Eltrombopag Cipla

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Eltrombopag Cipla 25 mg film-coated tablets
Eltrombopag Cipla 50 mg film-coated tablets
Eltrombopag Cipla 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Eltrombopag Cipla 25 mg film-coated tablets
Eltrombopag Cipla 50 mg film-coated tablets
Excipient with known effect
Each film-coated tablet contains 0.78 mg of sunset yellow.
Eltrombopag Cipla 75 mg film-coated tablets
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.
Eltrombopag Cipla 25 mg film-coated tablets
Blue, round, biconvex, film-coated tablet (approximately 7.1 mm in diameter) with 'E 2' engraved on one side.
Eltrombopag Cipla 50 mg film-coated tablets
Orange, round, biconvex, film-coated tablet (approximately 8.2 mm in diameter) with 'E 5' engraved on one side.
Eltrombopag Cipla 75 mg film-coated tablets
Dark pink, round, biconvex, film-coated tablet (approximately 10.1 mm in diameter) with 'E 7' engraved on one side.

4. CLINICAL INFORMATION

4.1 Therapeutic Indications
Eltrombopag Cipla is indicated for the treatment of adult patients with primary immune thrombocytopenia (ITP)
who are refractory to other treatments (e.g., corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).
Eltrombopag Cipla is indicated for the treatment of paediatric patients aged 1 year and older with primary immune
thrombocytopenia (ITP) lasting at least 6 months from diagnosis and who are refractory to other treatments (e.g.,
corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).
Eltrombopag Cipla is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of
thrombocytopenia when the degree of thrombocytopenia is the main factor preventing initiation or limiting the
ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1).

4.2 Posology and Method of Administration
Treatment with eltrombopag must be initiated and remain under the supervision of a physician experienced in the
management of haematological disorders or in the treatment of chronic hepatitis C and its complications.

Posology
The required dose of eltrombopag must be individualised based on the patient's platelet count.
The goal of treatment with eltrombopag should not be to normalise the platelet count.
The oral suspension powder may result in higher exposure to eltrombopag compared to the tablet formulation (see section 5.2). When switching from the tablet formulation to the oral suspension powder, platelet counts should be monitored weekly for 2 weeks.

Immune (primary) thrombocytopenia

The lowest dose of eltrombopag required to achieve and maintain a platelet count ≥50,000/µl should be used. Dose adjustments are based on platelet count response. Eltrombopag should not be used to normalise platelet counts. In clinical studies, platelet counts generally increased within 1–2 weeks after starting eltrombopag and decreased within 1–2 weeks after discontinuation.

Adults and paediatric population aged 6 to 17 years

The recommended initial dose of eltrombopag is 50 mg once daily. For patients of East or Southeast Asian ancestry, treatment with eltrombopag should be initiated at the reduced dose of 25 mg once daily (see section 5.2).

Paediatric population 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 necessary to reduce the risk of bleeding. The maximum daily dose of 75 mg must not be exceeded.

Haematological and liver function parameters should be monitored regularly during treatment with eltrombopag, and the eltrombopag dosing regimen should be adjusted according to platelet count as shown in Table 1. During eltrombopag therapy, a complete blood count, including platelet count and peripheral blood smear, should be assessed weekly until a stable platelet count (≥50,000/µl for at least 4 weeks) is achieved. Thereafter, a complete blood count, including platelet count and peripheral blood smear, should be performed monthly.

Table 1 Dose adjustments of eltrombopag in ITP patients

* For patients taking eltrombopag 25 mg every other day, increase the dose to 25 mg once daily.
♦ For patients taking eltrombopag 25 mg once daily, consider reducing the dose to 25 mg every other day.
Eltrombopag may be administered in addition to other medicinal products for ITP. The dosing regimen of concomitant medicinal products for the treatment of ITP should be modified as clinically appropriate.
At least 2 weeks should be allowed to observe the effect of any dose adjustment on the patient's platelet response before considering another dose modification.
The standard dose adjustment of eltrombopag, either up or down, should be in increments of 25 mg once daily.

Discontinuation of treatment
Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with 75 mg of eltrombopag once daily.
Patients should be periodically evaluated clinically, and continuation of treatment should be decided by the physician on an individual basis. In non-splenectomized patients, this evaluation should include an assessment regarding splenectomy. Recurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4).

Thrombocytopenia associated with chronic HCV hepatitis
When eltrombopag is administered in combination with antiviral agents, reference should be made to the Summary of Product Characteristics of the respective concomitantly administered medicinal products for comprehensive information on relevant safety details and contraindications.
In clinical studies, platelet counts generally began to increase within 1 week after initiation of treatment. The goal is to achieve the platelet count required to initiate antiviral therapy, in accordance with clinical practice recommendations. During antiviral therapy, the treatment objective should be to maintain the platelet count at a level that prevents the risk of hemorrhagic complications, typically around 50,000 – 75,000 /µl. A platelet count >75,000 /µl should be avoided. The lowest dose of eltrombopag necessary to achieve treatment goals should be used. Dose adjustments should be based on the platelet count response.

Initial dosing regimen
Eltrombopag should be initiated at a dose of 25 mg once daily. No dose adjustment is required for patients with chronic HCV hepatitis of East/Southeast Asian origin or for patients with mild hepatic impairment (see section 5.2).

Monitoring and dose adjustment
The dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored weekly before starting antiviral therapy. At the initiation of antiviral therapy, platelet counts may decrease; therefore, immediate dose adjustments of eltrombopag should be avoided (see Table 2).
During antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose reductions of peginterferon due to decreases in platelet count that could expose the patient to a risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, typically around 50,000–75,000 /µl. Thereafter, a complete blood count, including platelet count and peripheral blood smear, should be performed monthly. Dose reductions of 25 mg from the daily dose should be considered if the platelet count exceeds the required target. It is advisable to wait 2 weeks to evaluate the effects of this and any subsequent dose adjustment.
The dose of eltrombopag should not exceed 100 mg once daily.

Table 2: Dose adjustments of eltrombopag in patients with chronic HCV hepatitis during antiviral therapy

* In patients taking 25 mg of eltrombopag once daily, consideration should be given to restarting treatment at a dose of 25 mg on alternate days.
At the beginning of antiviral therapy, platelet count may decrease; therefore, the following should be avoided:
Discontinuation of treatment
Treatment with eltrombopag must be discontinued if, after 2 weeks of therapy at 100 mg, the required platelet count to initiate antiviral therapy has not been achieved.
Unless otherwise justified, treatment with eltrombopag should be stopped when antiviral therapy is suspended. Discontinuation of treatment is also required in cases of excessive platelet count response or significant abnormalities in liver function tests.
Special populations
Renal impairment
No dose adjustment is required in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and under close monitoring, for example, by monitoring serum creatinine and/or urine analysis (see section 5.2).
Hepatic impairment
Eltrombopag must not be used in patients with ITP and hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal vein thrombosis (see section 4.4).
If the use of eltrombopag is considered necessary for patients with ITP and hepatic impairment, the initial dose should be 25 mg once daily. After initiating eltrombopag dosing in patients with hepatic impairment, a 3-week interval must be observed before increasing the dose.
No dose adjustment is required for thrombocytopenic patients with chronic hepatitis C and mild hepatic impairment (Child-Pugh score ≤6). Thrombocytopenic patients with chronic hepatitis C and hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After starting eltrombopag treatment in patients with hepatic impairment, a 2-week interval must be observed before increasing the dose.
There is an increased risk of adverse events, including hepatic decompensation and thromboembolic events (ETEs), in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedures or in patients with chronic hepatitis C receiving antiviral therapy (see sections 4.4 and 4.8).
Elderly
There are limited data on the use of eltrombopag in ITP patients aged 65 years and older, and no clinical experience in ITP patients over 85 years of age. In clinical studies with eltrombopag, no overall clinically significant differences in safety were observed between patients aged at least 65 years and younger patients. Other reported clinical experiences have not identified differences in responses between elderly and younger patients, but increased sensitivity in some older individuals cannot be excluded (see section 5.2).
There are limited data on the use of eltrombopag in patients with chronic hepatitis C aged over 75 years. Caution should be exercised in these patients (see section 4.4).
East/Southeast Asian patients
In adult and pediatric patients of East/Southeast Asian origin, including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2).
Platelet count should continue to be monitored and standard criteria followed for any further dose adjustments.
Paediatric population
The use of Eltrombopag Cipla is not recommended in children under 1 year of age with ITP due to insufficient data on safety and efficacy. The safety and efficacy of eltrombopag in children and adolescents (<18 years) with chronic HCV-related thrombocytopenia have not been established. No data are available.
Method of administration
Oral use.
Tablets should be taken at least 2 hours before or 4 hours after any product such as antacids, dairy products (or other food products containing calcium), or mineral supplements containing polyvalent cations (e.g., iron, calcium, magnesium, aluminium, selenium, and zinc) (see sections 4.5 and 5.2).
4.3 Contraindications
Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
There is an increased risk of adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic patients with chronic hepatitis C and advanced chronic liver disease, defined by low albumin levels ≤35 g/l or a Model for End-Stage Liver Disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. Additionally, the treatment benefits in terms of the proportion of patients achieving sustained virological response (SVR) compared to placebo were modest in these patients (especially those with baseline albumin ≤35 g/l) compared to the overall group. Treatment with eltrombopag in these patients should only be initiated by physicians experienced in treating advanced chronic hepatitis C, and only when the risks of thrombocytopenia or antiviral therapy discontinuation necessitate intervention. If treatment is considered clinically indicated, careful monitoring of these patients is required.
Combination with direct-acting antiviral agents
Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for the treatment of chronic hepatitis C.
Risk of hepatotoxicity
Administration of eltrombopag may cause liver function abnormalities and severe hepatotoxicity, which can be life-threatening (see section 4.8).
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum bilirubin must be measured before starting eltrombopag, every 2 weeks during the dose-adjustment phase, and monthly after reaching a stable dose. Eltrombopag inhibits UDP-glucuronosyltransferase (UGT 1A1) and organic anion transporting polypeptide (OATP 1B1), which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, fractionation should be performed. Abnormalities in liver function tests should be evaluated by repeating tests within 3–5 days. If abnormalities are confirmed, liver function tests must be monitored until abnormalities resolve, stabilize, or return to baseline levels. Administration of eltrombopag must be discontinued if ALT levels increase (≥3 times the upper limit of normal [× ULN] in patients with normal liver function, or ≥3 times baseline or >5 times ULN, whichever is lower, in patients with pre-treatment transaminase elevations) and are:

