Elpatro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELPTARO (ELPATRO)

Composition:

Active substance: eltrombopag;

1 tablet contains 25 mg or 50 mg or 75 mg of eltrombopag (in the form of eltrombopag olamine);

Excipients: microcrystalline cellulose, mannitol (421), sodium starch glycolate (type A), povidone, magnesium stearate; film coating: Instacoat Universal Yellow A05E04419 (hypromellose, polyethylene glycol, talc, titanium dioxide [E 171], iron oxide yellow [E 172]).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg: yellow, round, bevel-edged, biconvex tablets, film-coated, with the markings «5» and «5» on both sides of the break line on one side and «EH» on the other;

50 mg: yellow, round, bevel-edged, biconvex tablets, film-coated, with the marking «E56» on one side and «H» on the other;

75 mg: yellow, round, bevel-edged, biconvex tablets, film-coated, with the marking «E57» on one side and «H» on the other.

Pharmacotherapeutic group. Antihemorrhagics, systemic hemostatics.

ATC code B02B X05.

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 the human thrombopoietin receptor 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).

The safety and efficacy of eltrombopag in adult patients with previously treated chronic ITP were evaluated in two randomized, double-blind, placebo-controlled phase III studies, RAISE (TRA102537) and TRA100773B, and two open-label studies, REPEAT (TRA108057) and EXTEND (TRA105325).

No clinical trial comparing eltrombopag treatment with other treatment options (e.g., splenectomy) has 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 studied in two trials.

TRA115450 (PETIT2): The primary endpoint was durable response, defined as the proportion of subjects receiving eltrombopag who achieved platelet counts ≥ 50,000/μL for at least 6 out of 8 weeks (in the absence of rescue therapy) during weeks 5 to 12 in the double-blind, randomized phase. Participants had confirmed chronic ITP lasting at least 1 year and had either failed to respond to at least one prior ITP therapy, relapsed during such therapy, or were unable to continue other ITP treatments for medical reasons, and had platelet counts < 30,000/μL. Ninety-two patients were randomized in a 2:1 ratio across three age groups to receive either eltrombopag (n = 63) or placebo (n = 29). The dose of eltrombopag could be adjusted based on individual patient platelet counts.

Overall, a significantly higher 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

Durable platelet response in children with chronic ITP by age group

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 — data 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 their 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, primarily corticosteroids, without requiring emergency therapy.

TRA108062 (PETIT): The primary endpoint was the proportion of participants achieving a platelet count ≥ 50,000/µL at least once between weeks 1 and 6 of the randomized period. Patients had failed to respond to at least one prior ITP therapy or experienced relapse during such therapy and had platelet counts < 30,000/µL (n = 67). During the randomized 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 individual patient platelet counts.

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 treating thrombocytopenia in patients with viral 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, and in the ENABLE 2 study, pegylated interferon alfa-2b plus ribavirin was 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), with platelet counts ≤ 30,000/µL.

Most participants, 33 (77%), were considered to have primary refractory disease, defined as lack of adequate response to prior IST on any parameter. In the other 10 participants, there was 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 a PNH clone in neutrophils ≥ 50%, were excluded from the study. At baseline, the median platelet count was 20,000/µL, hemoglobin levels were 8.4 g/dL, 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 at 12 weeks of eltrombopag treatment. Hematologic response was defined as meeting one or more of the following criteria: increase in platelet count to 20,000/µL from baseline or stabilization of platelet count with independence from transfusions for at least 8 weeks; increase in hemoglobin levels by > 1.5 g/dL or reduction by ≥ 4 units in red blood cell transfusions over 8 consecutive weeks; increase in absolute neutrophil count (ANC) by 100% or 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 on one parameter (13/17, 76%), while at 12 weeks, 3 responses were observed on two parameters and 1 response on three parameters. 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 response on multiple parameters, 4 of the 9 continued therapy, and 5 reduced eltrombopag treatment and maintained response (median follow-up: 20.6 months, range: 5.7 to 22.5 months). The other 5 patients discontinued therapy: three due to relapse after 3 months in the 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 conducted 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 to treat adults with idiopathic thrombocytopenic purpura (ITP) are as follows: when administered at a dose of 50 mg once daily, the maximum plasma concentration (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 to treat adult patients with chronic viral hepatitis C (HCV) are as follows: when administered at a dose of 50 mg once daily, the maximum plasma concentration (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 equivalent doses of eltrombopag are administered, its exposure in treating patients with chronic HCV is higher than its exposure in treating 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, oral absorption of drug-related substances after a single 75 mg dose of eltrombopag 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 it is 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 excreted in feces (59%), with 31% of the dose recovered in urine as metabolites. Unchanged eltrombopag is 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 certain UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not expected due to the limited impact of UGT enzymes on the glucuronidation of eltrombopag 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 the exposure of 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 groups.

