Revolade film-coated tablets 25 mg blister No. 28

Instructions Revolad film-coated tablets 25 mg blister No. 28

Composition

active ingredient: eltrombopag;

1 tablet contains 25 or 50 mg of eltrombopag (as eltrombopag olamine);

excipients: magnesium stearate, mannitol (E 421), microcrystalline cellulose, povidone K30, sodium starch glycolate (type A); Opadry White YS-1-7706-G coating: hypromellose, macrogol 400, titanium dioxide (E 171), polysorbate 80 (for 25 mg tablets); Opadry Brown 03B26716 coating: hypromellose, titanium dioxide (E 171), macrogol 400, iron oxide yellow (E 172), iron oxide red (E 172) (for 50 mg tablets).

Dosage form

Film-coated tablets.

Main physicochemical properties: 25 mg tablets: round, biconvex, film-coated tablets of white color with GS NX3 and 25 marking on one side; 50 mg tablets: round, biconvex, film-coated tablets of brown color with GS UFU and 50 marking on one side.

Pharmacotherapeutic group

Antihemorrhagic agents, systemic hemostatics.

ATX code B02B X05.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Thrombopoietin is a major cytokine involved in the regulation of megakaryopoiesis and platelet formation and is the endogenous ligand for thrombopoietin receptors. Eltrombopag interacts with the transmembrane domain of human thrombopoietin receptors and initiates a signaling cascade similar but not identical to that triggered by endogenous thrombopoietin, inducing the proliferation and differentiation of megakaryocytes from progenitor 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.

There has been no clinical trial comparing eltrombopag with other treatment options (e.g. splenectomy). The long-term safety of eltrombopag should be considered before initiating therapy.

Children (ages 1-17)

The safety and effectiveness of eltrombopag in children were studied in two studies.

TRA115450 (PETIT2): The primary endpoint was sustained response, defined as the proportion of subjects receiving eltrombopag who achieved a platelet count ≥50,000/μL for at least 6 of 8 weeks (in the absence of rescue therapy) from Weeks 5 to 12 during the double-blind, randomized phase. Participants had confirmed chronic ITP for at least 1 year and had failed to respond to at least one prior course of ITP therapy or had relapsed on such therapy, or were unable to continue other ITP therapy for medical reasons and had a platelet count <30,000/μL. 92% of patients were randomized 2:1 to receive eltrombopag (n=63) or placebo (n=29) and stratified into three baseline groups. The dose of eltrombopag could be adjusted depending on the platelet count of the individual patient.

Overall, a significantly higher proportion of patients receiving eltrombopag (40%) compared with placebo (3%) achieved the primary endpoint (odds ratio: 18.0 [95% CI: 2.3; 140.9], p < 0.001). This result was consistent across all three age groups (Table 1).

Table 1

Persistent platelet response in children with chronic ITP by age

DV — data missing

Statistically fewer patients receiving eltrombopag required emergency treatment during the randomized period compared to the placebo group (19% [12/63] vs. 24% [7/29], p=0.032).

At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO grade 1–4). After 12 weeks, the proportion of patients receiving eltrombopag who reported any bleeding had decreased to half of baseline (36%). In comparison, after 12 weeks, 55% of patients receiving placebo reported any bleeding.

Participants were allowed to reduce their baseline 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 baseline ITP therapy, primarily corticosteroids, without the need for rescue therapy.

Overall, a significantly higher proportion of patients receiving eltrombopag (62%) compared to placebo (32%) achieved the primary endpoint (odds ratio: 4.3 [95% CI: 1.4; 13.3] p=0.011).

A durable response was observed in 50% of initial responders for 20 of 24 weeks in the PETIT 2 study and for 15 of 24 weeks in the PETIT study.

Study in patients with thrombocytopenia associated with chronic hepatitis C

The efficacy and safety of eltrombopag in the treatment of thrombocytopenia in patients with HCV were evaluated in two randomized, double-blind, placebo-controlled trials. ENABLE 1 used peginterferon alfa-2a plus ribavirin for antiviral treatment, and ENABLE 2 used peginterferon alfa-2b plus ribavirin. Patients did not receive direct-acting antivirals.

Severe aplastic anemia

Eltrombopag was studied in a single-center, open-label, single-arm trial in 43 patients with severe aplastic anemia and refractory thrombocytopenia after at least one course of immunosuppressive therapy (IST) who had a platelet count ≤30,000/μL.

