eltrombopag: prescribing information – dosing, contraindications, interactions, side effects

Revolade 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).

Revolade is indicated for the treatment of paediatric patients aged 1 year and above with primary immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).

Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1).

Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation (see section 5.1).

Eltrombopag treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications.

Posology

Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The objective of treatment with eltrombopag should not be to normalise platelet counts.

The powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation (see section 5.2). When switching between the tablet and the powder for oral suspension formulations, platelet counts should be monitored weekly for 2 weeks.

Immune (primary) thrombocytopenia

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

Adults and paediatric population aged 6 to 17 years
The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East-/Southeast- Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2).

Paediatric population aged 1 to 5 years
The recommended starting dose of eltrombopag is 25 mg once daily.

Monitoring and dose adjustment
After initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count ≥50 000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded.

Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in Table 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50 000/µl for at least 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter.

Table 1
Dose adjustments of eltrombopag in ITP patients

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 25 mg to a maximum of 75 mg/day*.
50 000/µl to 150 000/µl
Use lowest dose of eltrombopag and/or concomitant ITP treatment to maintain platelet counts that avoid or reduce bleeding.
>150 000/µl to 250 000/µl
Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦.
>250 000/µl
Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is ≤ 100 000/µl, reinitiate therapy at a daily dose reduced by 25 mg.
*
For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily.
♦
For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at 12.5 mg once daily or alternatively a dose of 25 mg once every other day.

Eltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of concomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag.

It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet response prior to considering another dose adjustment.

The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily.

Discontinuation
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 eltrombopag therapy at 75 mg once daily.

Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. In non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4).

Chronic hepatitis C (HCV) associated thrombocytopenia

When eltrombopag is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications.

In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag.
The aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50 000-75 000/µl. Platelet counts >75 000/µl should be avoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response.

Initial dose regimen
Eltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of East-/Southeast-Asian ancestry or 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 as necessary to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments 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 decreasing platelet counts that may put patients at risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50 000-75 000/µl. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for 2 weeks to assess the effects of this and any subsequent dose adjustments.

A dose of 100 mg eltrombopag once daily must not be exceeded.

Table 2
Dose adjustments of eltrombopag in HCV patients during antiviral therapy

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥50 000/µl to ≤100 000/µl
Use lowest dose of eltrombopag as necessary to avoid dose reductions of peginterferon.
>100 000/µl to ≤150 000/µl
Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦.
>150 000/µl
Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a daily dose reduced by 25 mg*.
*
For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosing at 25 mg every other day.
♦
On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided.

Discontinuation
If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued.

Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation.

Severe aplastic anaemia

Initial dose regimen
Eltrombopag should be initiated at a dose of 50 mg once daily. For patients of East-/Southeast-Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment should not be initiated when the patient has existing cytogenetic abnormalities of chromosome 7.

Monitoring and dose adjustment
Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50 000/µl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose amount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag modified based on platelet counts as outlined in Table 3.

Table 3
Dose adjustments of eltrombopag in patients with severe aplastic anaemia

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 50 mg to a maximum of 150 mg/day.

For patients taking 25 mg once daily, increase the dose to
50 mg daily before increasing the dose amount by 50 mg.
≥50 000/µl to ≤150 000/µl
Use lowest dose of eltrombopag to maintain platelet counts.
>150 000/µl to ≤250 000/µl
Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
>250 000/µl
Stop eltrombopag; for at least one week.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a daily dose reduced by 50 mg.

Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50%.

If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and blood counts monitored. If platelet counts drop to <30 000/µl, haemoglobin drops to < 9 g/dl or absolute neutrophil count (ANC) to <0.5 x 109/l, eltrombopag may be reinitiated at the previous effective dose.

Discontinuation
If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of eltrombopag (see section 4.8).

Special populations

Renal impairment
No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see section 5.2).

Hepatic impairment
Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4).

If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 3 weeks should be observed before increasing the dose.

No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and SAA patients with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose.