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 reduced in patients with renal impairment, there is considerable variability in exposure parameters when comparing patients with renal impairment to healthy volunteers. Eltrombopag should be used with caution in patients with renal impairment and under continuous monitoring, for example, 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 considerable variability in exposure parameters when comparing patients with hepatic impairment to healthy volunteers.

The effect of hepatic impairment on the pharmacokinetics of eltrombopag after repeated administration was studied by population pharmacokinetic analysis of data from 28 healthy volunteers and 714 patients with impaired liver function (673 patients with HCV and 41 patients with chronic liver disease of other etiology). Of these 714 patients, 642 had mild liver dysfunction, 67 had moderate liver dysfunction, and 2 had severe liver 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 patients with ITP and hepatic impairment (Child–Pugh score ≥ 5) unless the expected benefit outweighs the risk of portal vein thrombosis (see sections "Dosage and administration" and "Special precautions").

Eltrombopag should be used with caution in patients with hepatic impairment. For patients with chronic ITP and mild, moderate, or severe hepatic impairment, treatment with eltrombopag should be initiated 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 individuals) and 88 patients with ITP (18 East Asian individuals). According to population pharmacokinetic analysis, AUC values of eltrombopag in East Asian patients with ITP 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 patients with HCV (145 East Asian and 69 Southeast Asian individuals). Based on population pharmacokinetic analysis estimates, AUC values of eltrombopag in East/Southeast Asian patients were approximately 55% higher compared to patients of other races, primarily Caucasians (see section "Dosage and administration").

Sex.

The effect of sex on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy adults (14 women) and 88 patients with ITP (57 women). According to population pharmacokinetic analysis, AUC values of eltrombopag in female patients with ITP were approximately 23% higher than in male patients, without correction for body weight.

The effect of sex on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 635 patients with HCV (260 women). According to modeling results, AUC values of eltrombopag 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 patients with HCV, and 41 patients with chronic disease of other etiology aged 19 to 74 years. Pharmacokinetic data for eltrombopag in patients aged 75 years and older are lacking. According to population pharmacokinetic analysis, AUC values of eltrombopag in elderly patients (≥ 65 years) were 41% higher compared to younger patients.

Children (1 to 17 years).

According to clinical study data, the clearance of eltrombopag from plasma after oral administration increases with increasing body weight. The effects of race and sex on the pharmacokinetic parameters of eltrombopag in pediatric and adult patients are similar. AUC values of eltrombopag in East/Southeast Asian patients were approximately 43% higher compared to patients of other races. AUC values of eltrombopag in female patients with ITP were approximately 25% higher compared to male patients.

Pharmacokinetic parameters of eltrombopag in children with ITP are presented in Table 2.

Table 2

Mean plasma pharmacokinetic parameters of eltrombopag at steady state in children 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 (ITP) who are refractory to other medicinal treatments (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 from the time of diagnosis, who are refractory to other medicinal treatments (e.g., corticosteroids, immunoglobulins).

For the treatment of thrombocytopenia in adult patients with chronic hepatitis C (HCV), when the degree of thrombocytopenia is the main factor preventing initiation or limiting the ability to continue optimal interferon-based therapy.

For the treatment of adult patients with severe acquired aplastic anemia (SAA) who have not previously received immunosuppressive therapy or who 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 (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors.

In vitro studies have demonstrated that eltrombopag is not a substrate of organic anion transporting polypeptides (OATP1B1), but is an inhibitor of these transporters. In vitro studies also showed that eltrombopag is both 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%). Interactions with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, are also expected. When co-administered with eltrombopag, statin doses should be reduced and statin-induced 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) in vitro does not inhibit CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 4A4/5, and 4A9/11, and inhibits CYP2C8 and CYP2C9 when paclitaxel and diclofenac are used as probe substrates. Administration of 75 mg eltrombopag to 24 healthy male volunteers did not inhibit or induce the metabolism of probe 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. Co-administration of a single 200 mg dose of eltrombopag with 750 mg telaprevir every 8 hours does not alter telaprevir plasma concentrations.