• progressive, or
• persist for ≥4 weeks, or
• accompanied by an increase in direct bilirubin, or
• accompanied by clinical symptoms of liver damage or evidence of hepatic decompensation.

Caution is required when administering eltrombopag to patients with liver disease. In patients with ITP and SAA, a lower initial dose of eltrombopag should be used. Careful monitoring is required when administering to patients with hepatic impairment (see section 4.2).
Hepatic decompensation (use with interferon)
Monitoring is required in patients with chronic hepatitis C and low albumin levels (≤35 g/l) or baseline MELD score ≥10.
Patients with chronic hepatitis C and liver cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In two controlled clinical trials in thrombocytopenic patients with chronic hepatitis C, hepatic decompensation (ascites, hepatic encephalopathy, esophageal variceal bleeding, spontaneous bacterial peritonitis) occurred more frequently in the eltrombopag arm (11%) compared to the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or baseline MELD score ≥10, there was a threefold increased risk of hepatic decompensation and an increased risk of fatal adverse events compared to those with less advanced liver disease. Furthermore, the treatment benefits in terms of the proportion achieving SVR compared to placebo were modest in these patients (especially those with baseline albumin ≤35 g/l) compared to the overall group. Eltrombopag should only be administered to these patients after careful consideration of expected benefits versus risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. Refer to the respective Summary of Product Characteristics of interferon for discontinuation criteria. Eltrombopag must be discontinued if antiviral therapy is discontinued due to hepatic decompensation.
Thrombotic/thromboembolic complications
In controlled clinical trials in thrombocytopenic patients with chronic hepatitis C receiving interferon-based therapy (n=1,439), 38 out of 955 (4%) patients treated with eltrombopag and 6 out of 484 (1%) in the placebo group experienced ETEs. Reports of thrombotic/thromboembolic complications included both venous and arterial events. The majority of ETEs were non-severe and resolved by the end of the study. Portal vein thrombosis was the most common ETE in both treatment groups (2% in eltrombopag-treated patients versus <1% in placebo). No specific temporal relationship between treatment initiation and observed ETE was noted. Patients with low albumin levels (≤35 g/l) or MELD score ≥10 had a twofold higher risk of ETE compared to patients with higher albumin levels; those aged ≥60 years had a twofold higher risk of ETE compared to younger patients. Eltrombopag should only be administered to these patients after careful consideration of expected benefits versus risks. Patients must be closely monitored for signs and symptoms of ETE.
The risk of ETE was increased in patients with chronic liver disease (CLD) treated with eltrombopag 75 mg once daily for 2 weeks in preparation for invasive procedures. Six out of 143 (4%) adult CLD patients receiving eltrombopag experienced ETEs (all involving the portal venous system), and two out of 145 (1%) in the placebo group experienced ETEs (one involving the portal venous system and one myocardial infarction). Five out of six eltrombopag-treated patients developed thrombotic complications with a platelet count >200,000/µl and within 30 days after the last dose of eltrombopag in patients with chronic liver disease prior to invasive procedures.
In clinical trials with eltrombopag in ITP, thromboembolic events were observed with both low and normal platelet counts. Caution should be exercised when administering eltrombopag to patients with known risk factors for thromboembolism, including but not limited to hereditary (e.g., Factor V Leiden) or acquired (e.g., ATIII deficiency, antiphospholipid syndrome) risk factors, advanced age, prolonged immobilization, malignant neoplasms, contraceptive or hormone replacement therapy, surgery/trauma, obesity, and smoking. Platelet count should be closely monitored, and dose reduction or discontinuation of eltrombopag should be considered if platelet counts exceed required levels (see section 4.2). The risk-benefit ratio should be considered in patients at risk of ETEs of any etiology.
No cases of ETE were identified in a clinical trial in refractory SAA; however, the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. Since the maximum authorized dose is indicated in SAA patients (150 mg/day) and considering the nature of the response, ETEs could occur in this patient population.
Eltrombopag must not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal vein thrombosis. When treatment is considered appropriate, caution is required when administering eltrombopag to patients with hepatic impairment (see sections 4.2 and 4.8).
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to recur upon discontinuation of treatment, usually within 1–2 weeks in most patients, increasing the risk of bleeding and in some cases leading to bleeding. This risk is increased if treatment with eltrombopag is discontinued while anticoagulants and antiplatelet agents are being used. It is recommended that, if treatment with eltrombopag is discontinued, ITP management should resume according to current guidelines. Additionally, medical management may include discontinuation of anticoagulant and/or antiplatelet therapy, reversal of anticoagulation, or platelet support. Platelet count should be monitored weekly.
In clinical trials in chronic hepatitis C, a higher incidence of bleeding was reported.
Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal bleeding.
Bone marrow reticulin formation and risk of bone marrow fibrosis
Eltrombopag may increase the risk of development or progression of reticulin fibres in the bone marrow. As with other thrombopoietin receptor (TPO-R) agonists, the clinical relevance of these changes has not yet been established.
Prior to initiating eltrombopag, a careful examination of the peripheral blood smear should be performed to establish baseline levels of morphological cellular abnormalities. After identifying a stable dose of eltrombopag, a complete blood count with white blood cell differential should be performed monthly. If immature or dysplastic cells are observed, the peripheral blood smear should be examined for the presence of new morphological abnormalities (e.g., teardrop-shaped red blood cells [dacrocytes] and nucleated red blood cells, immature white blood cells) or worsening of existing abnormalities or cytopenia. If a patient develops new morphological abnormalities, worsening of existing abnormalities, or cytopenia, treatment with eltrombopag should be discontinued and a bone marrow biopsy, including assessment for fibrosis, should be considered.
Progression of pre-existing Myelodysplastic Syndrome (MDS)
There is a theoretical risk that TPO-R agonists may stimulate the progression of pre-existing haematological neoplasms such as MDS. TPO-R agonists are growth factors that induce proliferation and differentiation of thrombopoietic progenitor cells and platelet production. TPO-R is predominantly expressed on the surface of myeloid lineage cells.
In clinical trials with a TPO-R agonist in MDS patients, transient increases in blast cell count have been observed, and cases of disease progression from MDS to acute myeloid leukaemia (AML) have been reported.
The diagnosis of ITP or SAA in adult and elderly patients must be confirmed by excluding other conditions presenting with thrombocytopenia, particularly MDS. Bone marrow aspiration and biopsy should be considered during the course of the disease and treatment, especially in patients over 60 years of age, with systemic symptoms or abnormal signs such as increased peripheral blast cells.
The efficacy and safety of Eltrombopag Cipla have not been established in the treatment of thrombocytopenia due to MDS. Eltrombopag Cipla must not be used outside clinical trials for the treatment of thrombocytopenia due to MDS.
Chromosomal abnormalities and progression of MDS/AML in SAA patients
Chromosomal abnormalities may develop in patients with SAA. It is not known whether eltrombopag increases the risk of chromosomal abnormalities in SAA patients. In a phase II clinical trial in refractory SAA where eltrombopag was used at an initial dose of 50 mg/day (increased every 2 weeks up to a maximum of 150 mg/day) (ELT112523), the incidence of new chromosomal abnormalities was observed in 17.1% of adult patients [7/41 (of which 4 had chromosome 7 abnormalities)]. The median time to onset of a chromosomal abnormality during the study was 2.9 months.
In a phase II clinical trial in refractory SAA where eltrombopag was administered at a dose of 150 mg/day (with dose modifications based on ethnicity or age as indicated) (ELT116826), the incidence of new chromosomal abnormalities was observed in 22.6% of adult patients [7/31 (where 3 patients had chromosome 7 abnormalities)]. All 7 patients had normal baseline cytogenetic findings. Six patients developed a chromosomal abnormality by the third month of eltrombopag therapy, and one patient developed a chromosomal abnormality by the sixth month.
In clinical trials with eltrombopag in SAA, MDS was diagnosed in 4% of patients (5/133). The median time to diagnosis from the start of eltrombopag treatment was three months.
For patients with refractory or heavily pre-treated SAA and prior immunosuppressive therapy, bone marrow examination with aspiration for cytogenetics is recommended before starting eltrombopag, at 3 months of treatment, and every 6 months thereafter. If new chromosomal abnormalities are detected, eltrombopag should be discontinued and a bone marrow biopsy considered.
Ocular alterations
Cataract was observed in eltrombopag toxicology studies in rodents (see section 5.3). In controlled clinical trials in thrombocytopenic patients with chronic hepatitis C receiving interferon therapy (n=1,439), progression of pre-existing baseline cataract or development of new cataract was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, were reported in patients with chronic hepatitis C receiving interferon, ribavirin, and eltrombopag (2% in the eltrombopag group and 2% in the placebo group). Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within retinal tissue. Routine ophthalmological monitoring of patients is recommended.
QT/QTc prolongation
A QTc study in healthy volunteers at a daily dose of 150 mg of eltrombopag did not show a clinically significant effect on cardiac repolarization. QTc prolongation has been reported in clinical trials with ITP patients and thrombocytopenic patients with chronic hepatitis C. The clinical significance of these QTc prolongation cases is unknown.
Loss of response to eltrombopag
Loss of response or failure to maintain platelet response to eltrombopag within the recommended therapeutic range should prompt investigation for causative factors, including increased bone marrow reticulin.
Paediatric population
The warnings and precautions for ITP mentioned above also apply to the paediatric population.
Interference with laboratory tests