The majority of participants, 33 (77%), were considered to have primary refractory disease, defined as a lack of adequate response to prior IST by any measure. The remaining 10 participants had 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 refractory to appropriate therapy, or 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% were dependent 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 as 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 without transfusion for at least 8 weeks; an increase in hemoglobin levels of >1.5 g/dL or a decrease in red blood cell transfusions of ≥4 units for 8 consecutive weeks; an increase in absolute neutrophil count (ANC) of 100% or an increase in ANC of >0.5 × 109/L.

The hematological response rate was 40% (17/43 patients; 95% CI 25, 56), with the majority responding on one measure (13/17, 76%), while 3 responded on 2 measures and 1 responded on 3 measures at 12 weeks. Eltrombopag was discontinued after 16 weeks if a hematological response or transfusion independence was not achieved. Responders continued treatment in the extension phase of the study. A total of 14 patients entered this phase. 9 of these patients achieved a response on multiple measures, 4 of the 9 continued therapy, and 5 reduced eltrombopag therapy and maintained response (median follow-up 20.6 months, range 5.7 to 22.5 months). The remaining 5 patients discontinued therapy: three due to relapse after 3 months of the extension phase.

During treatment with eltrombopag, 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 >80% reduction in both platelet and RBC transfusion requirements from baseline.

Preliminary data from the confirmatory study (study ELT116826), an ongoing, single-arm, non-randomized, open-label Phase II study in patients with refractory TAA, have shown consistent results. Data are limited to 21 of the planned 60 patients with hematologic response reported in 52% of patients at 6 months. Responses on multiple measures were observed in 45% of patients.

Pharmacokinetics.

The pharmacokinetic parameters of eltrombopag when using this drug for the treatment of adult patients with chronic hepatitis C (HCV) are as follows: when using the drug at a dose of 50 mg 1 time per day, the maximum concentration of the drug (Cmax) is 9.08 μg/ml (7.96; 10.35), and the area under the curve "concentration/time" (AUC) is 166 μg/h/ml (143; 192). When using the drug at a dose of 75 mg 1 time per day, Cmax is 16.71 μg/ml (14.26; 19.58), and AUC is 301 μg/h/ml (250; 363). When using the drug at a dose of 100 mg 1 time per day, Cmax is 19.19 μg/ml (16.81; 21.91), and AUC is 354 μg/h/ml (304; 411). Thus, when using the same doses of eltrombopag, its exposure in the treatment of patients with chronic HCV is higher than its exposure in the treatment of patients with ITP.

Absorption and bioavailability.

Peak eltrombopag concentrations occur 2-6 hours after oral administration. Co-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, eltrombopag in the form of a powder for oral suspension resulted in an AUC(0-¥) value that was 22% higher than that of the tablets. The absolute bioavailability of eltrombopag in humans has not been established. Based on urinary excretion and fecal excretion of metabolites, oral absorption of drug-related material following a single 75 mg dose of eltrombopag is approximately 52%.

Distribution

Eltrombopag is highly bound to human plasma proteins (> 99.9%), primarily albumin. Eltrombopag is a substrate for breast cancer resistance protein, but is not a substrate for P-glycoprotein and organic anion transporting polypeptides.

Metabolism.

Eltrombopag is primarily metabolized by cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In a radiological study, eltrombopag accounted for approximately 64% of the plasma radiocarbon AUC. Minor metabolites resulting from glucuronidation and oxidation, each accounting for less than 10% of the plasma radioactivity, were also identified. Based on data from a human study of radiolabeled eltrombopag, approximately 20% of the dose is expected to be metabolized by oxidation. According to in vitro studies, it was identified that the isoenzymes CYP1A2 and CYP2C8 are responsible for oxidative metabolism, the isoenzymes uridine diphosphoglucuronyltransferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria from the lower gastrointestinal tract may be responsible for the drug breakdown process.

Elimination.

Absorbed eltrombopag is extensively metabolized. Eltrombopag is excreted primarily in the feces (59%), with 31% of the dose recovered in the urine as metabolites. No unchanged eltrombopag was recovered in the urine. Unchanged eltrombopag excreted in the feces accounted for approximately 20% of the dose. The plasma half-life of eltrombopag is approximately 21-32 hours.

Pharmacokinetic interactions.

Based on studies with radiolabeled eltrombopag, glucuronidation appears to play a minor role in its metabolism. Studies using human liver microsomes have shown that UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not expected due to the limited contribution of individual UGT enzymes to the glucuronidation of eltrombopag and potential concomitant medications.

