risk of hepatotoxicity.
Eltrombopag may cause liver function abnormalities and potentially life-threatening hepatotoxic effects (see section "Adverse reactions").
Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be measured before starting eltrombopag treatment, every 2 weeks during dose adjustment, and monthly after dose stabilization. Eltrombopag is an inhibitor of UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin levels are elevated, direct and indirect bilirubin should be monitored. If liver test abnormalities occur, repeat testing should be performed within 3–5 days. If abnormalities are confirmed, liver enzyme levels should be monitored until they normalize or stabilize. Treatment with eltrombopag should be discontinued in cases of ALT elevation (≥ 3 × ULN [upper limit of normal] in patients with normal liver function or ≥ 3 times from baseline or > 5 × ULN, whichever is lower, in patients with elevated transaminases before treatment), as well as in the presence of:
- disease progression;
- persistence of abnormalities ≥ 4 weeks;
- concomitant elevation of direct bilirubin;
- development of concomitant clinical symptoms of liver dysfunction or signs of hepatic decompensation.
Eltrombopag should be administered with caution in patients with liver disease. Patients with immune thrombocytopenia (ITP) and liver impairment should start treatment with a reduced dose. Careful monitoring is required when administering eltrombopag to patients with impaired liver function (see section "Dosage and administration").
Hepatic failure (when used in combination with interferon).
Hepatic failure in patients with chronic HCV: patients with low albumin levels (≤ 35 g/L) or baseline MELD score ≥ 10 should be closely monitored.
In patients with HCV and liver cirrhosis, there is a risk of hepatic decompensation when using alpha-interferon. In two controlled clinical trials in patients with HCV and thrombocytopenia, signs of hepatic failure (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis) were observed more frequently in the eltrombopag group (11%) than in the placebo group (6%). Patients with low albumin levels (< 35 g/L) or MELD score ≥ 10 at baseline had a threefold higher risk of hepatic failure and an increased risk of fatal complications compared to those with less advanced liver disease. Moreover, the benefits of treatment in terms of achieving SVR compared to placebo in these patients were minimal (especially in patients with baseline albumin levels ≤ 35 g/L). Eltrombopag should be prescribed to such patients only after careful assessment of expected benefits versus risks. Close monitoring for signs and symptoms of hepatic failure is necessary when treating patients with these characteristics. For information on criteria for discontinuation of interferon therapy, refer to the relevant product information. Eltrombopag treatment should be discontinued if antiviral therapy is stopped due to hepatic failure.
Thrombotic/thromboembolic complications.
In controlled trials involving patients with thrombocytopenia and HCV receiving interferon therapy (n = 1439), thromboembolic complications (TECs) occurred in 38 of 955 patients (4%) receiving eltrombopag and in 6 of 484 patients (1%) in the placebo group. These thrombotic/thromboembolic complications included both venous and arterial events. Most TECs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEC in both treatment groups (2% of patients receiving eltrombopag vs. <1% of those receiving placebo). No association was observed between the timing of treatment initiation and the development of TECs. Patients with low albumin levels (≤ 35 g/L) or MELD ≥ 10 had twice the risk of developing TECs compared to patients with higher albumin levels; patients aged ≥ 60 years had a twofold higher risk of TECs compared to younger patients. Eltrombopag should be prescribed to such patients only after careful consideration of expected benefits and potential risks. Close monitoring for signs and symptoms of TEC development is necessary in these patients.
An increased risk of TECs has been observed in patients with chronic liver failure (CLF) receiving eltrombopag 75 mg once daily for two weeks prior to invasive procedures. TECs (all in the portal venous system) developed in 6 of 143 (4%) adult patients with CLF receiving eltrombopag, compared to 2 of 145 (1%) in the placebo group (one case of complication in the portal venous system and one case of myocardial infarction). In 5 of 6 patients receiving eltrombopag, thrombotic complications occurred when platelet counts exceeded 200,000/µL within 30 days after the last dose. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver failure in preparation for invasive procedures.
In clinical trials of eltrombopag in patients with ITP, thromboembolic events were observed at both low and normal platelet levels. Eltrombopag should be used with caution in patients with risk factors for thromboembolism, including inherited (e.g., factor V Leiden) or acquired risk factors (e.g., antithrombin III deficiency, antiphospholipid syndrome), advanced age, prolonged immobilization, malignancies, use of contraceptives and hormone replacement therapy, surgery/trauma, obesity, and smoking. Platelet counts should be continuously monitored, and if counts rise above the required level, consideration should be given to reducing the dose or discontinuing eltrombopag treatment (see section "Dosage and administration"). The risk/benefit ratio should always be evaluated when treating patients at risk of TECs of any etiology.
In clinical trials for refractory aplastic anemia (AA), no cases of TECs were reported; however, the risk of such events cannot be excluded in this patient population due to the limited number of treated patients. Since patients with AA indication receive the maximum approved dose (150 mg/day) and considering the nature of the response, TEC development may be expected in this patient population.
Eltrombopag should not be used to treat patients with moderate to severe hepatic impairment (Child-Pugh ≥ 5) unless the potential benefit outweighs the risk of portal vein thrombosis. If use of the drug is necessary, eltrombopag should be prescribed with caution for the treatment of patients with ITP and hepatic impairment (see sections "Dosage and administration" and "Adverse reactions").
Hemorrhage after discontinuation of eltrombopag treatment.
After discontinuation of eltrombopag in patients with ITP, thrombocytopenia may recur. In most patients, platelet counts return to baseline levels within 2 weeks after stopping eltrombopag, increasing the risk of bleeding. This risk is heightened if eltrombopag treatment is discontinued while anticoagulants or antiplatelet agents are being used. Upon discontinuation of eltrombopag therapy, management of idiopathic thrombocytopenic purpura should be resumed according to current clinical guidelines. Additional measures may include discontinuation of anticoagulant and/or antiplatelet therapy and reassessment of anticoagulant or platelet support. Platelet counts should be checked weekly for 4 weeks after stopping eltrombopag.