There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events (TEEs), in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing 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 aged over 85 years. In the clinical studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag were observed between patients aged at least 65 years and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see section 5.2).

There are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years.
Caution should be exercised in these patients (see section 4.4).

East-/Southeast-Asian patients
For adult and paediatric patients of East-/Southeast-Asian ancestry including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2).

Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed.

Paediatric population
Revolade is not recommended for use in children under the age of 1 year with ITP due to insufficient data on safety and efficacy.

The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia. No data are available.

The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with SAA. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Oral use
The tablets should be taken at least two hours before or four hours after any products containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc), such as antacids, dairy products (or other calcium containing food products), or mineral supplements (see sections 4.5 and 5.2).

Eltrombopag treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications.

Posology

Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The objective of treatment with eltrombopag should not be to normalise platelet counts.

The powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation (see section 5.2). When switching between the tablet and the powder for oral suspension formulations, platelet counts should be monitored weekly for 2 weeks.

Immune (primary) thrombocytopenia

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

Adults and paediatric population aged 6 to 17 years
The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East-/Southeast- Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2).

Paediatric population aged 1 to 5 years
The recommended starting dose of eltrombopag is 25 mg once daily.

Monitoring and dose adjustment
After initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count ≥50 000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded.

Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in Table 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50 000/µl for at least 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter.

Table 1
Dose adjustments of eltrombopag in ITP patients

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 25 mg to a maximum of 75 mg/day*.
50 000/µl to 150 000/µl
Use lowest dose of eltrombopag and/or concomitant ITP treatment to maintain platelet counts that avoid or reduce bleeding.
>150 000/µl to 250 000/µl
Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦.
>250 000/µl
Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a daily dose reduced by 25 mg.
*
For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily.
♦
For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at 12.5 mg once daily or alternatively a dose of 25 mg once every other day.

Eltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of concomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag.

It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet response prior to considering another dose adjustment.

The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily.

Discontinuation
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 eltrombopag therapy at 75 mg once daily.

Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. In non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4).

Chronic hepatitis C (HCV) associated thrombocytopenia

When eltrombopag is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications.

In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag.
The aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50 000-75 000/µl. Platelet counts >75 000/µl should be avoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response.

Initial dose regimen
Eltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of East-/Southeast-Asian ancestry or 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 as necessary to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments 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 decreasing platelet counts that may put patients at risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50 000-75 000/µl. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for 2 weeks to assess the effects of this and any subsequent dose adjustments.

A dose of 100 mg eltrombopag once daily must not be exceeded.

Table 2
Dose adjustments of eltrombopag in HCV patients during antiviral therapy

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥50 000/µl to ≤100 000/µl
Use lowest dose of eltrombopag as necessary to avoid dose reductions of peginterferon.
>100 000/µl to ≤150 000/µl
Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦.
>150 000/µl
Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a daily dose reduced by 25 mg*.
*
For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosing at 25 mg every other day.
♦
On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided.

Discontinuation
If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued.

Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation.

Severe aplastic anaemia

Initial dose regimen
Eltrombopag should be initiated at a dose of 50 mg once daily. For patients of East-/Southeast-Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment should not be initiated when the patient has existing cytogenetic abnormalities of chromosome 7.

Monitoring and dose adjustment
Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50 000/µl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose amount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag modified based on platelet counts as outlined in Table 3.

Table 3
Dose adjustment of eltrombopag in patients with severe aplastic anaemia

Platelet count
Dose adjustment or response
<50 000/µl following at least
2 weeks of therapy
Increase daily dose by 50 mg to a maximum of 150 mg/day.

For patients taking 25 mg once daily, increase the dose to
50 mg daily before increasing the dose amount by 50 mg.
50 000/µl to 150 000/µl
Use lowest dose of eltrombopag to maintain platelet counts.
>150 000/µl to 250 000/µl
Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
>250 000/µl
Stop eltrombopag; for at least one week.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a daily dose reduced by 50 mg.

Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50%.