Eltrombopag is highly coloured and therefore has the potential to interfere with certain laboratory tests. In patients taking Eltrombopag Cipla, changes in serum colour and interference with total bilirubin and creatinine tests have been reported. If laboratory results and clinical observations are inconsistent, repeating the test using another method may help determine result validity.
Information on excipients
Eltrombopag Cipla 25 mg, 50 mg, and 75 mg
Sodium content
This medicinal product contains less than 1 mmol of sodium (23 mg) per film-coated tablet, i.e., essentially 'sodium-free'.
Eltrombopag Cipla 50 mg
Orange yellow
May cause allergic reactions.
4.5 Interactions with other medicinal products and other forms of interaction
Effects of eltrombopag on other medicinal products
HMG-CoA reductase inhibitors
Administration of eltrombopag 75 mg once daily for 5 days to 39 healthy adult subjects, together with a single 10 mg dose of rosuvastatin, a substrate of OATP1B1 and BCRP, increased rosuvastatin plasma Cmax by 103% (90% confidence interval [CI]: 82%, 126%) and AUC by 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. When co-administered with eltrombopag, consideration should be given to reducing the statin dose, and careful monitoring for statin adverse reactions should be undertaken (see section 5.2).
OATP1B1 and BCRP substrates
Co-administration of eltrombopag with OATP1B1 substrates (e.g., methotrexate) and BCRP substrates (e.g., topotecan and methotrexate) should be undertaken with caution (see section 5.2).
Cytochrome P450 substrates
In studies using human liver microsomes, eltrombopag (up to 100 µM) showed no inhibition in vitro of CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11, and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interaction is expected when eltrombopag and CYP450 substrates are administered concomitantly (see section 5.2).
HCV protease inhibitors
No dose adjustment is required when eltrombopag is co-administered with telaprevir or boceprevir.
Co-administration of a single 200 mg dose of eltrombopag with telaprevir 750 mg every 8 hours did not alter telaprevir plasma exposure.
Co-administration of a single 200 mg dose of eltrombopag with boceprevir 800 mg every 8 hours did not alter boceprevir AUC, but increased Cmax by 20% and decreased Cmin by 32%.
The clinical relevance of the Cmin reduction is unknown: more careful clinical and laboratory monitoring for HCV suppression is recommended.
Effects of other medicinal products on eltrombopag
Cyclosporine
Reduced exposure to eltrombopag was observed with co-administration of 200 mg and 600 mg cyclosporine (BCRP inhibitor). Co-administration of cyclosporine 200 mg reduced eltrombopag Cmax and AUC by 25% and 18%, respectively. Co-administration of cyclosporine 600 mg reduced eltrombopag Cmax and AUC by 39% and 24%, respectively. Dose adjustment of eltrombopag during treatment is permitted based on the patient's platelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 or 3 weeks when eltrombopag is co-administered with cyclosporine. An increase in eltrombopag dose may be necessary based on platelet count results.
Polyvalent cations (chelation)
Eltrombopag chelates polyvalent cations such as iron, calcium, magnesium, aluminium, selenium, and zinc. Administration of a single 75 mg dose of eltrombopag with an antacid containing a polyvalent cation (1,524 mg aluminium hydroxide and 1,425 mg magnesium carbonate) reduced eltrombopag plasma AUC by up to 70% (90% CI: 64%, 76%) and Cmax by up to 70% (90% CI: 62%, 76%). Eltrombopag should be taken at least 2 hours before or 4 hours after products such as antacids, dairy products, or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2).
Lopinavir/ritonavir
Co-administration of eltrombopag with lopinavir/ritonavir may cause a reduction in eltrombopag exposure. Administration of a single 100 mg dose of eltrombopag with repeated 400/100 mg doses of lopinavir/ritonavir twice daily resulted in a 17% reduction in eltrombopag AUC (90% CI: 6.6%, 26.6%). Therefore, caution should be exercised when administering eltrombopag concomitantly with lopinavir/ritonavir. Platelet count should be carefully monitored to ensure appropriate clinical management of eltrombopag dosing when lopinavir/ritonavir therapy is initiated or discontinued.
Inhibitors and inducers of CYP1A2 and CYP2C8
Eltrombopag is metabolized through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). It is unlikely that medicinal products that inhibit or induce a single enzyme will significantly affect plasma concentrations of eltrombopag, whereas medicinal products that inhibit or induce multiple enzymes have the potential to increase (e.g., fluvoxamine) or decrease eltrombopag exposure.
HCV protease inhibitors
Results from a drug-drug interaction pharmacokinetic study show that repeated co-administration of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single 200 mg dose of eltrombopag did not alter eltrombopag plasma exposure at clinically significant levels.
Medicinal products for the treatment of ITP
Medicinal products used in clinical trials for the treatment of ITP in combination with eltrombopag included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulins (IVIG), and anti-D immunoglobulins. Platelet count should be monitored when eltrombopag is administered in combination with other medicinal products for the treatment of ITP to prevent platelet count from exceeding the recommended range (see section 4.2).
Interaction with food
Administration of eltrombopag tablets or oral suspension powder with a high-calcium meal (e.g., a meal including dairy products) significantly reduced AUC and Cmax. Administration with a high-calcium meal or low-calcium foods [<50 mg calcium] did not alter eltrombopag plasma exposure at clinically significant levels (see section 4.2).
Administration of a single 50 mg eltrombopag tablet with a standard high-calorie, high-fat breakfast including dairy products reduced mean plasma AUC by 59% and mean Cmax by 65%.
Administration of a single 25 mg dose of eltrombopag oral suspension powder with a high-calcium, moderate-fat, moderately caloric meal reduced mean plasma AUC by 75% and mean Cmax by 79%. This reduction in exposure was attenuated when a single 25 mg dose of eltrombopag oral suspension powder was administered 2 hours before a high-calcium meal (mean AUC decreased by 20% and mean Cmax by 14%).
Low-calcium food (calcium <50 mg), including fruit, raw ham, beef, and unfortified fruit juice (without added calcium, magnesium, or iron), unfortified soy milk, and unfortified grain, did not significantly impact eltrombopag plasma exposure, regardless of calorie and fat content (see sections 4.2 and 4.5).
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data, or limited data, on the use of eltrombopag in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk in humans is unknown.
Eltrombopag Cipla is not recommended during pregnancy.
Women of childbearing potential / Contraception in men and women
Eltrombopag Cipla is not recommended in women of childbearing potential who are not using contraception.
Lactation
It is not known whether eltrombopag/metabolites are excreted in human milk. Animal studies have shown that eltrombopag is likely excreted in milk (see section 5.3); therefore, risk to the breastfed infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to continue/abstain from Eltrombopag Cipla therapy, taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the woman.
Fertility
Fertility was not affected in male and female rats at exposures comparable to those in humans. However, risk in humans cannot be excluded (see section 5.3).
4.7 Effects on ability to drive and use machines
Eltrombopag has a negligible effect on the ability to drive and use machines. The patient's clinical status 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 judgment, motor, and cognitive skills.
4.8 Undesirable effects
Summary of safety profile
Adult and paediatric autoimmune thrombocytopenia
The safety of Eltrombopag was evaluated in adult patients (N=763) based on the pooled data from the double-blind, placebo-controlled trials TRA100773A and B, TRA102537 (RAISE), and TRA113765, in which 403 patients were exposed to Eltrombopag and 179 to placebo, in addition to data from completed open-label trials (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND), and TRA112940 (see section 5.1). Patients received study drug for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increased alanine aminotransferase, and back pain.
The safety of Eltrombopag in paediatric patients (aged 1 to 17 years) with previously treated ITP was demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double-blind, placebo-controlled, randomized, open-label study. Patients were randomized 2:1 to receive Eltrombopag (n=63) or placebo (n=29) for up to 13 weeks in the randomized phase. PETIT (TRA108062) was a three-part, staggered-cohort, open-label, double-blind, placebo-controlled study. Patients were randomized 2:1 to receive Eltrombopag (n=44) or placebo (n=21) for up to 7 weeks. The adverse reaction profile was comparable to that observed in adults, with some additional adverse reactions marked with ♦ in the following table. The most common adverse reactions in paediatric patients aged 1 year and older with ITP (≥3% and higher than placebo) were upper respiratory tract infections, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache, and rhinorrhoea.
Thrombocytopenia with HCV infection in adult patients
The multicentre studies ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805) were randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Eltrombopag in thrombocytopenic patients with HCV infection who were otherwise eligible to start antiviral therapy. In the HCV studies, the safety population consisted of all randomized patients who received double-blind medication during part 2 of ENABLE 1 (eltrombopag-treated n=450, placebo-treated n=232) and ENABLE 2 (eltrombopag-treated n=506, placebo-treated n=252). Patients were analysed according to treatment received (total double-blind safety population: eltrombopag n=955, placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included: headache, anaemia, decreased appetite, cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, fever, fatigue, influenza-like illness, asthenia, chills, and oedema.
Severe aplastic anaemia in adult patients
The safety of Eltrombopag Cipla in severe aplastic anaemia was evaluated in a single-arm, open-label clinical study (N=43), in which 11 patients (26%) were treated for >6 months and 7 patients (16%) for >1 year (see section 5.1). The most common adverse reactions occurring (in at least 10% of patients) included: headache, dizziness, cough, oropharyngeal pain, rhinorrhoea, nausea, diarrhoea, abdominal pain, increased transaminases, arthralgia, limb pain, muscle spasms, fatigue, and pyrexia.
List of adverse reactions
Adverse reactions in studies in adult patients with ITP (N=763), paediatric patients with ITP (N=171), HCV infection (N=1,520), SAA (N=43), and post-marketing reports are listed below by system organ class according to MedDRA and frequency. Within each system organ class, ADRs are listed in order of decreasing frequency, starting with the most frequent. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (frequency cannot be estimated from the available data).
Clinical study population in ITP