In clinical trials of patients with HCV, gastrointestinal bleeding, including severe and fatal cases, was reported at higher rates after discontinuation of peginterferon, ribavirin, and eltrombopag. After stopping therapy, patients should be monitored for symptoms of gastrointestinal bleeding.
Bone marrow reticulin formation and risk of bone marrow fibrosis.
Eltrombopag increases the risk of development or increased formation of reticulin fibers in the bone marrow. The significance of this, as with other thrombopoietin receptor agonists, has not been fully established.
Prior to initiating eltrombopag treatment, a peripheral blood smear should be carefully examined to determine baseline morphological abnormalities in blood cells. After establishing a stable dosing regimen, a complete blood count with differential should be performed monthly. If immature or dysplastic cells appear, the peripheral blood smear should be analyzed for new or worsening morphological abnormalities (e.g., red blood cell fragmentation, nucleated red blood cells, immature leukocytes) or cytopenias. If new or worsening morphological abnormalities or cytopenias develop, eltrombopag treatment should be discontinued and a bone marrow biopsy, including staining for fibrosis, should be considered.
Malignant neoplasms and their progression.
There is a theoretical concern that thrombopoietin receptor (TPO-R) agonists may stimulate the progression of existing hematopoietic neoplasms, such as myelodysplastic syndrome (MDS). Thrombopoietin receptor agonists are growth factors that stimulate the development of thrombopoietic precursor cells, their differentiation, and platelet production. Thrombopoietin receptors are primarily expressed on the surface of myeloid-derived cells.
In clinical trials of thrombopoietin receptor agonists in patients with myelodysplastic syndrome (MDS), transient increases in blast cell counts and progression of MDS to acute myeloid leukemia (AML) have been reported.
The diagnosis of ITP or AA in adult and elderly patients should be confirmed by excluding other conditions associated with thrombocytopenia, particularly MDS. Bone marrow aspiration and biopsy should be considered during the course of the disease and treatment, especially in patients aged 60 years or older with systemic symptoms or abnormalities, such as increased peripheral blast cells.
The efficacy and safety of eltrombopag for treating other thrombocytopenic conditions, including MDS or chemotherapy-induced thrombocytopenia, have not been established. Eltrombopag should be used only for approved indications and should not be used to treat thrombocytopenia caused by MDS or any other cause.
Chromosomal abnormalities and progression to MDS/AML in patients with AA.
Chromosomal abnormalities are known to occur in patients with AA. It is unknown whether eltrombopag increases the risk of chromosomal abnormalities in patients with AA. In a phase II clinical trial of eltrombopag at an initial dose of 50 mg/day (with dose escalation every 2 weeks up to a maximum of 150 mg/day) (ELT112523) in patients with refractory AA, new chromosomal abnormalities were observed in 17.1% of adult patients [7/41 (4 of whom had changes in chromosome 7)]. The median time to chromosomal abnormality was 2.9 months.
In a phase II clinical trial of eltrombopag at a dose of 150 mg/day (with adjustments based on ethnicity or age according to indications) (ELT116826) in patients with refractory AA, new chromosomal abnormalities were observed in 22.6% of adult patients [7/31 (3 of whom had changes in chromosome 7)]. All 7 patients had normal baseline cytogenetic parameters. Chromosomal abnormalities were noted in 6 patients at month 3 of eltrombopag treatment and in 1 patient at month 6. In clinical trials of eltrombopag in patients with AA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment.
For patients with AA who are refractory to or poorly responsive to prior immunosuppressive therapy, bone marrow examination with cytogenetic studies is recommended before starting eltrombopag and then at months 3 and 6 of treatment. If new cytogenetic abnormalities are detected, the need for continuing eltrombopag treatment should be evaluated.
Cataract and other ocular changes.
Toxicological studies in animals have shown that eltrombopag may cause cataracts. In controlled trials in patients with HCV and thrombocytopenia (n = 1439) receiving interferon therapy, progression of pre-existing cataracts or new-onset cataracts occurred in 8% of patients in the eltrombopag group and 5% in the placebo group. Retinal hemorrhages, mostly grade 1 or 2, were reported in patients with HCV receiving interferon, ribavirin, and eltrombopag (2% in the eltrombopag group and 2% in the placebo group). Hemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within retinal tissue. Regular ophthalmological monitoring, including screening for cataracts, is recommended.
QT/QTc interval prolongation.
A study of QTc interval in healthy volunteers receiving 150 mg eltrombopag daily did not show a clinically significant effect on cardiac repolarization. QTc prolongation has been observed in clinical trials in patients with ITP and in patients with HCV and thrombocytopenia. The clinical significance of these QTc prolongation events is unknown.
Reduced therapeutic effect of eltrombopag treatment.
If the therapeutic effect of eltrombopag treatment decreases or if maintaining a platelet response within recommended doses becomes impossible, causal factors should be investigated, including increased reticulin fiber content in the bone marrow.
Children.
The aforementioned special considerations for the use of eltrombopag in the treatment of ITP should be taken into account when prescribing the drug to children.
Effect on laboratory test results.
Eltrombopag is highly colored and may therefore affect certain laboratory test results. Changes in serum color and interference with total bilirubin and creatinine levels have been observed in patients receiving eltrombopag. If laboratory results and clinical observations are inconsistent, repeat testing using an alternative method may be performed to verify result validity.
Important information on excipients.
This medicinal product contains less than 1 mmol sodium (23 mg)/film-coated tablet, i.e., essentially "sodium-free."