Approximately 21% of the eltrombopag dose may be metabolized by oxidation. Studies using human liver microsomes have shown that CYP1A2 and CYP2C8 are responsible for the oxidation of eltrombopag. In vitro and in vivo studies have shown that eltrombopag is not an inhibitor of CYP enzymes.

In vitro studies have shown 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-drug interaction study. A 50% reduction in the dose of statins was recommended in clinical studies with eltrombopag. Co-administration of 200 mg of cyclosporine (a BCRP inhibitor) decreased eltrombopag Cmax and AUCinf by 25% and 18%, respectively. Co-administration of 600 mg of cyclosporine decreased eltrombopag Cmax and AUCinf by 39% and 24%, respectively.

Eltrombopag forms chelate complexes with polyvalent cations such as iron, calcium, magnesium, aluminum, selenium, and zinc.

In vitro studies have shown that eltrombopag is not a substrate for the organic anion transport polypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value 2.7 μM [1.2 μg/mL]). In vitro studies have also shown that eltrombopag is an inhibitor and substrate of the breast cancer resistance protein (BCRP) transporters (IC50 value 2.7 μM [1.2 μg/mL])

Certain patient groups

The pharmacokinetics of eltrombopag have been studied in adult patients with renal impairment. Following a single 50 mg dose, the AUC of eltrombopag was reduced by 32% in patients with mild renal impairment, 36% in patients with moderate renal impairment, and 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 substantial variability in exposure between patients with renal impairment and healthy volunteers. Eltrombopag should be used with caution in patients with renal impairment and with ongoing monitoring, such as by measuring serum creatinine and/or urinalysis. The efficacy and safety of eltrombopag in patients with moderate or severe renal impairment and hepatic impairment have not been established.

Liver failure.

The pharmacokinetics of eltrombopag have been studied in adult patients with hepatic impairment. Following a single 50 mg dose, the AUC of eltrombopag was increased by 41% in patients with mild hepatic impairment, 80% in patients with moderate hepatic impairment, and 93% in patients with severe hepatic impairment compared to healthy volunteers. There is significant variability in exposure between patients with hepatic impairment and healthy volunteers.

The effect of hepatic impairment on the pharmacokinetics of eltrombopag during repeated dosing was studied using a population pharmacokinetic analysis in 28 healthy volunteers and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other etiologies). Of these 714 patients, 642 had mild hepatic impairment, 67 had moderate hepatic impairment, and 2 had severe hepatic impairment. Patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher plasma eltrombopag AUC values, and patients with moderate hepatic impairment had 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC values compared to healthy volunteers.

Therefore, eltrombopag should not be used in patients with ITP and hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the risk of portal vein thrombosis (see sections 4.2 and 4.4).

Eltrombopag should be used with caution in patients with hepatic impairment. In patients with chronic ITP and mild, moderate, and severe hepatic impairment, eltrombopag treatment should be initiated at a reduced dose of 25 mg once daily.

Racial affiliation.

The effect of East Asian ethnicity on the pharmacokinetics of eltrombopag was assessed using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 ITP patients (18 East Asians). In a population pharmacokinetic analysis, the AUC of eltrombopag in East Asian ITP patients was approximately 49% higher than in patients of other races, primarily Caucasians (see section 4.2).

The effect of East/Southeast Asian ethnicity (e.g. Chinese, Japanese, Taiwanese, Korean or Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 HCV patients (145 East Asian and 69 Southeast Asian). Based on population pharmacokinetic analysis estimates, the AUC of eltrombopag in East/Southeast Asian patients was approximately 55% higher compared to patients of other races, primarily Caucasian (see section 5.2).

Sex.

The effect of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 ITP patients (57 females). In the population pharmacokinetic analysis, eltrombopag AUC values were approximately 23% higher in female ITP patients than in male patients, without adjustment for body weight.

The effect of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (260 women). Modeling revealed that AUC values for eltrombopag were approximately 41% higher in women with HCV compared to men.

Age.

The effect of age on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 28 healthy subjects, 673 HCV patients, and 41 patients with other chronic diseases aged 19 to 74 years. There are no pharmacokinetic data for eltrombopag in patients aged 75 years or older. In a population pharmacokinetic analysis, elderly patients (> 65 years) had a 41% higher plasma AUC of eltrombopag compared to younger patients.

In clinical studies, the oral clearance of eltrombopag increases with increasing body weight. The effects of race and gender on the pharmacokinetics of eltrombopag in pediatric and adult patients are similar. Plasma eltrombopag AUC values in patients of East/Southeast Asian descent were approximately 43% higher compared to patients of other races. Plasma eltrombopag AUC values in female ITP patients were approximately 25% higher compared to male patients.