If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and blood counts monitored. If platelet counts drop to <30 000/µl, haemoglobin drops to <9 g/dl or absolute neutrophil count (ANC) to <0.5 x 109/l, eltrombopag may be reinitiated at the previous effective dose.

Discontinuation
If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of eltrombopag (see section 4.8).

Special populations

Renal impairment
No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see section 5.2).

Hepatic impairment
Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4).

If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 3 weeks should be observed before increasing the dose.

No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and SAA patients with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose.

There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events (TEEs), in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing 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 aged over 85 years. In the clinical studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag were observed between patients aged at least 65 years and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see section 5.2).

There are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years.
Caution should be exercised in these patients (see section 4.4).

East-/Southeast-Asian patients
For adult and paediatric patients of East-/Southeast-Asian ancestry, including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2).

Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed.

Paediatric population
Revolade is not recommended for use in children under the age of 1 year with ITP due to insufficient data on safety and efficacy.

The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia. No data are available.

The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with SAA. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration (see section 6.6)

Oral use.
The suspension should be taken at least two hours before or four hours after any products containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc), such as antacids, dairy products (or other calcium containing food products), or mineral supplements (see sections 4.5 and 5.2).

Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.

Summary of the safety profile

Immune thrombocytopenia in adult and paediatric patients

The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). Patients received study medication 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 Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double- blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study.
PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea.

Thrombocytopenia with HCV infection in adult patients

ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and 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, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema.

Severe aplastic anaemia in adult patients

The safety of Revolade in adult patients with SAA was assessed in a single-arm, open-label study (N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated 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, transaminases increased, arthralgia, pain in extremity, muscle spasms, fatigue and pyrexia.

Severe aplastic anaemia in paediatric population

The safety of Revolade in paediatric patients with refractory/relapsed (cohort A; n=14) or treatment- naive (cohort B; n=37) SAA was assessed in an open-label, uncontrolled, intra-patient dose escalation study (total N=51) (see also section 5.1 for study details). Adverse events of special interest, including acute kidney injury, hepatotoxicity, thromboembolic events, and clonal evolution or cytogenetic abnormality, were reported in 29 (56.9%), 39 (76.5%), 2 (3.9%), and 1 (2.0%) patients, respectively.
Overall, the frequency, type and severity of adverse reactions observed for eltrombopag in paediatric patients with SAA were consistent with those observed in adult patients with SAA.

List of adverse reactions

The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1 520), the adult SAA study (N=43), the paediatric SAA study (N=51) and post-marketing reports are listed below by MedDRA system organ class and by frequency (Tables 4, 5 and 6). Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. 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); not known (cannot be estimated from the available data).

Table 4
Adverse reactions in the ITP study population

System organ class
Frequency
Adverse reaction
Infections and infestations
Very common
Nasopharyngitis♦, upper respiratory tract infection♦
Common
Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis Uncommon Skin infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Rectosigmoid cancer Blood and lymphatic system disorders Common Anaemia, eosinophilia, leukocytosis, thrombocytopenia, haemoglobin decreased, white blood cell count decreased Uncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased, haemoglobin increased Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Common Hypokalaemia, decreased appetite, blood uric acid increased Uncommon Anorexia, gout, hypocalcaemia Psychiatric disorders Common Sleep disorder, depression Uncommon Apathy, mood altered, tearfulness

Nervous system disorders
Common
Paraesthesia, hypoaesthesia, somnolence, migraine
Uncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache Eye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced Uncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual impairment, visual acuity tests abnormal, blepharitis, keratoconjunctivitis sicca Ear and labyrinth disorders Common Ear pain, vertigo Cardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged Vascular disorders Common Deep vein thrombosis, haematoma, hot flush Uncommon Embolism, thrombophlebitis superficial, flushing Respiratory, thoracic and mediastinal disorders Very common Cough♦ Common Oropharyngeal pain♦, rhinorrhoea♦ Uncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome Gastrointestinal disorders Very common Nausea, diarrhoea Common Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence * Very common in paediatric ITP Uncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort Hepatobiliary disorders Very common Alanine aminotransferase increased† Common Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury Skin and subcutaneous tissue disorders Common Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation Musculoskeletal and connective tissue disorders Very common Back pain Common Myalgia, muscle spasm, musculoskeletal pain, bone pain Uncommon Muscular weakness Renal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡ Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased Reproductive system and breast disorders Common Menorrhagia