Use during pregnancy or breastfeeding.
Pregnancy.
There are insufficient data on the use of eltrombopag in pregnant women. Animal studies have shown reproductive toxicity of the drug. The potential risk to humans is unknown.
Eltrombopag-Vista is not recommended for use during pregnancy.
Women of reproductive potential / contraception in men and women.
Eltrombopag-Vista is not recommended for the treatment of women of reproductive potential who are not using contraception.
Breastfeeding.
It is unknown whether eltrombopag or its metabolites pass into human breast milk. Animal studies indicate that eltrombopag passes into breast milk; therefore, a risk to the infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or to refrain from eltrombopag treatment, taking into account the expected benefit of treatment for the mother and the potential risk to the child.
Fertility.
Reproductive function in male and female rats was not affected when administered doses comparable to human eltrombopag doses. However, the risk to humans cannot be completely excluded.
Ability to affect reaction speed when driving or operating machinery.
Eltrombopag has a minor influence on the ability to drive or operate machinery. The patient's clinical condition and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, should be considered when assessing the patient's ability to perform tasks requiring concentration and psychomotor speed.
Administration and Dosage.
Treatment with eltrombopag should be initiated and supervised by a physician experienced in the management of hematological disorders or chronic hepatitis C and its complications.
The dosage regimen is individual and is based on the platelet count of each patient. The goal of eltrombopag treatment is not to normalize platelet counts. Treatment of patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP). To achieve and maintain a platelet count ≥ 50,000/μL, the minimum effective dose of eltrombopag should be used. Dose adjustments are based on changes in platelet counts. Eltrombopag should not be used to normalize platelet counts. In clinical studies, increases in platelet counts were observed within 1–2 weeks after initiation of eltrombopag therapy, and decreases in platelet counts were observed within 1–2 weeks after discontinuation of the drug. Adult patients and children aged 6 to 17 years.
The recommended initial dose of eltrombopag is 50 mg once daily. Treatment should be initiated at a reduced dose of 25 mg once daily in patients of East Asian or Southeast Asian ancestry.
Children aged 1 to 5 years.
The recommended initial dose of eltrombopag is 25 mg once daily.
Dose Monitoring and Adjustment.
After initiating eltrombopag treatment, the dose should be adjusted to achieve and maintain a platelet count ≥ 50,000/μL to reduce the risk of bleeding. The dose should not exceed 75 mg per day.
During treatment with eltrombopag, liver function tests and hematological parameters should be monitored regularly, and the eltrombopag dose should be adjusted according to platelet levels as outlined in Table 3. A complete blood count, including platelet count and peripheral blood smear, should be performed weekly until a stable platelet level (≥ 50,000/μL for at least 4 weeks) is achieved. Thereafter, a complete blood count should be performed monthly.
The lowest effective dose of the medicinal product should be used to maintain the required platelet level.
Table 3
Dose adjustment of eltrombopag for patients with ITP
| Platelet count |
Dose |
| < 50000/μL after at least 2 weeks of therapy |
Increase daily dose by 25 mg up to the maximum dose of 75 mg per day.* |
| ≥ 50000/μL and ≤ 150000/μL |
Use the lowest effective dose of eltrombopag and/or concomitant ITP medication to maintain platelet counts that prevent or reduce bleeding. |
| > 150000/μL and ≤ 250000/μL |
Decrease daily dose by 25 mg. Wait 2 weeks to assess the effect and for further appropriate dose adjustment.** |
| > 250000/μL |
Discontinue eltrombopag, increase platelet monitoring frequency to twice weekly. When platelet count is ≤ 100000/μL, restart eltrombopag at a daily dose reduced by 25 mg. |
* For patients receiving eltrombopag therapy at a dose of 25 mg once daily, increase the dose to 25 mg once daily.
** For patients receiving eltrombopag therapy at a dose of 25 mg once daily, reinitiate treatment at a dose of 25 mg every other day.
Eltrombopag may be used in addition to other medicinal products for the treatment of ITP. Concomitant medicinal products for the treatment of ITP should be adjusted according to the clinical condition in order to avoid excessive increase in platelet count during eltrombopag treatment.
At least 2 weeks should be waited after each dose adjustment before making any further adjustments, in order to observe the patient's platelet response to treatment.
The standard increment for increasing or decreasing the daily dose of eltrombopag is 25 mg per day.
Discontinuation of treatment.
Eltrombopag treatment should be discontinued if platelet counts do not increase to a level sufficient to avoid clinically significant bleeding after 4 weeks of treatment with eltrombopag at a dose of 75 mg once daily.
Patients should be periodically clinically evaluated and decisions regarding continuation of treatment should be made on an individual basis. In patients with intact spleen, splenectomy should be considered. Thrombocytopenia may recur after discontinuation of treatment.
Treatment of thrombocytopenia in adult patients with chronic HCV.
When eltrombopag is used in combination with antiviral agents, refer to the prescribing information for these agents.
In clinical studies, increases in platelet counts were generally observed within 1 week after initiation of eltrombopag treatment. The goal of treatment should be to achieve the minimum required platelet count necessary to initiate antiviral therapy. During antiviral therapy, the treatment goal should be to maintain platelet counts at a level that prevents bleeding—typically 50,000–75,000/μL. Platelet counts >75,000/μL should be avoided. The lowest effective dose of eltrombopag should be used to achieve and maintain the platelet count required to initiate and optimize antiviral therapy. Dose selection is based on platelet count recovery.
Initial dose.
The initial dose of the medicinal product is 25 mg once daily. Dose adjustment is not required for patients of East/Southeast Asian ancestry or for patients with mild hepatic impairment.
Dose monitoring and adjustment.