♦ Additional adverse reactions observed in studies in the pediatric population (from 1 to 17 years).
Increased alanine aminotransferase and aspartate aminotransferase may occur
simultaneously, although at a lower frequency.
Term grouped with preferred terms: acute renal failure and renal failure.
Clinical study population in HCV infection (in combination with interferon-based antiviral therapy and ribavirin)

Term grouped with preferred terms oliguria, renal failure, and renal impairment
Clinical study population in SAA

Description of selected adverse reactions
Thrombotic/thromboembolic events (TEEs)
In 3 controlled and 2 uncontrolled clinical studies, among adult patients with ITP receiving eltrombopag (n=446), 17 patients experienced a total of 19 thromboembolic events, 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 4.4).
In a placebo-controlled study (n=288, safety-evaluable population), after 2 weeks of treatment prior to invasive procedures, 6 out of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 portal venous system TEEs, compared to 2 out of 145 (1%) in the placebo group who experienced 3 TEEs. Five of the 6 eltrombopag-treated patients who experienced TEEs had platelet counts >200,000/µL.
No specific risk factors were identified in patients who experienced a TEE, except for a platelet count ≥200,000/µL (see section 4.4).
In controlled studies in thrombocytopenic patients with HCV infection (n=1,439), 38 out of 955 (4%) patients treated with eltrombopag experienced TEEs, compared to 6 out of 484 (1%) in the placebo group. Portal vein thrombosis was the most common TEE in both treatment groups (2% in eltrombopag-treated patients versus <1% in placebo) (see section 4.4). Patients with low albumin levels (≤35 g/L) or MELD score ≥10 had a twofold higher risk of TEE compared to those with higher albumin levels; those aged ≥60 years had a twofold higher risk of TEE compared to younger patients.
Hepatic decompensation (use with interferon)
Patients with chronic HCV hepatitis and cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV infection, hepatic decompensation (ascites, hepatic encephalopathy, esophageal variceal bleeding, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) compared to the placebo arm (6%). In patients with low albumin levels (≤35 g/L) or baseline MELD score ≥10, a threefold higher risk of hepatic decompensation and an increased risk of fatal adverse events occurred compared to those with less advanced liver disease. Eltrombopag should be administered to such patients only after careful consideration of the expected benefits versus risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4).
Hepatotoxicity
In controlled clinical studies of eltrombopag in chronic ITP, increases in serum ALT, AST, and bilirubin were observed (see section 4.4).
These increases were mostly mild (Grade 1–2), reversible, and not accompanied by clinically significant symptoms indicating impaired liver function. In the 3 placebo-controlled studies conducted in adults with chronic ITP, one patient in the placebo group and one in the eltrombopag group experienced Grade 4 abnormalities in liver function tests. In two placebo-controlled studies in pediatric patients (aged 1 to 17 years) with chronic ITP, ALT≥3 × ULN was observed in 4.7% and 0% of the eltrombopag and placebo groups, respectively.
In 2 controlled clinical studies in patients with HCV, ALT or AST≥3 × ULN was observed in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients treated with eltrombopag in combination with peginterferon/ribavirine therapy will develop indirect hyperbilirubinemia.
Overall, total bilirubin ≥1.5 × ULN was observed in 76% and 50% of the eltrombopag and placebo groups, respectively.
In the single-arm Phase II study of eltrombopag monotherapy in refractory SAA, ALT or AST>3 × ULN together with total (indirect) bilirubin >1.5 × ULN were observed in 5% of patients. Total bilirubin >1.5 × ULN was observed in 14% of patients.
Thrombocytopenia after treatment discontinuation
In 3 controlled clinical studies in ITP, transient reductions in platelet count to levels below baseline were observed after treatment discontinuation in 8% of the eltrombopag group and 8% of the placebo group, respectively (see section 4.4).
Increased bone marrow reticulin
Within the clinical program, no patient showed evidence of clinically relevant bone marrow abnormalities or clinical signs indicating bone marrow dysfunction. In a small number of ITP patients, treatment with eltrombopag was discontinued due to bone marrow reticulin (see section 4.4).
Cyto genetic abnormalities
In the Phase II clinical study in refractory SAA with eltrombopag at an initial dose of 50 mg/day (increased every 2 weeks up to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 patients had chromosome 7 abnormalities)]. The median time to a cytogenetic abnormality was 2.9 months.
In the Phase II clinical study in refractory SAA with eltrombopag at a dose of 150 mg/day (with dose adjustments based on ethnicity and age as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 patients had chromosome 7 abnormalities)]. All 7 patients had normal baseline cytogenetics. Six patients developed cytogenetic abnormalities by the third month of eltrombopag therapy, and one patient developed a cytogenetic abnormality by the sixth month.
Haematological malignancies
Myelodysplastic syndrome (MDS) was diagnosed in 3 patients (7%) in the single-arm open-label clinical study in SAA after treatment with eltrombopag. In the two ongoing studies (ELT116826 and ELT116643), MDS or acute myeloid leukaemia (AML) was diagnosed in 1/28 (4%) and 1/62 (2%) patients, respectively.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important, as it allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system available at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
4.9 Overdose
In case of overdose, platelet count may increase excessively and lead to thrombotic/thromboembolic complications. In the event of overdose, consider oral administration of a preparation containing a metallic cation, such as calcium-, aluminium-, or magnesium-based preparations, to chelate eltrombopag and thereby limit its absorption. Platelet count should be closely monitored. Treatment with eltrombopag should be restarted in accordance with dosage and administration recommendations (see section 4.2).
In clinical studies, there was one reported case of overdose in which the patient ingested 5,000 mg of eltrombopag. The patient experienced nausea, vomiting, diarrhoea, abdominal pain, headache, dizziness, fatigue, and AST elevation. Liver enzymes measured between Day 2 and Day 18 after ingestion peaked at 1.6 times ULN for AST, 3.9 times ULN for ALT, and 2.4 times ULN for total bilirubin. Platelet count was 672,000/µL on Day 18 after ingestion, with a maximum platelet count of 929,000/µL. All events resolved without sequelae following treatment.
Since eltrombopag is not significantly renally excreted and is highly protein-bound, haemodialysis is not expected to be an effective method for enhancing its elimination.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic category: Antihemorrhagics, other systemic hemostatics, ATC code: B02BX05.
Mechanism of action
Thrombopoietin (TPO) is the primary cytokine involved in the regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO receptor (TPO-R). Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates a downstream signaling cascade that is similar but not identical to that of endogenous TPO, promoting proliferation and differentiation of bone marrow progenitor cells.
Clinical efficacy and safety
Studies in immune (primary) thrombocytopenia (ITP)
Two Phase III, randomized, double-blind, placebo-controlled 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 ITP.
Overall, eltrombopag was administered to 277 patients with ITP for at least 6 months and to 202 patients for at least 1 year. The single-arm Phase II TAPER study (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce a sustained response following treatment discontinuation in 105 adult patients with ITP who had relapsed or failed to respond to first-line corticosteroid therapy.
Double-blind, placebo-controlled studies
RAISE: 197 patients with ITP were randomized in a 2:1 ratio to receive eltrombopag (n=135) or placebo (n=62). Randomization was stratified according to splenectomy status, use of background ITP medications, and baseline platelet count. The dose of eltrombopag was adjusted during the 6-month treatment period based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg. From Day 29 to the end of treatment, 15–28% of patients receiving eltrombopag were maintained on doses ≤25 mg, and 29–53% received 75 mg.
In addition, patients were allowed to gradually taper concomitant ITP medications and to receive rescue treatments as per local treatment guidelines. More than half of all patients in each treatment group had received ≥3 prior ITP therapies, and 36% had undergone prior splenectomy.
The median baseline platelet count was 16,000/µL in both treatment groups. In the eltrombopag group, platelet counts remained above 50,000/µL at all visits during therapy, starting from Day 15; in contrast, the median platelet count in the placebo group remained below 30,000/µL throughout the study.
A significantly greater number of patients in the eltrombopag group achieved a platelet count response of 50,000–400,000/µL in the absence of rescue therapy compared to placebo during the 6-month treatment period (p <0.001). Fifty-four percent of patients treated with eltrombopag and 13% of those treated with placebo achieved this response level after 6 weeks of treatment. A similar platelet response was maintained throughout the study, with 52% and 16% of patients responding at the end of the 6-month treatment period, respectively.
Table 3 Secondary efficacy results from the RAISE study