General disorders and administration site conditions
Common
Pyrexia*, chest pain, asthenia
*Very common in paediatric ITP
Uncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body Investigations Common Blood alkaline phosphatase increased Uncommon Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased Injury, poisoning and procedural complications Uncommon Sunburn ♦ Additional adverse reactions observed in paediatric studies (aged 1 to 17 years).
†
Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency.
‡
Grouped term with preferred terms acute kidney injury and renal failure.

Table 5
Adverse reactions in the HCV study population (in combination with anti-viral interferon and ribavirin therapy)

System organ class
Frequency
Adverse reaction
Infections and infestations
Common
Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes Uncommon Gastroenteritis, pharyngitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Hepatic neoplasm malignant Blood and lymphatic system disorders Very common Anaemia Common Lymphopenia Uncommon Haemolytic anaemia Metabolism and nutrition disorders Very common Decreased appetite Common Hyperglycaemia, abnormal loss of weight Psychiatric disorders Common Depression, anxiety, sleep disorder Uncommon Confusional state, agitation Nervous system disorders Very common Headache Common Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia Eye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage Ear and labyrinth disorders Common Vertigo Cardiac disorders Common Palpitations

Respiratory, thoracic and mediastinal disorders
Very common
Cough
Common
Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough
Gastrointestinal disorders
Very common
Nausea, diarrhoea
Common
Vomiting, ascites, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, gastrooesophageal reflux disease, haemorrhoids, abdominal discomfort, varices oesophageal Uncommon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis Hepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury Uncommon Portal vein thrombosis, hepatic failure Skin and subcutaneous tissue disorders Very common Pruritus Common Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia Uncommon Skin lesion, skin discolouration, skin hyperpigmentation, night sweats Musculoskeletal and connective tissue disorder Very common Myalgia Common Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain Renal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria General disorders and administration site conditions Very common Pyrexia, fatigue, influenza-like illness, asthenia, chills Common Irritability, pain, malaise, injection site reaction, non- cardiac chest pain, oedema, oedema peripheral Uncommon Injection site pruritus, injection site rash, chest discomfort Investigations Common Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased, blood albumin decreased Uncommon Electrocardiogram QT prolonged † Grouped term with preferred terms oliguria, renal failure and renal impairment.

Table 6
Adverse reactions in the SAA study population

System organ class
Frequency
Adverse reaction
Blood and lymphatic system disorders
Common
Neutropenia, splenic infarction
Metabolism and nutrition disorders
Common
Iron overload, decreased appetite, hypoglycaemia, increased appetite
Psychiatric disorders
Common
Anxiety, depression
Nervous system disorders
Very common
Headache, dizziness
Common
Syncope
Eye disorders
Common
Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters

Respiratory, thoracic and mediastinal disorders
Very common
Cough, oropharyngeal pain, rhinorrhoea
Common
Epistaxis
Gastrointestinal disorders
Very common
Diarrhoea, nausea, abdominal pain
Common
Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, gingival bleeding, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder, flatulence Hepatobiliary disorders Very common Transaminases increased Common Blood bilirubin increased (hyperbilirubinemia), jaundice Not known Drug-induced liver injury Skin and subcutaneous tissue disorders Common Petechiae, rash, pruritus, urticaria, skin lesion, rash macular Not known Skin discolouration, skin hyperpigmentation Musculosketal and connective tissue disorders Very common Arthralgia, pain in extremity, muscle spasms Common Back pain, myalgia, bone pain Renal and urinary disorders Common Chromaturia General disorders and administration site conditions Very common Fatigue, pyrexia, chills Common Asthenia, oedema peripheral, malaise Investigations Common Blood creatine phosphokinase increased

Description of selected adverse reactions

Thrombotic/thromboembolic events (TEEs)

In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag (n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4).