The 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)

Indication

Treatment of adult patients with chronic immune (idiopathic) thrombocytopenic purpura who are not responsive 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 from the date of diagnosis, who are not amenable to treatment with other medicinal products (e.g. corticosteroids, immunoglobulins).

Treatment of thrombocytopenia in adult patients with chronic hepatitis C virus infection when the degree of thrombocytopenia is a major 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 responded to prior immunosuppressive therapy or have responded poorly to prior therapy and are not suitable for haematopoietic stem cell transplantation.

Contraindication

Hypersensitivity to eltrombopag or any other component of the drug.

Interaction with other medicinal products and other types of interactions

Effects of eltrombopag on other medicinal products

HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors.

An in vitro study demonstrated that eltrombopag is not a substrate for organic anion transporter polypeptide (OATP1B1) but is an inhibitor of these transporters. An in vitro study also demonstrated that eltrombopag is a substrate and inhibitor of BCRP. Coadministration 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 an increase in plasma rosuvastatin Cmax by 103% (90% confidence interval [CI]: 82%, 126%) and AUC0-∞ by 55% (90% CI: 42%, 69%). Interactions with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, are also expected. When used concomitantly with eltrombopag, statin doses should be reduced and statin-induced adverse reactions should be carefully monitored.

OATP1B1 and BCRP substrates.

Eltrombopag should be used with caution in combination with other OATP1B1 (e.g. methotrexate) and BCRP substrates (e.g. topotecan and methotrexate).

Cytochrome P450 substrates

Studies using human liver microsomes have shown that eltrombopag (at doses up to 100 µM) does not inhibit CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 4A4/5, and 4A9/11 in vitro and inhibits CYP2C8 and CYP2C9 when measured using paclitaxel and diclofenac as test substrates. Administration of 75 mg of eltrombopag to 24 healthy male volunteers did not inhibit or induce the metabolism of test substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam). No clinically significant interactions are expected when eltrombopag is co-administered with CYP450 substrates.

HCV protease inhibitors.

No dose adjustment is required when eltrombopag is co-administered with telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours does not alter telaprevir plasma concentrations.

Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter AUC(0-t), but increased Cmax by 20% and decreased Cmin by 32%. The clinical significance of the decrease in Cmin has not been established, and close clinical and laboratory monitoring of HCV suppression is recommended.

Effects of other medicinal products on eltrombopag

Cyclosporine.

In vitro studies have shown that eltrombopag is a substrate and inhibitor of breast cancer resistance protein. Reduced exposure to eltrombopag was observed with concomitant administration of 200 mg and 600 mg of cyclosporine (a BCRP inhibitor). Coadministration of 200 mg of cyclosporine decreased eltrombopag Cmax and AUC0-¥ by 25% and 18%, respectively. Coadministration of 600 mg of cyclosporine decreased eltrombopag Cmax and AUC0-¥ by 39% and 24%, respectively. Dose adjustments of eltrombopag during treatment are based on the patient’s platelet count. Platelet counts should be monitored at least weekly for 2 to 3 weeks after coadministration of eltrombopag with cyclosporine. Eltrombopag dose may need to be adjusted based on platelet count.

Eltrombopag chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc. Administration of a single 75 mg dose of eltrombopag with a polyvalent cation-containing antacid (1524 mg aluminum hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC0-¥ by 70% 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 tablet formulation with a high-calcium meal (e.g., a meal containing dairy products) significantly decreased AUC0-∞ and Cmax. Conversely, administration of eltrombopag 2 hours before or 4 hours after a high- or low-calcium meal (<50 mg calcium) did not alter plasma eltrombopag exposure to a clinically relevant extent.

Administration of a single dose of eltrombopag 50 mg tablet with a standard high-calorie, high-fat breakfast, including dairy products, decreased plasma eltrombopag AUC by 59% and Cmax by 65%.

Administration of a single 25 mg dose of eltrombopag powder for oral suspension with a moderate-calorie, high-calcium, moderate-fat meal decreased the mean plasma AUC0-∞ of eltrombopag by 75% and the mean Cmax by 79%. This decrease in exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before the high-calcium meal (mean AUC0-∞ decreased by 20% and mean Cmax decreased by 14%).

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

Lopinavir/ritonavir.