Concomitant administration of a single 200 mg dose of eltrombopag with 800 mg boceprevir every 8 hours does not change AUC(0–τ), but increases Cmax by 20% and decreases 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 both 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 administration of eltrombopag with cyclosporine. An increase in eltrombopag dose may be required based on platelet count.

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.

Lopinavir/ritonavir.

Co-administration of eltrombopag with lopinavir/ritonavir (LPV/R) may reduce eltrombopag concentrations. A study in 40 healthy volunteers showed that co-administration of a single 100 mg dose of eltrombopag with LPV/R 400/100 mg twice daily resulted in a 17% reduction in eltrombopag plasma AUC0–∞. Therefore, eltrombopag should be used with caution when co-administered with lopinavir/ritonavir. Platelet counts should be carefully monitored when initiating or discontinuing concomitant lopinavir/ritonavir therapy to ensure appropriate eltrombopag dosing.

Inhibitors and inducers of CYP1A2 and CYP2C8.

Eltrombopag is metabolized via 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 a pharmacokinetic interaction study indicate that co-administration of a single 200 mg dose of eltrombopag with repeated doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours 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. When eltrombopag is used concomitantly with other medicinal products for the treatment of ITP, platelet counts should be monitored to maintain them within the recommended range (see section "Dosage and administration").

Interaction with food.

Administration of eltrombopag in tablet form with food high in calcium (e.g., food containing dairy products) significantly reduced AUC0–∞ and Cmax. In contrast, administration of eltrombopag 2 hours before or 4 hours after food 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 standard high-calorie, high-fat meal including dairy products reduced plasma AUC of eltrombopag by 59% and Cmax by 65%.

Administration of a single 25 mg dose of eltrombopag oral suspension powder with a moderate-calorie meal high in calcium and moderate 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 meal high in calcium (mean AUC0–∞ decreased by 20%, mean Cmax decreased by 14%).

Foods low in calcium (<50 mg calcium), including fruits, lean ham, beef, and unfortified (without added calcium, magnesium, or iron) fruit juice, unfortified soy milk, and unfortified cereals, do not significantly affect eltrombopag plasma exposure, regardless of caloric content or fat content.

Special precautions for use.

In patients with chronic HCV and thrombocytopenia and advanced chronic liver disease, there is an increased risk of adverse reactions, including potentially fatal hepatic failure and thromboembolic complications. This increased risk is defined by 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 these 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 antiviral therapy support requires intervention. If treatment is clinically indicated, careful monitoring of these patients is required.

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.

Hepatotoxicity risk.

Eltrombopag may cause liver function abnormalities and induce serious hepatotoxic effects, which may be life-threatening (see section "Adverse reactions").

Serum ALT, AST, and bilirubin levels 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 the development of indirect hyperbilirubinemia. If bilirubin is 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 normalization or stabilization. Eltrombopag treatment should be discontinued if ALT levels increase (≥ 3 × ULN in patients with normal liver function or ≥ 3 × baseline level or > 5 × ULN, whichever is lower, in patients with elevated transaminases before treatment), and also in the following cases:

• disease progression;
• persistence of abnormalities for ≥ 4 weeks;
• concomitant elevation of direct bilirubin;
• occurrence 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 ITP and liver impairment should initiate 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 studies in patients with HCV and thrombocytopenia, signs of hepatic failure (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis) were reported 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 increased risk of fatal adverse events compared to those with less advanced liver disease. Furthermore, 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 these patients only after careful consideration 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 appropriate medical instructions. Eltrombopag treatment should be discontinued if antiviral therapy is stopped due to hepatic failure.

Thrombotic/thromboembolic complications.

In controlled studies 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 specific associations were 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 these patients only after careful consideration of expected benefits and potential risks. Close monitoring for signs and symptoms of TEC development is necessary in such patients.

An increased risk of TECs has been established in patients with chronic liver failure (CLF) when eltrombopag is administered at a dose of 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 event in the portal venous system and one myocardial infarction). In 5 of 6 patients receiving eltrombopag, thrombotic complications occurred with platelet counts > 200,000/μL within 30 days of the last dose. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver failure in preparation for invasive procedures.

According to clinical studies with eltrombopag in patients with ITP, thromboembolic events were observed at both low and normal platelet levels. Eltrombopag should be prescribed with caution in patients with risk factors for thromboembolism, including hereditary (e.g., factor V Leiden) or acquired risk factors (e.g., antithrombin III deficiency, antiphospholipid syndrome), advanced age, prolonged immobilization, malignancies, contraceptives and hormone replacement therapy, surgical interventions/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 balance should always be carefully weighed when treating patients at risk of TECs of any etiology.