The dose of eltrombopag should be increased by 25 mg every 2 weeks until the platelet count optimal for initiating antiviral therapy is achieved. Platelet counts should be monitored weekly prior to initiation of antiviral therapy. Platelet counts may decrease at the start of antiviral therapy; therefore, immediate dose adjustment is not recommended (see Table 3).
During antiviral therapy, the dose of eltrombopag should be adjusted to avoid dose reduction of pegylated interferon, as decreasing platelet counts increase the risk of bleeding in patients (see Table 4). Platelet counts should be monitored weekly until a stable level is achieved, typically 50,000–75,000/μL. Thereafter, complete blood counts, including platelet count and peripheral blood smear, should be monitored monthly.
Consider reducing the dose by 25 mg daily if platelet counts exceed the required level. The effect of the new dose should be evaluated after 2 weeks, and further dose adjustments decided accordingly.
The dose should not exceed 100 mg per day.
Table 4
Dose adjustment of eltrombopag for patients with chronic viral hepatitis C during antiviral therapy
| Platelet count |
Dosing |
| < 50,000/μL after at least 2 weeks of therapy |
Increase daily dose by 25 mg, but not exceeding 100 mg per day. |
| ≥ 50,000/μL and ≤ 100,000/μL |
The lowest eltrombopag dose that allows avoidance of peginterferon dose reduction. |
| ≥ 100,000/μL and ≤ 150,000/μL |
Reduce daily dose to 25 mg. Assess response to the new dose after 2 weeks and make further dose adjustment decisions accordingly*. |
| > 150,000/μL |
Discontinue eltrombopag; increase platelet monitoring frequency to twice weekly. Once platelet count is ≤ 100,000/μL, resume therapy at a daily dose reduced by 25 mg**. |
* At the beginning of antiviral therapy, platelet counts may decrease; therefore, immediate dose adjustment is not recommended.
** For patients receiving eltrombopag at a dose of 25 mg once daily, reinitiation of treatment at a dose of 25 mg should be attempted after a 1-day interval.
Discontinuation of treatment.
If the required platelet count for initiating antiviral therapy has not been achieved after 2 weeks of treatment with eltrombopag 100 mg, eltrombopag should be discontinued.
Eltrombopag treatment should be discontinued if antiviral therapy is discontinued. Excessively high platelet counts or severe abnormalities in liver function tests also require discontinuation of treatment.
Severe aplastic anemia.
Initial dose.
The initial dose of eltrombopag is 50 mg once daily. For patients of East or Southeast Asian ancestry, treatment with eltrombopag should be initiated at a dose of 25 mg once daily. Treatment should not be initiated in patients with known chromosome 7 cytogenetic abnormalities.
Dose monitoring and adjustment.
Hematologic response requires dose titration, typically up to 150 mg, and may take up to 16 weeks from the start of eltrombopag treatment. The dose of eltrombopag should be adjusted in 50-mg increments every 2 weeks to achieve the required platelet count of ≥ 50,000/μL. For patients taking 25 mg once daily, the dose should first be increased to 50 mg per day, followed by further increases in 50-mg increments. The daily dose should not exceed 150 mg. During eltrombopag therapy, clinical hematological parameters and liver function tests should be monitored, and the eltrombopag dose should be adjusted according to platelet counts as specified in Table 5.
Table 5
Eltrombopag dose adjustment for patients with severe aplastic anemia
| Platelet count |
Dose adjustment or response |
| < 50,000/μL after at least 2 weeks of therapy |
Increase daily dose by 50 mg up to the maximum dose of 150 mg per day. For patients taking 25 mg once daily, first increase to 50 mg per day, then increase the dose by 50 mg increments. |
| From ≥ 50,000/μL to ≤ 150,000/μL |
Use the lowest eltrombopag dose sufficient to maintain platelet count. |
| From > 150,000/μL to ≤ 250,000/μL |
Decrease daily dose by 50 mg. Wait two weeks to assess effects and further adjust dose (if necessary). |
| > 250,000/μL |
Discontinue eltrombopag for at least one week. Resume therapy when platelet count reaches ≤ 100,000/μL, reducing the daily dose by 50 mg. |
Gradual dose reduction for patients who respond in three parameters (white blood cell, red blood cell, and platelet counts).
For patients who have achieved a response in all three parameters, including no need for transfusions for at least 8 weeks: the dose of eltrombopag may be reduced by 50%.
If blood counts remain stable after 8 weeks at the reduced dose, eltrombopag should be discontinued and blood counts should be monitored. If platelet count drops to < 30,000/µL, hemoglobin to < 9 g/dL, or absolute neutrophil count to < 0.5 × 10⁹/L, eltrombopag may be restarted at the previous effective dose.
Discontinuation of treatment.
If no hematological response is observed after 16 weeks of therapy, eltrombopag should be discontinued. If no new cytogenetic abnormalities are detected, consideration should be given to whether continuing eltrombopag is appropriate. Eltrombopag should be discontinued in the case of excessive platelet counts (as specified in Table 4) or significant deviations in liver function tests from normal values.
Special populations.
Renal impairment. Dose adjustment is not required. Treatment of patients with renal impairment should be conducted with caution, and serum creatinine levels and/or urine tests should be monitored.
Hepatic impairment. Eltrombopag should not be used to treat patients with ITP and hepatic impairment (Child-Pugh score ≥ 5) unless the anticipated benefit outweighs the identified risk of portal vein thrombosis (see section "Special precautions").
If eltrombopag use is considered necessary for the treatment of idiopathic thrombocytopenic purpura, the initial dose should be 25 mg once daily. The dose of eltrombopag in patients with hepatic impairment should not be increased earlier than 3 weeks after initiation of therapy.