In a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200 000/µl

No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200 000/µl (see section 4.4).

In controlled studies in thrombocytopenic patients with HCV (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus < 1% for placebo) (see section 4.4). Patients with low albumin levels (≤ 35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients.

Hepatic decompensation (use with interferon)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%).
In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4).

Hepatotoxicity

In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4).

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported 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 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia.
Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively.

In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and placebo groups, respectively (see section 4.4).

Increased bone marrow reticulin

Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4).

Cytogenetic abnormalities

In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks 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 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

Haematologic malignancies

In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile

Immune thrombocytopenia in adult and paediatric patients

The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). Patients received study medication 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 Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double- blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study.
PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea.

Thrombocytopenia with HCV infection in adult patients

ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and 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, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema.

Severe aplastic anaemia in adult patients

The safety of Revolade in adult patients with SAA was assessed in a single-arm, open-label study (N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated 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, transaminases increased, arthralgia, pain in extremity, muscle spasms, fatigue and pyrexia.

Severe aplastic anaemia in paediatric population

The safety of Revolade in paediatric patients with refractory/relapsed (cohort A; n=14) or treatment- naive (cohort B; n=37) SAA was assessed in an open-label, uncontrolled, intra-patient dose escalation study (total N=51) (see also section 5.1 for study details). Adverse events of special interest, including acute kidney injury, hepatotoxicity, thromboembolic events, and clonal evolution or cytogenetic abnormality, were reported in 29 (56.9%), 39 (76.5%), 2 (3.9%), and 1 (2.0%) patients, respectively.
Overall, the frequency, type and severity of adverse reactions observed for eltrombopag in paediatric patients with SAA were consistent with those observed in adult patients with SAA.

List of adverse reactions

The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1,520), the adult SAA study (N=43), the paediatric SAA study (N=51) and post-marketing reports are listed below by MedDRA system organ class and by frequency (Tables 4, 5 and 6). Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. 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); not known (cannot be estimated from the available data).

Table 4
Adverse reactions in the ITP study population

System organ class
Frequency
Adverse reaction
Infections and infestations
Very common
Nasopharyngitis♦, upper respiratory tract infection♦
Common
Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis Uncommon Skin infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Rectosigmoid cancer Blood and lymphatic system disorders Common Anaemia, eosinophilia, leukocytosis, thrombocytopenia, haemoglobin decreased, white blood cell count decreased Uncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased, haemoglobin increased Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Common Hypokalaemia, decreased appetite, blood uric acid increased Uncommon Anorexia, gout, hypocalcaemia Psychiatric disorders Common Sleep disorder, depression Uncommon Apathy, mood altered, tearfulness Nervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine Uncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache Eye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced Uncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual impairment, visual acuity tests abnormal, blepharitis, keratoconjunctivitis sicca Ear and labyrinth disorders Common Ear pain, vertigo Cardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged Vascular disorders Common Deep vein thrombosis, haematoma, hot flush Uncommon Embolism, thrombophlebitis superficial, flushing Respiratory, thoracic and mediastinal disorders Very common Cough♦ Common Oropharyngeal pain♦, rhinorrhoea♦ Uncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome Gastrointestinal disorders Very common Nausea, diarrhoea Common Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence * Very common in paediatric ITP Uncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort

Hepatobiliary disorders
Very common
Alanine aminotransferase increased†
Common
Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury Skin and subcutaneous tissue disorders Common Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation Musculoskeletal and connective tissue disorders Very common Back pain Common Myalgia, muscle spasm, musculoskeletal pain, bone pain Uncommon Muscular weakness Renal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡ Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased Reproductive system and breast disorders Common Menorrhagia General disorders and administration site conditions Common Pyrexia*, chest pain, asthenia *Very common in paediatric ITP Uncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body Investigations Common Blood alkaline phosphatase increased Uncommon Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased Injury, poisoning and procedural complications Uncommon Sunburn ♦ Additional adverse reactions observed in paediatric studies (aged 1 to 17 years).
†
Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency.
‡
Grouped term with preferred terms acute kidney injury and renal failure.