In clinical trials for refractory AA, no cases of TECs were reported; however, the risk of these 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 due to the nature of the response, TEC development can be expected in this patient population.

Eltrombopag should not be used to treat patients with moderate to severe hepatic impairment (Child–Pugh score ≥ 5) unless the potential benefit outweighs the risk of portal vein thrombosis. If a decision is made to use the drug, eltrombopag should be administered with caution for the treatment of patients with ITP and hepatic impairment (see sections "Dosage and administration" and "Adverse reactions").

Bleeding after discontinuation of eltrombopag treatment.

After discontinuation of eltrombopag treatment 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 and in some cases causing bleeding. This risk is increased if eltrombopag treatment is discontinued while anticoagulants or antiplatelet agents are being used. Upon discontinuation of eltrombopag therapy, treatment for idiopathic thrombocytopenic purpura should be resumed according to existing clinical guidelines. As additional measures, anticoagulant and/or antiplatelet therapy may be discontinued, and anticoagulation or platelet support reviewed. Platelet counts should be checked weekly for 4 weeks after discontinuation of eltrombopag treatment.

In clinical studies of patients with HCV, after discontinuation of peginterferon, ribavirin, and eltrombopag, a higher incidence of gastrointestinal bleeding, including severe and fatal cases, was reported. After therapy discontinuation, patients should be monitored for symptoms of gastrointestinal bleeding.

Bone marrow reticulin formation and risk of bone marrow fibrosis.

Eltrombopag may increase the risk of new or increased reticulin fiber formation in the bone marrow. The significance of this, as with other thrombopoietin receptor agonists (TPO-R), has not yet been established.

A peripheral blood smear should be carefully examined before starting eltrombopag treatment to determine baseline levels of morphological blood cell abnormalities. After establishing a stable dosing regimen, a complete blood count with leukocyte differential should be performed monthly. If immature or dysplastic cells appear, a peripheral blood smear should be analyzed to detect new or worsening morphological abnormalities (e.g., schistocytes, nucleated erythrocytes, immature leukocytes) or cytopenias. If new or worsening morphological abnormalities or cytopenia occur, eltrombopag treatment should be discontinued and a bone marrow biopsy considered, including staining to assess fibrosis.

Progression of pre-existing myelodysplastic syndrome (MDS).

There is a theoretical concern that TPO-R agonists may stimulate the progression of pre-existing hematopoietic neoplasms, such as myelodysplastic syndrome. Thrombopoietin receptor agonists are growth factors that stimulate thrombopoietic precursor cells, their differentiation, and platelet production. Thrombopoietin receptors are primarily present on the surface of myeloid-derived cells.

In clinical studies, use of thrombopoietin receptor agonists in patients with MDS has been associated with transient increases in blast cells and progression of MDS to acute myeloid leukemia (AML).

The diagnosis of ITP or AA in adult and elderly patients should be confirmed by excluding other nosologies presenting with thrombocytopenia, including exclusion of 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 of abnormalities, such as increased peripheral blast cells.

The efficacy and safety of eltrombopag for the treatment of other thrombocytopenic conditions, including MDS or chemotherapy-induced thrombocytopenia, have not been established. Eltrombopag should only be used for approved indications and should not be used for the treatment of thrombocytopenia caused by MDS or any other cause of thrombocytopenia.

Cytogenetic defects and progression to MDS/AML in patients with AA.

Cytogenetic defects are known to occur in patients with AA. It is unknown whether eltrombopag increases the risk of cytogenetic defects 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 dose of 150 mg/day) (ELT112523) in patients with refractory AA, new cytogenetic abnormalities were observed in 17.1% of adult patients [7/41 (4 of whom had changes in chromosome 7)]. The median time to cytogenetic abnormality was 2.9 months.

In a phase II clinical study 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 cytogenetic abnormalities were observed in 22.6% of adult patients [7/31 (3 of whom had changes in chromosome 7)]. All 7 patients had normal cytogenetic parameters at baseline. Cytogenetic defects were observed in six patients by the third month of eltrombopag treatment and in one patient by the sixth month.

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 the third and sixth months of treatment. If new cytogenetic defects are detected, the appropriateness of continuing eltrombopag treatment should be evaluated.

Cataract and other ocular changes.