For patients with chronic HCV and hepatic impairment (Child-Pugh score ≤ 6), dose adjustment is not required. Patients with chronic HCV and patients with severe aplastic anemia and hepatic impairment should start eltrombopag treatment at a dose of 25 mg once daily. The dose of eltrombopag in patients with hepatic impairment should not be increased earlier than 2 weeks after initiation of therapy. An increased risk of adverse effects, including hepatic decompensation and thromboembolic complications, has been observed in patients with chronic liver disease treated with eltrombopag during preparation for invasive procedures or during antiviral therapy for HCV (see sections "Special precautions" and "Adverse reactions").
Elderly patients. Data on the use of eltrombopag for the treatment of ITP patients aged 65 years and older are limited; there is no clinical experience in ITP patients aged 85 years and older. Overall, clinical studies with eltrombopag have not revealed a substantial difference in safety between patients under 65 years of age and those over 65 years of age. Other clinical observations have not shown differences in therapeutic effect between elderly and younger patients, but increased sensitivity in some elderly patients cannot be ruled out. Data on the use of eltrombopag for the treatment of HCV patients aged 75 years and older are limited. This medication should be prescribed with caution to these patients (see section "Special precautions").
Patients of East/Southeast Asian origin. For children and adult patients from East and Southeast Asian countries, including those with hepatic impairment, the initial dose of eltrombopag should be 25 mg once daily (see section "Pharmacokinetics").
Platelet counts should be monitored and dose adjustments should be guided by standard criteria.
Method of administration.
Oral use.
Tablets should be taken at least 2 hours before or 4 hours after consuming any products such as antacids, dairy products (or other calcium-containing products), or mineral supplements containing polyvalent cations (e.g., iron, calcium, magnesium, aluminum, selenium, and zinc) (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").
Children.
Eltrombopag-Vista, film-coated tablets, is not recommended for the treatment of children under 1 year of age with chronic ITP due to insufficient data on efficacy and safety of the medicinal product.
There are no data on the efficacy and safety of eltrombopag in children and adolescents (< 18 years) with thrombocytopenia associated with chronic HCV or SAA. Data are lacking.
Overdose.
Symptoms. One case of overdose was reported during clinical trials in patients with ITP, in which a patient took 5000 mg of eltrombopag. Adverse reactions included mild rash, transient bradycardia, fatigue, and elevated transaminase levels. Liver enzyme levels measured between days 2 and 18 after overdose were 1.6 times the upper limit of normal for AST, 3.9 times for ALT, and 2.4 times for total bilirubin. Platelet count was 672,000/µL on day 18 after overdose, with a maximum platelet count of 929,000/µL. All adverse reactions resolved after treatment without complications.
Treatment. Overdose may lead to excessive increase in platelet count and may cause thrombotic/thromboembolic complications. In case of overdose, oral cation-containing metal products such as calcium, aluminum, or magnesium should be administered to form chelate complexes with eltrombopag and limit its absorption. Platelet levels should be closely monitored. Reinitiation of eltrombopag treatment may be considered according to the provided recommendations (see section "Dosage and administration").
Since eltrombopag is not significantly eliminated by the kidneys and is highly protein-bound, hemodialysis is not expected to be an effective method for eliminating eltrombopag.
Adverse Reactions
Immune thrombocytopenia in adult and pediatric patients with ITP.
The safety of eltrombopag was evaluated in adult patients (n = 763) from the combined double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE), and TRA113765, in which 403 patients received eltrombopag and 179 received placebo, as well as from completed open-label studies (n = 360) TRA108057 (REPEAT), TRA105325 (EXTEND), and TRA112940. Patients received the investigational product for up to 8 years (in EXTEND). The most serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic complications. The most common adverse reactions occurring in at least 10% of patients included: nausea, diarrhea, increased alanine aminotransferase levels, and back pain.
The safety of eltrombopag in pediatric patients (aged 1 to 17 years) with previously treated ITP was demonstrated in two studies (n = 171). PETIT2 (TRA115450) was a double-blind, open, randomized, placebo-controlled study consisting of two parts. Patients were randomized in a 2:1 ratio to receive eltrombopag (n = 63) or placebo (n = 29) for 13 weeks during the randomized period of the study. PETIT (TRA108062) was an open-label, double-blind, randomized, placebo-controlled study conducted in cohorts with staggered enrollment and consisting of three parts. Patients were randomized in a 2:1 ratio to receive eltrombopag (n = 44) or placebo (n = 21) for 7 weeks. The adverse reaction profile was comparable to that observed in adults, with the addition of certain adverse reactions marked with "♦" in the table below. The most commonly reported adverse reactions in children with ITP aged 1 year and older (≥ 3% and more frequent than in the placebo group) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache, and rhinorrhea.
Thrombocytopenia associated with hepatitis C virus in adult patients.
ENABLE 1 (TPL103922, n = 716, n = 715 treated with eltrombopag) and ENABLE 2 (TPL108390, n = 805) were randomized, double-blind, placebo-controlled, multicenter studies evaluating the safety and efficacy of eltrombopag in patients with thrombocytopenia associated with hepatitis C virus who would otherwise be eligible to initiate antiviral therapy. In the hepatitis C studies, the safety population consisted of all randomized patients who received study treatment during the double-blind period of part 2 of ENABLE 1 (eltrombopag treatment n = 450, placebo treatment n = 232) and ENABLE 2 (eltrombopag treatment n = 506, placebo treatment n = 252). Patients were analyzed according to the treatment regimen received (overall safety population in the double-blind period: eltrombopag n = 955, placebo n = 484).
The most serious adverse reactions identified during ITP or HCV treatment studies were hepatotoxicity and thrombotic/thromboembolic complications. The most common adverse reactions (occurring in at least 10% of patients) of any grade in the ITP or HCV treatment studies were: headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, hyperbilirubinemia, alopecia, pruritus, muscle pain, fever, fatigue, influenza-like illness, asthenia, chills, and peripheral edema.