a Adjusted for stratification randomization variables using a logistic regression model
b 21 out of 63 (33%) eltrombopag-treated patients with ITP who were receiving background ITP medication permanently discontinued all background ITP medications.
At baseline, more than 70% of patients with ITP in each treatment group reported bleeding of any type (WHO Grade 1–4), and more than 20% reported clinically significant bleeding (WHO Grade 2–4), respectively. The proportion of eltrombopag-treated patients with bleeding of any type (Grades 1–4) and clinically significant bleeding (Grades 2–4) decreased from baseline by approximately 50% from Day 15 through the end of treatment over the entire 6-month treatment period.
TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as patients with ITP who achieved an increase in platelet count to ≥ 50,000/µL on Day 43 from a baseline count of <30,000/µL; patients who discontinued early due to a platelet count >200,000/µL were considered responders, while those who discontinued for any other reason were considered non-responders, regardless of platelet count. A total of 114 patients with previously treated ITP were randomized in a 2:1 ratio to receive eltrombopag (n=76) or placebo (n=38).
Table 4 Efficacy results from study TRA100773B

a Logistic regression model adjusted for randomization stratification variables
In both the RAISE and TRA100773B studies, the response to eltrombopag compared to placebo was similar
regardless of concomitant ITP medication, splenectomy status, and baseline platelet count (≤15,000/µl,

15,000/µl) at randomization.
In the RAISE and TRA100773B studies, among the subgroup of ITP patients with a baseline platelet count ≤15,
000/µl, the required platelet count level (>50,000/µl) for median platelet count was not achieved, although in
both studies 43% of these patients treated with eltrombopag responded at the end of the 6-week treatment
period. Furthermore, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/µl treated with
eltrombopag responded at the end of the 6-month treatment period. In the RAISE study, between 42% and
60% of patients treated with eltrombopag received 75 mg from Day 29 until the end of treatment.

Open-label, uncontrolled studies

REPEAT (TRA108057):
This open-label, repeated-dose study (3 cycles of 6 weeks of treatment separated by 4-week treatment-free
intervals) showed that intermittent, multiple-cycle use of eltrombopag did not result in a reduced response.

EXTEND (TRA105325):
Eltrombopag was administered to 302 patients with ITP in this open-label extension study; 218 completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years, and 18 completed 6 years. The median baseline platelet count at years 1 through 7 of the study was 85,000/µl, 85,000/µl, 105,000/µl, 64,000/µl, 75,000/µl, 119,000/µl, and 76,000/µl, respectively.

TAPER (CETB115J2411):
This was a single-arm Phase II study involving patients with ITP treated with eltrombopag after failure of first-line corticosteroid therapy, regardless of time from diagnosis. A total of 105 patients were enrolled in the study and started treatment with eltrombopag 50 mg once daily (25 mg once daily for patients of Asian/Southeast Asian origin). The dose of eltrombopag was adjusted during the treatment period based on individual platelet counts with the goal of achieving a platelet count ≥100,000/µl.

Of the 105 patients enrolled in the study and who received at least one dose of eltrombopag, 69 patients (65.7%) completed treatment and 36 patients (34.3%) discontinued treatment prematurely.

Analysis of sustained response off-treatment
The primary endpoint was the percentage of patients achieving sustained off-treatment response by Month 12. Patients who achieved a platelet count ≥100,000/µl and maintained platelet counts around 100,000/µl for 2 months (no count below 70,000/µl) were eligible for dose reduction and discontinuation of treatment. To be considered as having achieved a sustained off-treatment response, a patient had to maintain platelet counts ≥30,000/µl, in the absence of bleeding events or use of rescue therapy, both during the dose reduction period and after treatment discontinuation up to Month 12.

The duration of dose reduction was individualized based on initial dose and patient response. The dose reduction regimen recommended 25 mg reductions every 2 weeks in the presence of stable platelet counts. After reducing the daily dose to 25 mg for 2 weeks, the 25 mg dose was then administered on alternate days for 2 weeks until treatment discontinuation. For patients of East/Southeast Asian origin, dose reduction was performed in smaller increments of 12.5 mg every second week. In case of relapse (defined as platelet count <30,000/µl), patients were offered a new cycle of treatment with eltrombopag at the appropriate starting dose.

Eighty-nine patients (84.8%) achieved a complete response (platelet count ≥100,000/µl) (Step 1, Table 5), and 65 patients (61.9%) maintained complete response for at least 2 months without platelet counts below 70,000/µl (Step 2, Table 5). Forty-four patients (41.9%) were able to undergo dose reduction of eltrombopag up to treatment discontinuation while maintaining platelet counts ≥30,000/µl in the absence of bleeding events or use of rescue therapy (Step 3, Table 5).

The study met its primary objective, demonstrating that eltrombopag was able to induce a sustained off-treatment response, in the absence of bleeding events or use of rescue therapy, by Month 12 in 32 of the 105 enrolled patients (30.5%; p<0.0001; 95% CI: 21.9, 40.2) (Step 4, Table 5). By Month 24, 20 of the 105 enrolled patients (19.0%; 95% CI: 12.0, 27.9) maintained a sustained off-treatment response in the absence of bleeding events or use of rescue therapy (Step 5, Table 5).