Toxicological studies in animals have reported cases of cataract development with eltrombopag use. In controlled studies in patients with HCV and thrombocytopenia (n = 1439) receiving interferon therapy, progression of pre-existing cataract or newly diagnosed cataract occurred in 8% of the eltrombopag group and 5% of the placebo group. Retinal hemorrhages, mostly grade 1 or 2, were recorded in patients with HCV receiving interferon, ribavirin, and eltrombopag (2% in the eltrombopag group and 2% in the placebo group). Hemorrhages occurred on the retinal surface (preretinal), under the retina (subretinal), or within retinal tissue. Regular ophthalmological monitoring of patients is recommended, including for the detection of cataracts.

QT/QTc interval prolongation.

A study of QTc interval in healthy volunteers receiving 150 mg eltrombopag daily did not show clinically significant effects on cardiac repolarization. QTc prolongation has been reported in clinical trials involving patients with ITP and patients with HCV and thrombocytopenia. The clinical significance of these QTc prolongation cases is unknown.

Reduced therapeutic effect of eltrombopag treatment.

If a reduced therapeutic effect of treatment or inability to maintain platelet response to eltrombopag treatment within recommended doses occurs, causal factors should be investigated, including increased reticulin fiber content in the bone marrow.

Children.

The aforementioned special features of eltrombopag use for the treatment of ITP should be considered when prescribing the drug to children.

Effect on laboratory test results.

Eltrombopag is strongly colored and may therefore affect certain laboratory test results. Changes in serum color and effects on total bilirubin and creatinine levels have been observed in patients receiving eltrombopag. If laboratory test results and clinical observations are inconsistent, repeat testing using another method may be performed to verify result validity.

Sodium content.

This medicinal product contains less than 1 mmol sodium (23 mg)/film-coated tablet, i.e., practically 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 is not recommended for use during pregnancy.

Women of reproductive potential / contraception in men and women

Eltrombopag is not recommended for the treatment of women of reproductive potential who are not using contraceptive methods.

Breastfeeding

It is unknown whether eltrombopag or its metabolites pass into human breast milk. Animal studies have shown that eltrombopag passes into breast milk; therefore, risk to the infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or to refrain from drug treatment, weighing the expected benefit of treatment for the mother against 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, risk to humans cannot be completely excluded.

Ability to affect reaction speed when driving vehicles or operating machinery.

Eltrombopag has a minor influence on reaction speed when driving vehicles or operating 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 attention and psychomotor speed.

Method of Administration and Dosage

Treatment with eltrombopag should be initiated and conducted under the supervision of a physician experienced in the management of hematological disorders or chronic hepatitis C and its complications.

The dosage regimen should be individualized according to the patient's platelet count. The goal of eltrombopag treatment should not be to normalize platelet counts.

Treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP).

To achieve and maintain a platelet count ≥ 50,000/μL, the lowest effective dose of eltrombopag should be used. Dose adjustments should be based on changes in platelet counts. Eltrombopag should not be used with the aim of normalizing platelet counts. In clinical studies, increases in platelet counts were observed within 1–2 weeks after initiation of eltrombopag therapy, and platelet counts decreased 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 initiation of eltrombopag treatment, the dose should be adjusted to achieve and maintain a platelet count ≥ 50,000/μL in order to reduce the risk of bleeding. The daily dose should not exceed 75 mg.

During treatment with eltrombopag, liver function tests and hematological parameters should be monitored regularly, and the eltrombopag dose should be adjusted based on platelet counts as outlined in Table 3. A complete blood count, including platelet count and peripheral blood smear, should be performed weekly until a stable platelet count (≥ 50,000/μL for at least 4 weeks) is achieved. Thereafter, complete blood counts should be performed monthly.

The lowest effective dose of the drug should be used to maintain the required platelet count.

Table 3

Dose adjustment of eltrombopag for patients with ITP

Platelet count	Dose adjustment or response
< 50,000/μL after at least 2 weeks of therapy	Increase daily dose by 25 mg up to a maximum dose of 75 mg daily.*
≥ 50,000/μL and ≤ 150,000/μL	Use the lowest effective dose of eltrombopag and/or concomitant ITP medication to maintain platelet counts that prevent bleeding or reduce bleeding.
> 150,000/μL and ≤ 250,000/μL	Decrease daily dose by 25 mg. Wait 2 weeks to assess effect and further appropriate dose adjustment**.
> 250,000/μL	Discontinue eltrombopag, increase frequency of platelet monitoring to twice weekly. When platelet count ≤ 100,000/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 who will receive eltrombopag therapy at a dose of 25 mg once daily, attempt to resume treatment at a dose of 25 mg once daily.

Eltrombopag may be used in addition to other medicinal products for the treatment of ITP. The dose of 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 the previous dose adjustment before each new dose adjustment to allow assessment of the patient's platelet response to treatment.