Severe aplastic anemia in adult patients.
The safety of eltrombopag in severe aplastic anemia was evaluated in an uncontrolled, open-label study involving 43 patients, in which 11 patients (26%) received treatment for > 6 months and 7 patients (16%) received treatment for > 1 year. The most serious adverse reactions were febrile neutropenia and sepsis/infection. The most common adverse reactions occurring in at least 10% of patients included: headache, dizziness, insomnia, cough, dyspnea, oropharyngeal pain, rhinorrhea, nausea, diarrhea, abdominal pain, increased transaminase levels, ecchymosis, arthralgia, muscle spasms, limb pain, fatigue, febrile neutropenia, and pyrexia.
Adverse reactions reported in studies involving 763 adult patients and 171 pediatric patients with ITP, 1520 patients with HCV, 43 patients with SAA, and in post-marketing reports are listed below according to MedDRA (Medical Dictionary for Regulatory Activities) system organ class and frequency of occurrence. Within each organ system class, adverse drug reactions are listed in descending order of frequency, starting with the most common. The frequency of adverse reactions is categorized using the following convention (CIOMS III): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).
Treatment of ITP.
| Organ systems |
Frequency |
Adverse reaction |
| Infections and infestations |
Very common |
Nasopharyngitis♦, upper respiratory tract infection♦ |
| Common |
Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infections, gingivitis |
|
| Uncommon |
Skin infection |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Uncommon |
Rectosigmoid colon cancer |
| Blood and lymphatic system disorders |
Common |
Anemia, eosinophilia, leukocytosis, thrombocytopenia, decreased hemoglobin levels, decreased leukocyte count |
| Uncommon |
Anisocytosis, hemolytic anemia, myelocytosis, increased levels of band neutrophils, presence of myelocytes, increased platelet count, increased hemoglobin levels |
|
| Immune system disorders |
Uncommon |
Hypersensitivity |
| Metabolism and nutrition disorders |
Common |
Hypokalemia, decreased appetite, increased blood uric acid levels |
| Uncommon |
Anorexia, gout, hypocalcemia |
|
| Psychiatric disorders |
Common |
Sleep disorders, depression |
| Uncommon |
Apathy, mood changes, tearfulness |
|
| Nervous system disorders |
Common |
Paresthesia, hypesthesia, somnolence, migraine |
| Uncommon |
Tremor, balance disorder, dysesthesia, hemiparesis, migraine with aura, peripheral neuropathy, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache |
|
| Eye disorders |
Common |
Dry eyes, blurred vision, eye pain, decreased visual acuity |
| Uncommon |
Lenticular opacities, astigmatism, cortical cataract, increased lacrimation, retinal hemorrhages, retinal pigment epitheliopathy, vision deterioration, visual acuity disorder, blepharitis and dry keratoconjunctivitis |
|
| Ear and labyrinth disorders |
Common |
Ear pain, vertigo |
| Cardiac disorders |
Uncommon |
Tachycardia, acute myocardial infarction, cardiovascular disorders, cyanosis, sinus tachycardia, QT interval prolongation on electrocardiogram |
| Vascular disorders |
Common |
Deep vein thrombosis, hematoma, hot flushes |
| Uncommon |
Embolism, superficial thrombophlebitis, facial flushing |
|
| Respiratory, thoracic and mediastinal disorders |
Very common |
Cough♦ |
| Common |
Oropharyngeal pain♦, rhinorrhea♦ |
|
| Uncommon |
Pulmonary embolism, lung infarction, nasal discomfort, development of blisters and pain in oropharynx, nasal sinus complications, sleep apnea syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea, diarrhea |
| Common |
Oral ulcer, dry mouth, toothache♦, vomiting, abdominal pain*, oral hemorrhage, bloating. |
|
| Uncommon |
Dry mouth, glossodynia, abdominal tenderness, discolored stools, food poisoning, frequent defecation, hematemesis, oral discomfort |
|
| Hepatobiliary disorders |
Very common |
Increased alanine aminotransferase levels† |
| Common |
Increased aspartate aminotransferase levels†, hyperbilirubinemia, liver function abnormalities |
|
| Uncommon |
Cholestasis, hepatic damage, hepatitis, drug-induced liver injury |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash, alopecia, hyperhidrosis, generalized pruritus, petechiae |
| Uncommon |
Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorders, skin discoloration, skin exfoliation |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Back pain |
| Common |
Myalgia, muscle cramps, musculoskeletal pain, bone pain |
|
| Uncommon |
Muscle weakness |
|
| Renal and urinary disorders |
Common |
Proteinuria, increased blood creatinine levels, thrombotic microangiopathy with renal failure‡ |
| Uncommon |
Renal failure, leukocyturia, lupus nephritis, nocturia, increased blood urea levels, increased urine protein/creatinine ratio |
|
| Reproductive system and breast disorders |
Common |
Menorrhagia |
| General disorders and administration site conditions |
Common |
Pyrexia*, chest pain, asthenia |
| Uncommon |
Feeling of warmth, hemorrhage at puncture site, feeling of anxiety, wound inflammation, malaise, foreign body sensation |
|
| Investigations |
Common |
Increased blood alkaline phosphatase levels |
| Uncommon |
Increased blood albumin levels, increased total protein levels, decreased blood albumin levels, increased urine pH |
|
| Injury, poisoning and procedural complications |
Uncommon |
Sunburn |
♦ Additional adverse reactions observed during pediatric studies (in children aged 1 to 17 years).
† Elevations in alanine aminotransferase and aspartate aminotransferase levels may occur simultaneously, although less frequently.
‡ Grouped under preferred terms: acute kidney injury and renal failure.
