Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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.
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.
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.
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).
The recommended starting dose of eltrombopag is 25 mg once daily.
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.
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).
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.
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).
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.
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.
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.
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. |
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) <0.5 × 109/l, eltrombopag may be reinitiated at the previous effective dose.
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).
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).
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 severe aplastic anaemia 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).
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).
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.
Revolade is not recommended for use in children under the age of one 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 or SAA. No data are available.
Oral use.
The tablets should be taken at least two hours before or four hours after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see sections 4.5 and 5.2).
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.
3 years.
This medicinal product does not require any special storage conditions.
Film-coated tablets:
Aluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets and multipacks containing 84 (3 packs of 28) film-coated tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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