The standard amount for increasing or decreasing the daily dose of eltrombopag is 25 mg per day.

Discontinuation of treatment.

Eltrombopag treatment should be discontinued if the platelet count does 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, consider the possibility of splenectomy. Thrombocytopenia may recur after discontinuation of treatment (see section "Special precautions").

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, an increase in platelet count was generally observed within 1 week after initiation of eltrombopag treatment. The goal of treatment should be to achieve the minimum necessary platelet count required to initiate antiviral therapy. During antiviral therapy, the goal of treatment should be to maintain platelet count at a level that prevents the risk of bleeding, usually 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 necessary to initiate and optimize antiviral therapy. Dose titration is based on platelet count recovery.

Initial dose.

The initial dose of the drug is 25 mg once daily. Dose adjustment is not required for patients of East/Southeast Asian origin 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 count should be checked weekly before initiation of antiviral therapy. Platelet count may decrease at the start of antiviral therapy; therefore, immediate dose adjustment is not recommended (see Table 4).

During antiviral therapy, the dose of eltrombopag should be adjusted to avoid dose reduction of pegylated interferon, as a decrease in platelet count increases the risk of bleeding in patients (see Table 4). Platelet count should be monitored weekly until a stable level is achieved, usually 50,000–75,000/μL. Thereafter, complete blood count, including platelet count and peripheral blood smear, should be monitored monthly.

Consider reducing the dose by 25 mg daily if the platelet count exceeds 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	Dose adjustment or response
< 50000/μL after at least 2 weeks of therapy	Increase the daily dose by 25 mg, but not exceeding 100 mg per day.
≥ 50000/μL and ≤ 100000/μL	The lowest eltrombopag dose that allows to avoid peginterferon dose reduction.
≥ 100000/μL and ≤ 150000/μL	Reduce the daily dose to 25 mg. After 2 weeks, assess the effect of the new dose and make a decision on further dose adjustment*.
> 150000/μL	Discontinue eltrombopag treatment; increase platelet monitoring frequency to twice weekly. Once platelet count is ≤ 100000/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 should be attempted at a dose of 25 mg once daily.

Discontinuation of treatment.

If the required platelet level for initiation of antiviral therapy has not been achieved after two weeks of treatment with eltrombopag 100 mg, eltrombopag should be discontinued.

Eltrombopag therapy should be discontinued if antiviral therapy is discontinued. Excessively high platelet levels or serious 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/Southeast Asian ancestry, 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, usually up to 150 mg, and may take up to 16 weeks from the start of eltrombopag. The dose of eltrombopag should be adjusted in 50-mg increments every 2 weeks to achieve the required platelet count ≥ 50,000/μL. For patients taking 25 mg once daily, the dose should first be increased to 50 mg per day, and then further increased 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 adjusted according to platelet count as specified in Table 5.

Table 5

Eltrombopag dose adjustment in patients with severe aplastic anemia

Platelet count	Dose adjustment or response
< 50000/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, initially increase to 50 mg per day, then increase the dose by 50 mg increments.
From ≥ 50000/μL to ≤ 150000/μL	Use the lowest eltrombopag dose sufficient to maintain platelet count.
From > 150000/μL to ≤ 250000/μL	Decrease daily dose by 50 mg. Wait two weeks to assess effects and further adjust dose (if necessary).
> 250000/μL	Discontinue eltrombopag; for at least one week. When platelet count reaches ≤ 100000/μL, resume therapy with the daily dose reduced by 50 mg.

Gradual dose reduction in patients responding in three cell lineages (white blood cells, red blood cells, and platelets).

For patients who have achieved a response in all three lineages, including no need for transfusions lasting at least 8 weeks: eltrombopag dose 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 falls to < 30,000/µL, hemoglobin to < 9 g/dL, or absolute neutrophil count (ANC) to < 0.5 × 10^9/L, eltrombopag may be restarted at the previously effective dose.

Discontinuation of treatment.

If no hematologic response is observed after 16 weeks of therapy, eltrombopag should be discontinued. If no new cytogenetic abnormalities are detected, consider whether continuing eltrombopag is appropriate (see sections «Special precautions» and «Adverse reactions»). Eltrombopag should be discontinued in case of excessive platelet count increases (as specified in Table 5) 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 performed with caution, and serum creatinine levels and/or urine analysis should be monitored (see section «Pharmacokinetics»).

Hepatic impairment.