Treatment of HCV (in combination with antiviral therapy using interferon and ribavirin).
| System Organ Classes |
Frequency |
Adverse Reaction |
| Infections and infestations |
Common |
Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes |
| Uncommon |
Gastroenteritis, pharyngitis |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Common |
Hepatic malignancies |
| Blood and lymphatic system disorders |
Very common |
Anemia |
| Common |
Lymphopenia |
|
| Uncommon |
Hemolytic anemia |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Hyperglycemia, pathological weight loss |
|
| Psychiatric disorders |
Common |
Depression, restlessness, sleep disorder |
| Uncommon |
Altered consciousness, excitement |
|
| Nervous system disorders |
Very common |
Headache |
| Common |
Dizziness, attention disturbance, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paresthesia |
|
| Eye disorders |
Common |
Cataract, retinal exudates, dry eyes, yellowing of eyes, retinal hemorrhage |
| Ear and labyrinth disorders |
Common |
Vertigo |
| Cardiac disorders |
Common |
Palpitations |
| Respiratory, thoracic and mediastinal disorders |
Very common |
Cough |
| Common |
Dyspnea, oropharyngeal pain, dyspnea on exertion, productive cough |
|
| Gastrointestinal disorders |
Very common |
Nausea, diarrhea |
| Common |
Vomiting, ascites, stomach pain, upper abdominal pain, dyspepsia, dry mouth, constipation, bloating, toothache, stomatitis, gastroesophageal reflux disease, hemorrhoids, gastric discomfort, varicose veins |
|
| Uncommon |
Esophageal varices hemorrhage, gastritis, ulcerative stomatitis |
|
| Hepatobiliary disorders |
Common |
Hyperbilirubinemia, jaundice, drug-induced liver injury |
| Uncommon |
Portal vein thrombosis, hepatic failure |
|
| Skin and subcutaneous tissue disorders |
Very common |
Pruritus |
| Common |
Rash, dry skin, eczema, pruritic rash, erythema, hyperhidrosis, generalized pruritus, alopecia |
|
| Uncommon |
Skin lesions, skin color changes, skin hyperpigmentation, night sweats |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Myalgia |
| Common |
Arthralgia, muscle spasms, back pain, limb pain, musculoskeletal pain, bone pain |
|
| Renal and urinary disorders |
Uncommon |
Thrombotic microangiopathy with acute kidney injury†, dysuria |
| General disorders and administration site conditions |
Very common |
Pyrexia, fatigue, influenza-like illness, asthenia, chills |
| Common |
Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, edema, peripheral edema |
|
| Uncommon |
Injection site pruritus, injection site rash, chest discomfort |
|
| Investigations |
Common |
Increased blood bilirubin, weight decreased, leukopenia, hemoglobin decreased, neutropenia, increased international normalized ratio, prolonged activated partial thromboplastin time, increased blood glucose, blood albumin decreased |
| Uncommon |
QT interval prolongation on electrocardiogram |
†Grouped by preferred terms oliguria, renal failure and renal function disorders.
Study population TAA.
| Body systems |
Frequency |
Adverse reaction |
| Blood and lymphatic system disorders |
Common |
Neutropenia, splenic infarction |
| Metabolism and nutrition disorders |
Common |
Iron overload, decreased appetite, hypoglycemia, increased appetite |
| Psychiatric disorders |
Common |
Anxiety, depression |
| Nervous system disorders |
Very common |
Headache, dizziness |
| Common |
Syncope |
|
| Eye disorders |
Common |
Dry eyes, cataract, yellowing of eyes, blurred vision, vision deterioration, floaters |
| Respiratory, thoracic and mediastinal disorders |
Very common |
Cough, oropharyngeal pain, rhinorrhea |
| Common |
Nosebleeds |
|
| Gastrointestinal disorders |
Very common |
Diarrhea, nausea, gum bleeding, stomach pain |
| Common |
Mucosal blistering in the mouth, oral pain, vomiting, stomach discomfort, constipation, bloating, dysphagia, discolored stools, tongue swelling, gastrointestinal motility disorder, flatulence |
|
| Hepatobiliary disorders |
Very common |
Elevated transaminase levels |
| Common |
Elevated blood bilirubin levels (hyperbilirubinemia), jaundice |
|
| Unknown |
Drug-induced liver injury* * Cases of drug-induced liver injury have been reported in patients with ITP and HCV. |
|
| Skin and subcutaneous tissue disorders |
Common |
Petechiae, rash, pruritus, urticaria, skin lesions, macular rash |
| Unknown |
Skin color changes, skin hyperpigmentation |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Arthralgia, limb pain, muscle spasms |
| Common |
Back pain, myalgia, bone pain |
|
| Renal and urinary disorders |
Common |
Chromaturia |
| General disorders and administration site conditions |
Very common |
Fatigue, pyrexia, chills |
| Common |
Asthenia, peripheral edema, malaise |
|
| Investigations |
Common |
Elevated blood creatine phosphokinase levels |
Description of some adverse reactions.
Thromboembolic complications.
In 3 controlled and 2 uncontrolled clinical trials involving 446 adult patients with ITP treated with eltrombopag, a total of 19 thromboembolic complications occurred in 17 patients, including (in descending order of frequency) deep vein thrombosis (6), pulmonary embolism (6), acute myocardial infarction (2), cerebral infarction (2), and embolism (1) (see section "Special precautions for use"). In a placebo-controlled clinical trial (228 patients), after 2 weeks of treatment prior to invasive procedures, 7 thromboembolic complications in the portal venous system occurred in 6 out of 143 (4%) adult patients with chronic liver disease treated with eltrombopag, and 3 thromboembolic complications occurred in 2 out of 145 (1%) patients in the placebo group. In 5 out of 6 patients treated with eltrombopag who developed thromboembolic complications, platelet counts were > 200,000/µL.