Table 5
Adverse reactions in the HCV study population (in combination with anti-viral interferon and ribavirin therapy)

System organ class
Frequency
Adverse reaction
Infections and infestations
Common
Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes Uncommon Gastroenteritis, pharyngitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Hepatic neoplasm malignant

Blood and lymphatic system disorders
Very common
Anaemia
Common
Lymphopenia
Uncommon
Haemolytic anaemia
Metabolism and nutrition disorders
Very common
Decreased appetite
Common
Hyperglycaemia, abnormal loss of weight
Psychiatric disorders
Common
Depression, anxiety, sleep disorder
Uncommon
Confusional state, agitation
Nervous system disorders
Very common
Headache
Common
Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia Eye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage Ear and labyrinth disorders Common Vertigo Cardiac disorders Common Palpitations Respiratory, thoracic and mediastinal disorders Very common Cough Common Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough Gastrointestinal disorders Very common Nausea, diarrhoea Common Vomiting, ascites, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, gastrooesophageal reflux disease, haemorrhoids, abdominal discomfort, varices oesophageal Uncommon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis Hepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury Uncommon Portal vein thrombosis, hepatic failure

Skin and subcutaneous tissue disorders
Very common
Pruritus
Common
Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia Uncommon Skin lesion, skin discolouration, skin hyperpigmentation, night sweats Musculoskeletal and connective tissue disorder Very common Myalgia Common Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain Renal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria General disorders and administration site conditions Very common Pyrexia, fatigue, influenza-like illness, asthenia, chills Common Irritability, pain, malaise, injection site reaction, non- cardiac chest pain, oedema, oedema peripheral Uncommon Injection site pruritus, injection site rash, chest discomfort Investigations Common Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased, blood albumin decreased Uncommon Electrocardiogram QT prolonged † Grouped term with preferred terms oliguria, renal failure and renal impairment

Table 6
Adverse reactions in the SAA study population

System organ class
Frequency
Adverse reaction
Blood and lymphatic system disorders
Common
Neutropenia, splenic infarction
Metabolism and nutrition disorders
Common
Iron overload, decreased appetite, hypoglycaemia, increased appetite
Psychiatric disorders
Common
Anxiety, depression
Nervous system disorders
Very common
Headache, dizziness
Common
Syncope
Eye disorders
Common
Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters Respiratory, thoracic and mediastinal disorders Very common Cough, oropharyngeal pain, rhinorrhoea Common Epistaxis

Gastrointestinal disorders
Very common
Diarrhoea, nausea, abdominal pain
Common
Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, gingival bleeding, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder, flatulence Hepatobiliary disorders Very common Transaminases increased Common Blood bilirubin increased (hyperbilirubinemia), jaundice Not known Drug-induced liver injury Skin and subcutaneous tissue disorders Common Petechiae, rash, pruritus, urticaria, skin lesion, rash macular Not known Skin discolouration, skin hyperpigmentation Musculosketal and connective tissue disorders Very common Arthralgia, pain in extremity, muscle spasms Common Back pain, myalgia, bone pain Renal and urinary disorders Common Chromaturia General disorders and administration site conditions Very common Fatigue, pyrexia, chills Common Asthenia, oedema peripheral, malaise Investigations Common Blood creatine phosphokinase increased

Description of selected adverse reactions

Thrombotic/thromboembolic events (TEEs)

In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag (n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4).

In a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200 000/µl.

No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200 000/µl (see section 4.4).

In controlled studies in thrombocytopenic patients with HCV (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo) (see section 4.4). Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels;
those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients.

Hepatic decompensation (use with interferon)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%).
In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4).

Hepatotoxicity

In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4).