Eltrombopag should not be used to treat patients with ITP and hepatic impairment (Child–Pugh score ≥ 5) unless the expected 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 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 with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily. The dose 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 established 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 in ITP patients aged 65 years and older are limited, and there is no clinical experience with the drug in ITP patients aged 85 years and older. Overall, clinical studies of eltrombopag have not shown a significant difference in safety between patients under 65 years and those 65 years and older. According to other clinical observations, no differences in therapeutic effect have been identified between elderly and younger patients, but increased sensitivity in some elderly patients cannot be ruled out (see section «Pharmacokin游戏副本

Adverse Reactions

Immune thrombocytopenia in adult and pediatric patients

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 patients received placebo, in addition to data from completed open-label studies (n = 360) TRA108057 (REPEAT), TRA105325 (EXTEND), and TRA112940. Patients received the investigational drug for up to 8 years (within 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, elevated alanine aminotransferase levels, and back pain.

The safety of eltrombopag in children (aged 1 to 17 years) with previously treated ITP was demonstrated in two studies (n = 171). PETIT2 (TRA115450) was a double-blind, randomized, placebo-controlled trial consisting of two parts. Patients were randomized in a 2:1 ratio to receive either eltrombopag (n = 63) or placebo (n = 29) for 13 weeks during the randomized phase of the study. PETIT (TRA108062) was an open-label, double-blind, randomized, placebo-controlled study conducted in cohorts with time-delayed patient enrollment, consisting of 3 parts. Patients were randomized in a 2:1 ratio to receive either 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 some adverse reactions marked with a "♦" 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 hepatitis C virus-related thrombocytopenia who were otherwise eligible to initiate antiviral therapy. In the hepatitis C studies, the safety-evaluable population consisted of all randomized patients who received study drug during the double-blind period of part 2 of ENABLE 1 (eltrombopag treatment n = 450, placebo n = 232) and ENABLE 2 (eltrombopag treatment n = 506, placebo n = 252). Patients were analyzed according to the treatment received (overall safety-evaluable population in the double-blind period: eltrombopag n = 955, placebo n = 484).

The most serious adverse reactions observed 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, myalgia, 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 commonly occurring reactions. 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 available data).

Treatment of ITP.

System organ class	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 level, decreased white blood cell 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 opacity, astigmatism, cortical cataract, increased lacrimation, retinal hemorrhages, retinal pigment epitheliopathy, worsening of vision, visual acuity disorders, 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 venous thrombophlebitis, facial redness
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*, bleeding in oral cavity, bloating * Very common in children with ITP
	Uncommon	Dry mouth, glossodynia, abdominal tenderness, discoloration of stools, food poisoning, frequent defecation, hematemesis, oral discomfort
Hepatobiliary disorders	Very common	Increased alanine aminotransferase level†
	Common	Increased aspartate aminotransferase level†, hyperbilirubinemia, liver function abnormalities
	Uncommon	Cholestasis, liver 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 desquamation
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 level, thrombotic microangiopathy with renal failure‡
	Uncommon	Renal failure, leukocyturia, lupus nephritis, nocturia, increased blood urea level, increased urine protein/creatinine ratio
Reproductive system and breast disorders	Common	Menorrhagia
General disorders and administration site conditions	Common	Pyrexia*, chest pain, asthenia * Very common in children with ITP
	Uncommon	Feeling of warmth, hemorrhages at puncture site, anxiety, wound inflammation, malaise, foreign body sensation
Laboratory findings	Common	Increased blood alkaline phosphatase level
	Uncommon	Increased blood albumin level, increased total protein level, decreased blood albumin level, increased urine pH
Injury, poisoning and procedural complications	Uncommon	Sunburn

♦ Additional adverse reactions observed during pediatric studies (in children aged 1 to 17 years).

† Increased levels of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although less frequently.

‡ Grouped under preferred terms: acute kidney injury and renal failure.

During treatment of HCV (in combination with antiviral therapy with interferon and ribavirin).

System organ class	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	Malignant liver neoplasms
Blood and lymphatic system disorders	Very common	Anemia
	Common	Lymphopenia
	Uncommon	Hemolytic anemia
Metabolism and nutrition disorders	Very common	Decreased appetite
	Common	Hypoglycemia, pathological weight loss
Psychiatric disorders	Common	Depression, restlessness, sleep disturbance
	Uncommon	Consciousness disturbance, 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, exertional dyspnea, 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, stomach discomfort, esophageal varices
	Uncommon	Esophageal varices bleeding, 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 syndrome, asthenia, chills
	Common	Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, edema, peripheral edema
	Uncommon	Itching at injection site, rash at injection site, chest discomfort
Investigations	Common	Elevated blood bilirubin, weight loss, decreased white blood cell count, decreased hemoglobin, neutropenia, increased international normalized ratio, prolonged activated partial thromboplastin time, elevated blood glucose, decreased blood albumin
	Uncommon	QT interval prolongation on electrocardiogram

†Grouped by preferred terms oliguria, renal failure and renal function disorders.