The median duration of sustained response after treatment discontinuation by Month 12 was 33.3 weeks (min-max: 4–51), and the mean duration of sustained response after treatment discontinuation by Month 24 was 88.6 weeks (min-max: 57–107).

Following dose reduction and discontinuation of eltrombopag, 12 patients experienced loss of response; 8 of them restarted eltrombopag and 7 showed a recovery response.

During the 2-year follow-up, 6 out of 105 patients (5.7%) experienced thromboembolic events: 3 patients (2.9%) had deep vein thrombosis, 1 patient (1.0%) had superficial venous thrombosis, 1 patient (1.0%) had cavernous sinus thrombosis, 1 patient (1.0%) had cerebrovascular events, and 1 patient (1.0%) had pulmonary embolism. Of the 6 patients, 4 experienced thromboembolic events reported as Grade 3 or higher, and 4 experienced thromboembolic events reported as serious. No fatal cases were reported.

Twenty out of 105 patients (19.0%) experienced mild to severe bleeding events during treatment before the start of dose reduction. Five out of 65 patients (7.7%) who initiated dose reduction experienced mild to moderate bleeding events during the reduction phase. No severe bleeding events occurred during dose reduction. Two out of 44 patients (4.5%) who reduced and discontinued eltrombopag experienced mild to moderate bleeding events after treatment discontinuation up to Month 12. No severe bleeding events occurred during this period. None of the patients who discontinued eltrombopag and entered the second year of follow-up experienced bleeding events during the second year. Two fatal intracranial bleeding events were reported during the two-year follow-up. Both events occurred during treatment, not in the context of dose reduction. These events were not considered related to study treatment.

The overall safety analysis is consistent with previously reported data, and the benefit-risk assessment remains unchanged for the use of eltrombopag in patients with ITP.

Table 5 Percentage of patients with sustained off-treatment response at Month 12 and Month 24 (full analysis set) in the TAPER study

Results of response analysis of treatment over time from ITP diagnosis
An ad-hoc analysis was conducted on the 105 patients based on time from ITP diagnosis to evaluate the
response to eltrombopag across four different ITP categories according to time from diagnosis
(newly diagnosed ITP <3 months, persistent ITP from 3 to <6 months, persistent ITP from 6 to ≤12 months, and
chronic ITP >12 months). 49% of patients (n=51) had an ITP diagnosis <3 months, 20% (n=21) from 3 to
<6 months, 17% (n=18) from 6 to <12 months, and 14% (n=15) from >12 months.
Up to the cutoff date (22 October 2021), patients were exposed to eltrombopag for a median duration
(Q1–Q3) of 6.2 months (2.3–12.0 months). The median platelet count (Q1–Q3) at baseline was 16,000/µL (7,800–
28,000/µL).
Platelet response, defined as platelet count ≥50,000/µL at least once by week 9 without rescue therapy,
was achieved in 84% (95% CI: 71% to 93%) of patients with newly diagnosed ITP, in 91% (95% CI: 70% to 99%) and 94% (95% CI: 73% to 100%) of patients with persistent ITP (i.e., ITP diagnosed from 3 to <6 months and from 6 to ≤12 months, respectively), and in 87% (95% CI: 60% to 98%) of patients with chronic ITP.
The complete response rate, defined as platelet count ≥100,000/µL at least once by week 9 without rescue therapy, was 75% (95% CI: 60% to 86%) in patients with newly diagnosed ITP, 76% (95% CI: 53% to 92%) and 72% (95% CI: 47% to 90%) in patients with persistent ITP (ITP diagnosed from 3 to <6 months and from 6 to ≤12 months, respectively), and 87% (95% CI: 60% to 98%) in patients with chronic ITP.
The sustained response rate, defined as platelet count ≥50,000/µL for at least 6 out of 8 consecutive assessments without rescue therapy during the first 6 months of study, was 71% (95% CI: 56% to 83%) in patients with newly diagnosed ITP, 81% (95% CI: 58% to 95%) and 72% (95% CI: 47% to 90.3%) in patients with persistent ITP (ITP diagnosed from 3 to <6 months and from 6 to ≤12 months, respectively), and 80% (95% CI: 52% to 96%) in patients with chronic ITP.
When assessed using the WHO bleeding risk assessment scale, the proportion of patients with newly diagnosed ITP and persistent ITP without bleeding at week 4 ranged between 88% and 95%, compared to 37% to 57% at baseline. For patients with chronic ITP, it was 93% compared to 73% at baseline.
The safety of eltrombopag was consistent across all ITP categories and in line with its known safety profile.
No clinical studies have been conducted comparing eltrombopag with other therapeutic options (e.g.,
splenectomy). The long-term safety of eltrombopag should be considered before initiating treatment.
Paediatric population (age between 1 and 17 years)
The safety and efficacy of eltrombopag in paediatric patients was evaluated in two studies.
TRA115450 (PETIT2): The primary endpoint was sustained response, defined as the percentage of patients
treated with eltrombopag versus placebo who achieved a platelet count ≥50,000/µL for at least 6 weeks out of 8 (in the absence of rescue therapy) between weeks 5 and 12 during the double-blind randomized period. Patients had been diagnosed with chronic ITP for at least 1 year and were refractory or relapsed after at least one prior ITP therapy, or unable to continue other ITP treatments for medical reasons, and had a platelet count <30,000/µL. Ninety-two patients were randomized by age into three cohorts (2:1) to receive eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag was adjusted based on individual platelet counts.
Overall, a significantly higher proportion of patients in the eltrombopag group (40%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9], p <0.001) compared to the placebo group (3%), with similar results observed across the three age cohorts (Table 6).
Table 6 Sustained platelet response rates by age cohort in paediatric patients with chronic ITP

A statistically smaller number of eltrombopag-treated patients required rescue treatment during the randomized period compared to placebo-treated patients (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 bleeding (WHO Grades 1–4). By week 12, the percentage of eltrombopag-treated patients reporting bleeding had halved from baseline (36%). In comparison, by week 12, 55% of placebo-treated patients reported no bleeding.
Patients were allowed to reduce or discontinue background 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) background ITP therapy, primarily corticosteroids, without requiring rescue therapy.

TRA108062 (PETIT): The primary endpoint was the percentage of patients achieving a platelet count ≥50,000/µl at least once between weeks 1 and 6 of the randomized period. Patients had been diagnosed with ITP for at least 6 months, were refractory or had relapsed after at least one prior ITP therapy, and had a platelet count <30,000/µl (n=67). During the randomized period of the study, patients were randomized by age in a 2:1 ratio to receive eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag was adjusted based on individual platelet counts.
Overall, a significantly higher proportion of patients in the eltrombopag group (62%) compared to the placebo group (32%) achieved the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3]; p=0.011).
A sustained response was observed in 50% of initial responders for 20 out of 24 weeks in the PETIT 2 study and for 15 out of 24 weeks in the PETIT study.

Studies in thrombocytopenia associated with chronic hepatitis C virus (HCV)
The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomized, double-blind, placebo-controlled studies. 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 antiviral agents. In both studies, patients with a platelet count <75,000/µl were enrolled and stratified by baseline platelet count (<50,000/µl vs ≥50,000/µl to <75,000/µl), HCV RNA at screening (<800,000 IU/ml vs ≥800,000 IU/ml), and HCV genotype (genotype 2/3 vs genotype 1/4/6).

Baseline disease characteristics were similar in both studies and consistent with the population of patients with HCV infection and compensated cirrhosis. The majority of patients had HCV genotype 1 (64%) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had previously been treated for HCV infection, primarily with pegylated interferon plus ribavirin. The median platelet count at baseline was 59,500/µl in both treatment groups: 0.8%, 28%, and 72% of enrolled patients had platelet counts <20,000/µl, <50,000/µl, and ≥50,000/µl, respectively.

The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase platelet count to ≥90,000/µl in ENABLE 1 and ≥100,000/µl in ENABLE 2. The median time to achieve the target platelet count of ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was 2 weeks.

The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of HCV-infected patients with undetectable HCV RNA 24 weeks after completion of the planned treatment period.

In both HCV infection studies, a significantly higher proportion of patients treated with eltrombopag (n=201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The improvement in the proportion of patients achieving SVR was consistent across all subgroups within the randomization strata (baseline platelet count (<50,000 vs ≥50,000), viral load (<800,000 IU/ml vs ≥800,000 IU/ml), and genotype (2/3 vs 1/4/6)).