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported 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 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia.
Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively.

In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and placebo groups, respectively (see section 4.4).

Increased bone marrow reticulin

Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4).

Cytogenetic abnormalities

In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks 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 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All

7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

Haematologic malignancies

In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close 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 treatment of chronic hepatitis C infection.

Risk of hepatotoxicity

Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8).

Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:
- progressive, or
- persistent for ≥4 weeks, or
- accompanied by increased direct bilirubin, or
- accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA patients a lower starting dose of eltrombopag should be used. Close monitoring is required when administering to patients with hepatic impairment (see section 4.2).

Hepatic decompensation (use with interferon)

Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline.

Chronic HCV patients with liver cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In two controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks.
Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon summary of product characteristics should be referenced for discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for hepatic decompensation.

Thrombotic/thromboembolic complications

In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2- fold greater risk of TEEs compared to younger patients. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE.

The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous system) and two of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic complication at a platelet count >200 000/µl and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.

In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal platelet counts. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the target levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology.

No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population.

Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous 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 reoccur in ITP patients upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag.

In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. 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 for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin-receptor (TPO-R) agonists, has not been established yet.

Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis.

Progression of existing myelodysplastic syndrome (MDS)

There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage.

In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were reported.

The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, those with systemic symptoms, or abnormal signs such as increased peripheral blast cells.

The effectiveness and safety of Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.

Cytogenetic abnormalities and progression to MDS/AML in patients with SAA

Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks 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 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment.

For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of eltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate.

Ocular changes

Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1 439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended.

QT/QTc prolongation

A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown.

Loss of response to eltrombopag

A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin.

Paediatric population

The above warnings and precautions for ITP also apply to the paediatric population.

Interference with laboratory tests

Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close 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 treatment of chronic hepatitis C infection.

Risk of hepatotoxicity

Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8).

Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:
- progressive, or
- persistent for ≥4 weeks, or
- accompanied by increased direct bilirubin, or
- accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA patients a lower starting dose of eltrombopag should be used. Close monitoring is required when administering to patients with hepatic impairment (see section 4.2).

Hepatic decompensation (use with interferon)

Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline.

Chronic HCV patients with liver cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In two controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks.
Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon summary of product characteristics should be referenced for discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for hepatic decompensation.

Thrombotic/thromboembolic complications

In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2- fold greater risk of TEEs compared to younger patients. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE.

The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous system) and two of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic complication at a platelet count >200 000/µl and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.

In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal platelet counts. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the target levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology.

No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population.

Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous 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 reoccur in ITP patients upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag.

In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. 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 for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin-receptor (TPO-R) agonists, has not been established yet.

Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis.

Progression of existing myelodysplastic syndrome (MDS)

There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage.

In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were reported.

The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, those with systemic symptoms, or abnormal signs such as increased peripheral blast cells.

The effectiveness and safety of Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.

Cytogenetic abnormalities and progression to MDS/AML in patients with SAA

Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment.

For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of eltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate.

Ocular changes

Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1 439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended.

QT/QTc prolongation

A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown.

Loss of response to eltrombopag

A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin.

Paediatric population

The above warnings and precautions for ITP also apply to the paediatric population.

Interference with laboratory tests

Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result.

Effects of eltrombopag on other medicinal products

HMG CoA reductase inhibitors

Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0- 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, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 5.2).

OATP1B1 and BCRP substrates

Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g.
topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2).

Cytochrome P450 substrates

In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the 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 the 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 interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2).

HCV protease inhibitors

Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure.

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

Effects of other medicinal products on eltrombopag

Ciclosporin

A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and the AUC0- of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the Cmax and the AUC0- of eltrombopag by 39% and 24%, respectively.
Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s platelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts.

Polyvalent cations (chelation)

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1 524 mg aluminium hydroxide and 1 425 mg magnesium carbonate) decreased plasma eltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%).
Eltrombopag should be taken at least two hours before or four hours after any 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 decrease in the concentration of eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg dose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a reduction in eltrombopag plasma AUC0- by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should be used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count should be closely monitored in order to ensure appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy is initiated or discontinued.