Study population TAA.

System organ class	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, jaundice of the eyes, blurred vision, visual impairment, floaters
Respiratory, thoracic and mediastinal disorders	Very common	Cough, oropharyngeal pain, rhinorrhea
	Common	Nosebleed
Gastrointestinal disorders	Very common	Diarrhea, nausea, gum bleeding, stomach pain
	Common	Mouth mucosal blistering, 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 (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, maculopapular 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

Description of some adverse reactions.

Thromboembolic complications.

In three controlled and two uncontrolled clinical studies involving 446 adult patients with ITP treated with eltrombopag, 17 patients experienced a total of 19 thromboembolic complications, including (in descending order of frequency) deep vein thrombosis (n = 6), pulmonary embolism (n = 6), acute myocardial infarction (n = 2), cerebral infarction (n = 2), and embolism (n = 1) (see section "Special precautions for use"). In a placebo-controlled clinical study (n = 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, compared to 3 thromboembolic complications 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 studies involving patients with thrombocytopenia due to HCV who received interferon therapy (n = 1439), thromboembolic complications (TECs) 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 TEC 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 ≥ 10 had twice the risk of developing TECs compared to patients with higher albumin levels; patients aged 60 years or older had twice the risk of TECs compared to younger patients.

Hepatic decompensation (when used with interferon).

Patients with HCV and liver cirrhosis are at risk of hepatic decompensation when receiving alpha-interferon therapy. In two controlled clinical studies involving patients with thrombocytopenia and HCV, 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 an 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 the expected benefits versus risks. Patients with these characteristics require close monitoring for symptoms of hepatic decompensation (see section "Special precautions for use").

Risk of hepatotoxicity.

During controlled clinical trials of eltrombopag for the treatment of chronic ITP, increases in serum levels of ALT, AST, and bilirubin were observed (see section "Special precautions for use").

These abnormalities were mild (Grade 1–2), reversible, and not associated with clinically significant symptoms indicating impaired liver function. Among participants in three placebo-controlled ITP treatment studies, one patient in the placebo group and one patient in the eltrombopag group developed Grade 4 liver failure. In two placebo-controlled studies 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 studies in patients with HCV, 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 in combination with peginterferon/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.

During a non-comparative Phase II study of eltrombopag monotherapy in refractory AA, AST or ALT levels more than 3 times ULN and total (indirect) bilirubin levels more than 1.5 times UL0 were observed in 5 % of patients. Total bilirubin levels more than 1.5 times ULN were observed in 14 % of patients.

Thrombocytopenia following treatment discontinuation.

Based on data from three controlled clinical studies, transient decreases in platelet counts below baseline levels after treatment discontinuation were observed in 8 % of patients in the eltrombopag group and 8 % in the placebo group (see section "Special precautions for use").

Increased reticulin levels in bone marrow.

Clinical studies did not reveal evidence of clinically significant bone marrow disorders or clinical signs indicating impaired bone marrow function. In one patient, eltrombopag treatment 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 study of eltrombopag (ELT112523) in patients with refractory AA receiving an initial dose of 50 mg/day (with dose escalation every 2 weeks up to a maximum of 150 mg/day), new cytogenetic abnormalities were observed in 17.1 % of adult patients (7/41, of whom 4 had abnormalities in chromosome 7). The median time to onset of cytogenetic abnormality was 2.9 months.

In another Phase II clinical study (ELT116826) in patients with refractory AA receiving eltrombopag at a dose of 150 mg/day (with adjustments based on ethnicity or age according to indications), new cytogenetic abnormalities were observed in 22.6 % of adult patients (7/31, of whom 3 had abnormalities in chromosome 7). 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 AA, patients underwent bone marrow biopsy and cytogenetic abnormalities were assessed. Eight (19 %) patients developed new cytogenetic abnormalities, including 5 patients with abnormalities in chromosome 7. 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.

Based on data from an uncontrolled open-label study in AA, 3 (7 %) patients were diagnosed with MDS after eltrombopag treatment. 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 registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of 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.

Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of business operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.