Posology : מינונים

4.2    Posology and method of administration
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.

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 Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2).

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         Increase daily dose by 25 mg to a maximum of 75 mg/day*.
2 weeks of therapy
≥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 given as 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 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 75 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     Increase daily dose by 25 mg to a maximum of 75 mg/day.
2 weeks of therapy
≥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 75 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 (SAA)

First-Line severe aplastic anaemia
Initiate eltrombopag concurrently with standard immunosuppressive therapy [see section 5.1].
Initial Dose Regimen:
The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag.
Table 3      Recommended initial eltrombopag dose regimen in the first-line treatment of severe aplastic anaemia
Age                                         Dose Regimen
Patients 12 Years and Older        150 mg once daily for 6 months
Paediatric Patients 6 to 11 Years  75 mg once daily for 6 months
For patients with severe aplastic anaemia of East Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai) or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), decrease the initial eltrombopag dose by 50% as listed in Table 4.

If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of Normal (ULN), do not initiate eltrombopag until transaminase levels are < 5 x ULN.
Determine the initial dose for these patients based on Table 3 or Table 4.
Table 4      Recommended initial Eltrombopag Dose Regimen for Patients of East Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child- Pugh Class A, B, C) in the First-Line Treatment of Severe Aplastic Anaemia Age                                           Dose Regimen
Patients 12 Years and Older          75 mg once daily for 6 months
Paediatric Patients 6 to 11 Years    75 mg every other day for 6 months Monitoring and Dose Adjustment for eltrombopag: Perform clinical haematology and liver tests regularly throughout therapy with eltrombopag [see section 4.4].
Modify the dosage regimen of eltrombopag based on platelet counts as outlined in Table 5.
Table 5       Dose adjustments of eltrombopag for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anaemia


Platelet Count Result                             Dose Adjustment or Response > 200 x 109/L to ≤ 400 x 109/L      Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L.
In paediatric patients under 12 years of age, decrease the dose by
12.5 mg*.
> 400 x 109/L                      Discontinue eltrombopag for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag at a daily dose reduced by
25 mg (or 12.5 mg in paediatric patients under 12 years of age*).
* The dose should be decreased by 25 mg every other day.
Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of eltrombopag in the management of elevated liver transaminase levels and thromboembolic events.


Table 6   Recommended Dose Modifications for Eltrombopag for ALT or AST Elevations and Thromboembolic Events
Event                                      Recommendation
ALT or AST Elevations       Increase in ALT or AST > 6 x ULN
Discontinue eltrombopag. Once ALT or AST is < 5 x ULN,
reinitiate eltrombopag at the same dose.

Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag
Discontinue eltrombopag and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag at a daily dose reduced by 25 mg compared to the previous dose.

If ALT or AST returns to > 6 x ULN on the reduced dose
Reduce the daily dose of eltrombopag by 25 mg until ALT or AST is
< 5 x ULN.
In paediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g.,    Discontinue eltrombopag but remain on horse antithymocyte deep vein thrombosis, pulmonary globulin (h-ATG)* and cyclosporine.
embolus, stroke, myocardial infarction)
The total duration of eltrombopag treatment is 6 months.

* h-ATG was used in the single-arm, single-centre, open-label study [see section 5.1]. If h-ATG is not available, substitution with the appropriate local immunosuppressive therapy based on physician’s discretion is recommended. The local prescribing information for this therapy/these therapies or local treatment guidelines should be consulted for dosing information.


Refractory severe aplastic anaemia
Use the lowest dose of eltrombopag to achieve and maintain a haematologic response. Dose adjustments are based upon the platelet count. Haematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag (see section 5.1).


Initial Dose Regimen
Initiate eltrombopag at a dose of 50 mg once daily.


For patients with severe aplastic anaemia of East Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate eltrombopag at a reduced dose of 25 mg once daily (see Special populations and section 5.2).

Monitoring and Dose Adjustment

Adjust the dose of eltrombopag in 50-mg increments every 2 weeks as necessary to achieve the target platelet count ≥50 000/µl as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical haematology and liver tests regularly throughout therapy with eltrombopag and modify the dosage regimen of eltrombopag based on platelet counts as outlined in Table 7.

Table 7 Dose adjustments of eltrombopag in patients with refractory severe aplastic anaemia Platelet Count Result         Dose Adjustment or Response
<50 000/µl following at least Increase daily dose by 50 mg to a maximum of 150 mg/day.
2 weeks of eltrombopag
For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥200 000/µl to ≤400 000/µl at Decrease the daily dose by 50 mg. Wait 2 weeks to assess the any time                      effects of this and any subsequent dose adjustments.
>400 000/µl                   Stop eltrombopag for 1 week.

Once the platelet count is <150 000/µl, reinitiate therapy at a dose reduced by 50 mg.
>400 000/µl after 2 weeks of        Discontinue eltrombopag therapy at lowest dose of eltrombopag

For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50% (see section 5.1). If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag and monitor blood counts. If platelet counts drop to less than 30 000/µl, hemoglobin to less than 9 g/dL, or ANC to less than 0.5 x 109/L, eltrombopag may be reinitiated at the previous effective dose.

Discontinuation
If no haematologic response has occurred after 16 weeks of therapy with eltrombopag, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag (see section 4.8). Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag (see section 4.4).

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 refractory 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).

In a clinical trial in patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh Class A, B, C) initiates therapy with eltrombopag for the first-line treatment of severe aplastic anaemia, reduce the initial dose [see sections 4.2 and 4.4].


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 Asian patients
For patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a dose of 25 mg once daily for treatment of ITP, HCV and refractory SAA, and for treatment of patients with 1L SAA refer to Table 4. For treatment of patients with hepatic impairment, refer to hepatic impairment section above (see section 5.2).

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

Paediatric population
Revolade tablets are not indicated for use in children under the age of 6 years with ITP.
The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or refractory SAA.
No data are available.
Revolade tablets are indicated for definitive immunosuppressive therapy-naïve SAA aged 6 years and older.


Method of administration

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).