CYP1A2 and CYP2C8 inhibitors and inducers

Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect plasma eltrombopag concentrations, whereas medicinal products 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 drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat 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 eltrombopag exposure to a clinically significant extent.

Medicinal products for treatment of ITP

Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti- D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see section 4.2).

Food interaction

The administration of eltrombopag tablet or powder for oral suspension formulations with a high- calcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag AUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high- calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure to a clinically significant extent (see section 4.2).

Administration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and mean Cmax by 65%.

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

Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added calcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see sections 4.2 and 4.5).

Pregnancy

There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Revolade is not recommended during pregnancy.

Women of childbearing potential / Contraception in males and females

Revolade is not recommended in women of childbearing potential not using contraception.

Breast-feeding

It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Fertility was not affected in male or female rats at exposures that were comparable to those in humans.
However, a risk for humans cannot be ruled out (see section 5.3).

Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor and cognitive skills.

In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In case of an overdose, consideration should be given to oral administration of a metal cation-containing preparation, such as calcium, aluminium, or magnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should be closely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and administration recommendations (see section 4.2).

In the clinical studies there was one report of overdose where the patient ingested 5 000 mg of eltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and AST elevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a 1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin. The platelet counts were 672 000/µl on Day 18 after ingestion and the maximum platelet count was 929 000/µl. All events were resolved without sequelae following treatment.

Because eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, haemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05.

Mechanism of action

TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells.

Clinical efficacy and safety

Immune (primary) thrombocytopenia (ITP) studies

Two phase III, randomised, 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 ITP patients for at least 6 months and 202 patients for at least 1 year. The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce sustained response after treatment discontinuation in 105 adult ITP patients who relapsed or failed to respond to first-line corticosteroid treatment.

Double-blind placebo-controlled studies
RAISE:
197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline 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 to 28% of eltrombopag-treated patients were maintained on ≤25 mg and 29 to 53% received 75 mg.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥3 prior ITP therapies and 36% had a prior splenectomy.

Median platelet counts at baseline were 16 000/l for both treatment groups and in the eltrombopag group were maintained above 50 000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained <30 000/µl throughout the study.

Platelet count response between 50 000-400 000/l in the absence of rescue treatment was achieved by significantly more patients in the eltrombopag treated group during the 6-month treatment period, p <0.001 (Table 7). Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients achieved this level of response 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.

Table 7
Secondary efficacy results from RAISE

Eltrombopag
N=135
Placebo
N=62
Key secondary endpoints

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05.

Mechanism of action

TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells.

Clinical efficacy and safety

Immune (primary) thrombocytopenia (ITP) studies

Two phase III, randomised, 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 ITP patients for at least 6 months and 202 patients for at least 1 year. The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce sustained response after treatment discontinuation in 105 adult ITP patients who relapsed or failed to respond to first-line corticosteroid treatment.

Double-blind placebo-controlled studies
RAISE:
197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline 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 to 28% of eltrombopag-treated patients were maintained on ≤25 mg and 29 to 53% received 75 mg.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥3 prior ITP therapies and 36% had a prior splenectomy.

Median platelet counts at baseline were 16 000/l for both treatment groups and in the eltrombopag group were maintained above 50 000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained <30 000/µl throughout the study.

Platelet count response between 50 000-400 000/l in the absence of rescue treatment was achieved by significantly more patients in the eltrombopag treated group during the 6-month treatment period, p <0.001 (Table 7). Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients achieved this level of response 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.

Table 7
Secondary efficacy results from RAISE

Eltrombopag
N=135
Placebo
N=62
Key secondary endpoints

Pharmacokinetics

The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are presented (Table 12).

Table 12
Geometric mean (95% confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP

Eltrombopag dose, once daily
N
AUC(0-)a, g.h/ml
Cmaxa, g/ml
30 mg
47 (39, 58)