Table 7 Sustained virologic response in patients with HCV infection in ENABLE 1 and ENABLE 2

a Eltrombopag administered in combination with peginterferon alfa-2a (180 µg once weekly for 48 weeks for genotypes 1/4/6; for 24 weeks for genotypes 2/3) plus ribavirin (800 to 1,200 mg daily in two divided oral doses)
b Eltrombopag administered in combination with peginterferon alfa-2b (1.5 µg/kg once weekly for 48 weeks for genotype 1/4/6; for 24 weeks for genotype 2/3) plus ribavirin (800 to 1,400 mg orally in two divided doses)
c Platelet count target was ≥ 90,000/µL in ENABLE 1 and ≥ 100,000/µL in ENABLE 2. In ENABLE 1, 682 patients were randomized into the antiviral treatment phase; however, 2 patients withdrew consent before receiving antiviral therapy
d p value <0.05 for eltrombopag versus placebo
e 64% of patients enrolled in studies ENABLE 1 and ENABLE 2 had genotype 1
f Post-hoc analysis
Other secondary observations from the studies included the following: a significantly lower number of patients treated with eltrombopag prematurely discontinued antiviral therapy compared to those treated with placebo (45% vs. 60%, p<0.0001). A higher percentage of patients treated with eltrombopag did not require any antiviral dose reduction compared to those treated with placebo (45% versus 27%). Treatment with eltrombopag delayed and reduced the number of peginterferon dose reductions.
5.2 Pharmacokinetic properties
Pharmacokinetics
Plasma concentration-time data for eltrombopag collected from 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population pharmacokinetic analysis. Estimates of AUC and plasma C values for eltrombopag in patients with ITP are presented (Table 8).
Table 8 Geometric mean (95% confidence interval) of plasma pharmacokinetic parameters of eltrombopag at steady state in adults with ITP

a AUC and C estimates based on post-hoc population pharmacokinetic values.
Plasma concentration-time data of eltrombopag collected from 590 patients with HCV infection enrolled in the phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV infection enrolled in the phase II study TPL102357 and from healthy adult subjects in a population pharmacokinetic analysis. Estimates of plasma C and AUC of eltrombopag in patients with HCV infection enrolled in the phase III studies are listed for each dose in Table 9.
Table 9 Geometric mean (95% CI) at steady-state of plasma pharmacokinetic parameters of eltrombopag in patients with chronic HCV infection

The data are presented as geometric mean (95% CI).
AUC and C were based on post-hoc estimates from population pharmacokinetic modelling at the highest dose in data from each patient.

Absorption and bioavailability
Eltrombopag is absorbed with peak concentrations occurring 2 to 6 hours after oral administration. Concomitant administration of eltrombopag with antacids and other products containing polyvalent cations, such as dairy products and mineral supplements, significantly reduces exposure to eltrombopag (see section 4.2). In a relative bioavailability study in adults, the oral suspension powder achieved a plasma AUC that was 22% higher than the film-coated tablet formulation. The absolute oral bioavailability of eltrombopag after administration in humans has not been determined. Based on urinary excretion and metabolites excreted in faeces, oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%.

Distribution
Eltrombopag is highly bound to human plasma proteins (>99.9%), predominantly to albumin. Eltrombopag is a substrate of BCRP, but not a substrate of P-glycoprotein or OATP1B1.

Metabolism
Eltrombopag is primarily metabolized via cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In a human study with radiolabelled drug, eltrombopag accounted for approximately 64% of the plasma radiolabel AUC. Minor metabolites due to glucuronidation and oxidation were also identified. In vitro studies suggest that CYP1A2 and CYP2C8 are involved in oxidation, UGT1A3 is responsible for glucuronidation, and gut bacteria in the lower gastrointestinal tract may be responsible for cleavage.

Elimination
After absorption, eltrombopag is extensively metabolized. The predominant route of excretion is via faeces (59%), with 31% of the dose recovered in urine as metabolites. Unchanged drug (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21–32 hours.

Pharmacokinetic interactions
Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the overall clearance of eltrombopag. In vitro studies indicate that multiple UGT enzymes contribute to glucuronidation, and no single UGT enzyme is primarily responsible. Clinically significant interactions with drugs involving glucuronidation are not expected due to the limited contribution of individual UGT enzymes to eltrombopag glucuronidation and the potential for co-administered medicinal products.

Approximately 21% of an eltrombopag dose may undergo oxidative metabolism. Studies in human liver microsomes have identified CYP1A2 and CYP2C8 as the enzymes responsible for oxidative metabolism (see section 4.5).

In vitro studies have shown that eltrombopag is an inhibitor of the OATP1B1 transporter and is an inhibitor of the BCRP transporter; in a clinical interaction study, eltrombopag increased exposure to rosuvastatin, a substrate of OATP1B1 and BCRP (see section 4.5). In clinical studies with eltrombopag, a 50% dose reduction of statins has been recommended.

Eltrombopag chelates polyvalent cations such as iron, calcium, magnesium, aluminium, selenium, and zinc (see sections 4.2 and 4.5).

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

Special patient populations

Renal impairment
The pharmacokinetics of eltrombopag were studied after administration in adult patients with renal impairment. After a single 50 mg dose, eltrombopag AUC was 32% to 36% lower in patients with mild to moderate renal impairment and 60% lower in patients with severe renal impairment compared to healthy volunteers. There was substantial variability and significant overlap in exposures between renally impaired patients and healthy volunteers. Free (active) eltrombopag concentrations for this highly protein-bound drug were not measured. Patients with impaired renal function should use eltrombopag with caution and under close monitoring, for example by measuring serum creatinine and/or urine analysis (see section 4.2). The efficacy and safety of eltrombopag have not been established in patients with both moderate to severe renal impairment and hepatic impairment.

Hepatic impairment
The pharmacokinetics of eltrombopag were studied after administration in adult patients with hepatic impairment. After a single 50 mg dose, eltrombopag AUC was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in patients with moderate to severe hepatic impairment compared to healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Free (active) eltrombopag concentrations for this highly protein-bound drug were not measured.

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

Therefore, eltrombopag should not be used in patients with ITP and moderate to severe hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal vein thrombosis (see sections 4.2 and 4.4). For patients with HCV infection, initiate eltrombopag at a dose of 25 mg once daily (see section 4.2).

Ethnicity
The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy adults (31 East Asian) and 88 patients with ITP (18 East Asian). Based on estimates from population pharmacokinetic analyses, East Asian patients with ITP had eltrombopag plasma AUC values approximately 49% higher than non-East Asian patients, who were predominantly Caucasian (see section 4.2).

The influence of East/Southeast Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV infection (145 East Asian and 69 Southeast Asian). Based on estimates from the population pharmacokinetic analysis, East/Southeast Asian patients had eltrombopag plasma AUC values approximately 55% higher than patients of other races, who were predominantly Caucasian (see section 4.2).

Sex
The influence of sex on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 111 healthy adults (14 female) and 88 patients with ITP (57 female). Based on estimates from population pharmacokinetic analyses, female ITP patients had eltrombopag plasma AUC values approximately 23% higher than male patients, without adjustment for body weight differences.

The influence of sex on the pharmacokinetics of eltrombopag was also evaluated using population pharmacokinetic analysis in 635 patients with HCV infection (260 female). Based on model estimates, female HCV-infected patients had eltrombopag plasma AUC values approximately 41% higher than male patients.

Age
The influence of age on the pharmacokinetics of eltrombopag was evaluated using population pharmacokinetic analysis in 28 healthy subjects, 673 patients with HCV infection, and 41 patients with chronic liver disease of other etiology, with an age range of 19 to 74 years. Pharmacokinetic data for eltrombopag in patients aged ≥75 years are not available. Based on model estimates, elderly patients (≥65 years) had eltrombopag plasma AUC values approximately 41% higher than younger patients (see section 4.2).

Paediatric population (aged 1 to 17 years)
The pharmacokinetics of eltrombopag were evaluated in 168 paediatric patients with ITP in two once-daily dosing studies, TRA108062/PETIT and TRA115450/PETIT-2. Apparent oral plasma clearance of eltrombopag (CL/F) increased with increasing body weight. The effects of ethnicity and sex on plasma CL/F estimates were consistent between paediatric and adult patients. East/Southeast Asian paediatric ITP patients had eltrombopag plasma AUC approximately 43% higher than non-Asian paediatric patients. Female paediatric ITP patients had approximately 25% higher eltrombopag plasma AUC than male paediatric patients.

Eltrombopag pharmacokinetic parameters in paediatric patients with ITP are presented in Table 10.