Except for platelet counts ≥ 200,000/µL, no other specific risk factors were identified in patients who developed thromboembolic complications.
In controlled trials involving patients with thrombocytopenia due to hepatitis C virus (HCV) receiving interferon therapy (n = 1439), thromboembolic events (TEEs) occurred in 38 out of 955 (4%) patients receiving eltrombopag and in 6 out of 484 (1%) patients in the placebo group. These thrombotic/thromboembolic complications included both venous and arterial events. Portal vein thrombosis was the most common TEE in both treatment groups (2% of patients receiving eltrombopag vs. <1% of those receiving placebo) (see section "Special precautions for use"). Patients with low albumin levels (≤35 g/L) or MELD score ≥10 had twice the risk of developing TEE compared to patients with higher albumin levels; patients aged 60 years or older had twice the risk of TEE compared to younger patients.
Hepatic decompensation (when used with interferon).
HCV-infected patients with liver cirrhosis receiving alpha-interferon therapy are at risk of developing hepatic decompensation. In 2 controlled clinical trials involving thrombocytopenic HCV patients, signs of hepatic decompensation (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis) were observed more frequently in the eltrombopag group (11%) than in the placebo group (6%). Patients with low albumin levels (≤35 g/L) or baseline MELD score ≥10 had a threefold higher risk of hepatic decompensation and increased risk of fatal complications compared to those with less advanced liver disease. Eltrombopag should be administered to such patients only after careful assessment of expected benefits versus risks. Close monitoring for signs and symptoms of hepatic decompensation is required when treating patients with these characteristics (see section "Special precautions for use").
Hepatotoxicity risk.
During controlled clinical trials of eltrombopag for the treatment of chronic ITP, increases in serum levels of ALT, AST, and bilirubin were observed. These abnormalities were mild (grade 1–2), reversible, and not associated with clinically significant symptoms indicating impaired liver function. Among participants in 3 placebo-controlled ITP treatment trials, one patient in the placebo group and one in the eltrombopag group developed grade 4 liver failure. In two placebo-controlled trials of eltrombopag in children (aged 1 to 17 years) with chronic ITP, ALT levels more than 3 times the upper limit of normal (ULN) were observed in 4.7% and 0% of patients in the eltrombopag and placebo groups, respectively.
In two controlled clinical trials in HCV-infected patients, AST or ALT levels more than 3 times ULN were observed in 34% and 38% of patients in the eltrombopag and placebo groups, respectively. The use of eltrombopag with pegylated interferon/ribavirin is associated with indirect hyperbilirubinemia. Total bilirubin levels ≥1.5 × ULN were observed in 76% and 50% of patients in the eltrombopag and placebo groups, respectively.
In a non-comparative Phase II study of eltrombopag monotherapy in refractory aplastic anemia, AST or ALT levels more than 3 times ULN and total (indirect) bilirubin levels more than 1.5 times ULN were observed in 5% of patients. Total bilirubin levels more than 1.5 times ULN were observed in 14% of patients.
Thrombocytopenia after discontinuation of treatment.
Based on data from 3 controlled clinical trials, transient decrease in platelet count below baseline levels after discontinuation of treatment was observed in 8% of patients in the eltrombopag group and 8% in the placebo group (see section "Special precautions for use").
Increased bone marrow reticulin levels.
Clinical trials did not reveal evidence of clinically significant bone marrow disorders or clinical signs indicating impaired bone marrow function. In one patient, treatment with eltrombopag was discontinued due to the appearance of reticulin in the bone marrow (see section "Special precautions for use").
Cytogenetic abnormalities.
In a Phase II clinical trial of eltrombopag at an initial dose of 50 mg/day (with dose escalation every 2 weeks up to a maximum of 150 mg/day) (ELT112523) in patients with refractory aplastic anemia, new cytogenetic abnormalities occurred in 17.1% of adult patients (7/41, of whom 4 had chromosome 7 abnormalities). The median time to onset of cytogenetic abnormality was 2.9 months.
In a Phase II clinical trial (ELT116826) in patients with refractory aplastic anemia receiving eltrombopag at a dose of 150 mg/day (with adjustments based on ethnicity or age as indicated), new cytogenetic abnormalities occurred in 22.6% of adult patients (7/31, of whom 3 had chromosome 7 abnormalities). All 7 patients had normal baseline cytogenetic parameters. Six patients developed cytogenetic abnormalities by the third month of eltrombopag treatment, and one patient developed them by the sixth month.
During an uncontrolled open-label study in aplastic anemia, patients underwent bone marrow biopsy and cytogenetic abnormalities were assessed. Eight (19%) patients developed new cytogenetic abnormalities, including 5 patients with chromosome 7 abnormalities. In two ongoing studies (ELT116826 and ELT116643), cytogenetic abnormalities were detected in 4 out of 28 (14%) and 4 out of 62 (6%) patients, respectively.
Hematologic malignancies.
In an uncontrolled open-label study of aplastic anemia, 3 (7%) patients were diagnosed with MDS after treatment with eltrombopag. In two ongoing studies (ELT116826 and ELT116643), MDS and AML were diagnosed in 1 out of 28 (4%) and 1 out of 62 (2%) patients, respectively.
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/
Shelf life. 2 years.
Storage conditions.
No special storage conditions are required for this medicinal product. Keep out of reach of children.
Packaging. 7 tablets per blister; 2 or 4 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Synthon España, S.L. / Synthon Hispania, S.L.
Manufacturer's address and location of its business operations.
C/Castello, n° 1, Sant Boi de Llobregat, Barcelona, 08830, Spain / C/Castello, n° 1, Sant Boi de Llobregat, Barcelona, 08830, Spain