Co-administration of eltrombopag with lopinavir/ritonavir (LPV/RTV) may decrease eltrombopag concentrations. A study in 40 healthy volunteers showed that co-administration of a single dose of eltrombopag 100 mg with LPV/RTV 400/100 mg twice daily resulted in a 17% decrease in plasma eltrombopag AUC0-¥. Therefore, caution should be exercised when eltrombopag is used with lopinavir/ritonavir. Platelet counts should be closely monitored to ensure appropriate eltrombopag dosing when lopinavir/ritonavir is started or stopped.

Inhibitors and inducers of CYP1A2 and CYP2C8.

Eltrombopag is metabolized by multiple pathways, including CYP1A2, CYP2C8, UGT1A1, and UGT1A3. Drugs that inhibit or induce a single enzyme are unlikely to have a significant effect on eltrombopag plasma concentrations; whereas drugs that inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) eltrombopag concentrations.

HCV protease inhibitors.

Results of a pharmacokinetic interaction study between the two drugs indicate that co-administration of repeated doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter plasma concentrations of eltrombopag to a clinically relevant extent.

Medications for the treatment of ITP.

Medicinal products used in combination with eltrombopag in clinical trials 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 4.2).

Application features

Patients with chronic HCV infection with thrombocytopenia and advanced chronic liver disease are at increased risk of adverse events, including potentially fatal hepatic failure and thromboembolic complications. Increased risk is defined by a low albumin level ≤ 35 g/L or a Model for End-Stage Liver Disease (MELD) score ≥ 10 when treated with eltrombopag in combination with interferon therapy. In addition, the treatment benefit in terms of achieving sustained virological response (SVR) compared to placebo in these patients was modest (especially in patients with baseline albumin ≤ 35 g/L). Treatment with eltrombopag in these patients should only be initiated by physicians experienced in the management of patients with advanced chronic HCV infection, and only when there is a risk of thrombocytopenia or when maintenance of antiviral therapy requires intervention. If treatment is clinically indicated, close monitoring of these patients is necessary.

Interaction with direct-acting antiviral drugs

The safety and efficacy of the combination of eltrombopag with direct-acting antivirals approved for the treatment of chronic hepatitis C have not been established.

The use of eltrombopag may cause liver dysfunction and serious liver toxicity, which may be life-threatening (see section 4.8).

Serum ALT, AST, and bilirubin should be measured prior to initiating treatment with eltrombopag, every 2 weeks during dose adjustments, 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 function tests are abnormal, repeat measurements should be performed within 3-5 days. If abnormalities are confirmed, liver enzymes should be monitored until they normalize or stabilize. Eltrombopag should be discontinued if ALT levels increase (≥3 × ULN in patients with normal liver function or ≥3 × baseline or >5 × ULN, whichever is lower, in patients with elevated transaminases prior to treatment), and if:

progress of the process;

process persistence ≥ 4 weeks;

concomitant increase in direct bilirubin levels;

the appearance of concomitant clinical symptoms of liver dysfunction or signs of hepatic decompensation.

Eltrombopag should be used with caution in patients with liver disease. In patients with ITP and liver damage, treatment with eltrombopag should be initiated at a reduced dose. Close monitoring is required when prescribing to patients with impaired liver function (see section 4.2).

Liver failure (when used together with interferon).

Liver failure in patients with chronic HCV: Patients with low albumin levels (≤ 35 g/L) or with a baseline Model for End-Stage Liver Disease (MELD) score ≥10 should be closely monitored.

In HCV patients with cirrhosis, there is a potential risk of hepatic decompensation when interferon alfa is used. In 2 controlled clinical trials in HCV patients with 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 ≥ 10 on the MELD scale at baseline had a 3-fold greater risk of hepatic failure and an increased risk of fatal adverse events compared with those with less advanced liver disease. In addition, the treatment benefit in terms of achieving SVR compared with placebo in these patients was small (especially in patients with baseline albumin levels ≤ 35 g/L). Eltrombopag should be used in these patients only after careful consideration of the expected benefits versus the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic impairment. For information on criteria for discontinuation of interferon therapy, refer to the appropriate prescribing information. Eltrombopag should be discontinued if antiviral therapy is discontinued due to hepatic impairment.

Thrombotic/thromboembolic complications.

In controlled studies in thrombocytopenic HCV patients receiving interferon therapy (n = 1439), 38 of 955 patients (4%) treated with eltrombopag and 6 of 484 (1%) patients in the placebo group developed thromboembolic events (TEAs). These thrombotic/thromboembolic events included both venous and arterial events. Most TAEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TAE in both treatment groups (2% of patients treated with eltrombopag).