Table 10 Geometric mean (95% CI) of steady-state pharmacokinetic parameters of plasma eltrombopag concentration in paediatric patients with ITP (dosing regimen: 50 mg once daily)

Data presented as geometric mean (95% CI). AUC and C are based on post-hoc population pharmacokinetic estimates.
5.3 Preclinical safety data
Pharmacological safety and repeated-dose toxicity
Eltrombopag does not stimulate platelet production in mice, rats or dogs due to the specificity of the unique TPO receptor. Therefore, data derived from these animals do not represent a complete model for assessing potential adverse effects related to the pharmacology of eltrombopag in humans, including reproduction and carcinogenesis studies.

Cataracts related to treatment were observed in rodents and were dose- and time-dependent. At exposures greater than 6 times the clinical exposure in humans in adult ITP patients at the dose of 75 mg/day and at exposures 3 times the clinical exposure in humans in adult HCV-infected patients at the dose of 100 mg/day (exposures based on AUC), cataracts were observed in mice after 6 weeks and in rats after 28 weeks of treatment. At exposures greater than or equal to 4 times the clinical exposure in humans in ITP patients at the dose of 75 mg/day and at exposures 2 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC), cataracts were observed in mice after 13 weeks and in rats after 39 weeks of treatment. At non-tolerated doses in pre-weaning young rats administered from day 4 to day 32 (approximately equivalent to 2 human years at the end of the administration period), ocular opacities (histology not performed) were observed at doses of 75 mg/day, corresponding to 9 times the maximum clinical human exposure in pediatric ITP patients, based on AUC. However, cataracts were not observed in young rats receiving tolerated doses equivalent to 5 times the clinical exposure in humans in pediatric ITP patients, based on AUC. Cataracts were not observed in adult dogs after 52 weeks of treatment (2 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and equivalent to the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC).

Renal tubular toxicity was observed in mouse and rat studies of up to 14 days duration at exposures generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a range of regenerative changes. Exposure at the lowest dose was 1.2 or 0.8 times the clinical exposure in humans based on AUC in adult or pediatric ITP patients at the dose of 75 mg/day and 0.6 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC). Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times the clinical exposure in humans in adult ITP patients and 3 and 2 times the clinical exposure in humans in pediatric ITP patients at the dose of 75 mg/day, and at exposures 2 times and equivalent to the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC).

Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was observed in mice, rats and dogs at doses associated with morbidity and mortality or poorly tolerated doses. No hepatic effects were observed after chronic treatment in rats (28 weeks) and dogs (52 weeks) at exposures 4 or 2 times the clinical exposure in humans in adult ITP patients and exposures 3 or 2 times the clinical exposure in humans in pediatric ITP patients at the dose of 75 mg/day, and at 2 times or equivalent to the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC).

In short-term studies, at poorly tolerated doses in rats and dogs (exposure greater than 10 or 7 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and greater than 4 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC), decreased reticulocyte count and regenerative erythroid hyperplasia of the bone marrow (in rats only) were observed. There were no notable effects on red blood cell mass or reticulocyte count after treatment up to 28 weeks in rats, 52 weeks in dogs, and 2 years in mice or rats at the maximum tolerated doses, corresponding to exposures from 2 to 4 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and exposures less than 2 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC).

Endosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of 60 mg/kg/day (6 times or 4 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and 3 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). No bone changes were observed in mice or rats after lifetime exposure (2 years) at 4 or 2 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and at 2 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day (exposures based on AUC).

Carcinogenicity and mutagenicity
Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 or 2 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and 2 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutagenicity test or in two in vivo rat tests (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and 7 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on C ). In the in vitro mouse lymphoma test, eltrombopag was marginally positive (increase of <3-fold in mutation frequency). These in vitro and in vivo observations suggest that eltrombopag does not pose a genotoxic risk to humans.

Reproductive toxicity
Eltrombopag did not affect female fertility, early embryonic development or fetal development in rats at doses up to 20 mg/kg/day (2 times the clinical exposure in humans in adult or adolescent (12 to 17 years) ITP patients at the dose of 75 mg/day and equivalent to the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). Furthermore, there was no effect on embryofetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the clinical exposure in humans in ITP patients at the dose of 75 mg/day and in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). However, in rats, at a maternally toxic dose of 60 mg/kg/day (6 times the clinical exposure in humans in ITP patients at the dose of 75 mg/day and 3 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC), treatment with eltrombopag was associated with embryolethality (increased pre- and post-implantation loss), reduced fetal body weight and gravid uterine weight in the female fertility study, and a low incidence of cervical ribs and reduced fetal body weight in the embryofetal development study. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus (see section 4.6). Eltrombopag does not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the clinical exposure in humans in ITP patients at the dose of 75 mg/day and 2 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). In the pre- and postnatal development study in rats, there were no adverse effects on pregnancy, parturition or lactation in F female rats at doses non-toxic to the mother (10 and 20 mg/kg/day), and no effects on growth, development, neurological behavior or reproductive function of the offspring (F ). Eltrombopag was detected in plasma of all F rat offspring throughout the 22-hour sampling period following administration to F mothers, suggesting that neonatal rat exposure to eltrombopag likely occurred via lactation.

Phototoxicity
In vitro studies with eltrombopag suggest a potential risk of phototoxicity; however, in rodents there was no evidence of cutaneous phototoxicity (10 or 7 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and 5 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC) or ocular phototoxicity (exposures greater than 4 times the clinical exposure in humans in adult or pediatric ITP patients at the dose of 75 mg/day and 3 times the clinical exposure in humans in HCV-infected patients at the dose of 100 mg/day, exposures based on AUC). Additionally, a clinical pharmacology study in 36 subjects showed no evidence that eltrombopag affects the delayed phototoxic index. However, a potential risk of photoallergy cannot be excluded as specific preclinical studies cannot be conducted.

Studies in young animals
At non-tolerated doses in pre-weaning rats, ocular opacities were observed. Ocular opacities were not observed at tolerated doses (see above subsection "Pharmacological safety and repeated-dose toxicity"). In conclusion, considering the exposure margins based on AUC, a risk of eltrombopag administration-related cataract cannot be excluded in pediatric patients. There are no findings in young rats suggesting an increased risk of toxicity with eltrombopag treatment in pediatric patients compared to adults with ITP.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients
Eltrombopag Cipla 25 mg film-coated tablets
Tablet core
Maltose
Microcrystalline cellulose
Sodium starch glycolate
Povidone K30
Magnesium stearate
Film coating
Polyvinyl alcohol
Talc
Glyceryl monocaprylocaprate and dicaprylocaprate
Sodium lauryl sulfate
Titanium dioxide (E171)
Indigo carmine (E132)

Eltrombopag Cipla 50 mg film-coated tablets
Tablet core
Maltose
Microcrystalline cellulose
Sodium starch glycolate
Povidone K30
Magnesium stearate
Film coating
Polyvinyl alcohol
Talc
Glyceryl monocaprylocaprate and dicaprylocaprate
Sodium lauryl sulfate
Titanium dioxide (E171)
Orange-yellow S (E110)

Eltrombopag Cipla 75 mg film-coated tablets
Tablet core
Maltose
Microcrystalline cellulose
Sodium starch glycolate
Povidone K30
Magnesium stearate
Film coating
Polyvinyl alcohol
Talc
Glyceryl monocaprylocaprate and dicaprylocaprate
Sodium lauryl sulfate
Titanium dioxide (E171)
Red iron oxide (E172)

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
21 months.

6.4 Special precautions for storage
Do not store above 30°C.

6.5 Nature and contents of container
Film-coated tablets
OPA/Al/PVC/Al blisters in a pack containing 14, 28 or 84 film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal
Unused medicine and waste material derived from this medicine must be disposed of in accordance with
local applicable regulations.

7. MARKETING AUTHORISATION HOLDER

CIPLA EUROPE NV
De Keyserlei 60C, Bus-1301
2018 Antwerp
Belgium

8. MARKETING AUTHORISATION NUMBERS

052076015 - "25 mg film-coated tablets" 14 tablets in OPA/Al/PVC/Al blisters
052076027 - "25 mg film-coated tablets" 28 tablets in OPA/Al/PVC/Al blisters
052076039 - "25 mg film-coated tablets" 84 tablets in OPA/Al/PVC/Al blisters
052076041 - "50 mg film-coated tablets" 14 tablets in OPA/Al/PVC/Al blisters
052076054 - "50 mg film-coated tablets" 28 tablets in OPA/Al/PVC/Al blisters
052076066 - "50 mg film-coated tablets" 84 tablets in OPA/Al/PVC/Al blisters
052076078 - "75 mg film-coated tablets" 14 tablets in OPA/Al/PVC/Al blisters
052076080 - "75 mg film-coated tablets" 28 tablets in OPA/Al/PVC/Al blisters
052076092 - "75 mg film-coated tablets" 84 tablets in OPA/Al/PVC/Al blisters

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

First authorisation: 14 May 2025

10. DATE OF TEXT REVISION

15/09/2025