Usual Adult Dose for Aplastic Anemia

FIRST-LINE SEVERE APLASTIC ANEMIA:
Initial dose: 150 mg orally once a day

Patients of Asian Ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai):
Initial dose: 75 mg orally once a day

Duration of therapy: 6 months

Comments:

• If baseline ALT or AST levels are greater than 6 times the upper limit of normal (ULN), do not initiate this drug until transaminase levels are less than 5 x ULN.
• Initiate this drug concurrently with standard immunosuppressive therapy.
• Do not exceed the initial dose.

Use: In combination with standard immunosuppressive therapy as first-line treatment of patients with severe aplastic anemia.

REFRACTORY SEVERE APLASTIC ANEMIA:
Initial dose: 50 mg orally once a day; may adjust dose in 50 mg increments every 2 weeks as needed to achieve a platelet count between 50 and 200 x 10(9)/L.

Patients of Asian Ancestry:
Initial dose: 25 mg orally once a day; may adjust dose in 50 mg increments every 2 weeks as needed to achieve a platelet count between 50 and 200 x 10(9)/L.

Maintenance dose: The lowest dose needed to achieve and maintain a platelet count between 50 and 200 x 10(9)/L.

Maximum dose: 150 mg orally once a day

Duration of therapy: If no hematologic response has occurred after 16 weeks of therapy with this drug, discontinue therapy.

Comments:

• For patients who achieve trilineage response, including transfusion independence, lasting at least 8 weeks, the dose of this drug may be reduced by 50%. If counts remain stable after 8 weeks at the

reduced dose, then this drug may be discontinued. If platelet counts drop to less than 30 x 10(9)/L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10(9)/L, this drug may be reinitiated at the previous effective dose.

• If new cytogenetic abnormalities are observed, consider discontinuation of this drug.

Use: Treatment of severe aplastic anemia in patients who have had an insufficient response to
immunosuppressive therapy.

Usual Adult Dose for Idiopathic (Immune) Thrombocytopenic Purpura

Initial dose: 50 mg orally once a day

Patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean):
Initial dose: 25 mg orally once a day

Maintenance dose: The lowest dose to achieve and maintain a platelet count between 50 to 200 x 10(9)/L as necessary to reduce the risk of bleeding.
Maximum dose: 75 mg orally once a day

Duration: Treatment should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum daily dose.

Comments:

• Monitor CBC with differentials, including platelet counts, every week until the platelet count is stable, followed by monthly thereafter. Monitoring should continue every week for at least 4 weeks following treatment discontinuation.
• Platelet counts generally increase within 1 to 2 weeks after starting therapy and decrease within 1 to 2 weeks after treatment discontinuation.

Use: Treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Usual Adult Dose for Thrombocytopenia

Initial dose: 25 mg orally once a day
Maintenance dose: The lowest dose to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.
Maximum dose: 100 mg orally once a day
Duration: Treatment should be discontinued when concomitant antiviral therapy is discontinued

Comments:

• Adjust the daily dose by increments of 25 mg every two weeks as necessary according to platelet count response.
• Monitor platelet counts every week prior to starting antiviral therapy.
• During antiviral therapy, monitor CBC with differentials, including platelet counts, every week until the platelet count is stable. Monitor platelet counts monthly thereafter.
• Platelet counts generally begin to rise within the first week of treatment with eltrombopag.

Use: Treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.

Usual Pediatric Dose for Idiopathic (Immune) Thrombocytopenic Purpura

1 TO 5 YEARS:
Initial dose: 25 mg orally once a day

6 YEARS OR OLDER:
Initial dose: 50 mg orally once a day

Patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean):
Initial dose: 25 mg orally once a day

Maintenance dose: The lowest dose to achieve and maintain a platelet count between 50 to 200 x 10(9)/L as necessary to reduce the risk of bleeding.
Maximum dose: 75 mg orally once a day

Duration: Treatment should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum daily dose.

Comments:

• Monitor CBC with differentials, including platelet counts, every week until the platelet count is stable, followed by monthly thereafter. Monitoring should continue every week for at least 4 weeks following treatment discontinuation.
• Platelet counts generally increase within 1 to 2 weeks after starting therapy and decrease within 1 to 2 weeks after treatment discontinuation.

Use: Treatment of thrombocytopenia in patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Usual Pediatric Dose for Aplastic Anemia

FIRST-LINE SEVERE APLASTIC ANEMIA:
Initial dose:
2 to 5 years: 2.5 mg/kg orally once a day
6 to 11 years: 75 mg orally once a day
12 years or older: 150 mg orally once a day

Patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai):
Initial dose:
2 to 5 years: 1.25 mg/kg orally once a day
6 to 11 years: 37.5 mg orally once a day
12 years or older: 75 mg orally once a day

Duration of therapy: 6 months

Comments:

• If baseline ALT or AST levels are greater than 6 times the upper limit of normal (ULN), do not initiate this drug until transaminase levels are less than 5 x ULN.
• Initiate this drug concurrently with standard immunosuppressive therapy.
• Do not exceed the initial dose.

Use: In combination with standard immunosuppressive therapy as first-line treatment of patients with severe aplastic anemia.

Renal Dose Adjustments

No dose adjustment recommended; use with caution and close monitoring.

Liver Dose Adjustments

CHRONIC IMMUNE THROMBOCYTOPENIA:

• Mild to severe liver dysfunction (Child-Pugh A, B, or C): Initiate dose at 25 mg orally once a day
• Mild to severe liver dysfunction with East Asian ancestry: Initiate dose at 12.5 mg orally once a day
• In patients with liver dysfunction (Child-Pugh Class A, B, C), after initiating eltrombopag or after any subsequent dosing increase, wait 3 weeks before increasing the dose.

CHRONIC HEPATITIS C-ASSOCIATED THROMBOCYTOPENIA:
Liver dysfunction: No dosage adjustment recommended

FIRST-LINE SEVERE APLASTIC ANEMIA:
If baseline ALT or AST levels are greater than 6 times the upper limit of normal (ULN), do not initiate this drug until transaminase levels are less than 5 x ULN.

Mild to Severe Liver Dysfunction (Child-Pugh A, B, or C):
Initial dose:
2 to 5 years: 1.25 mg/kg orally once a day for 6 months
6 to 11 years: 37.5 mg orally once a day for 6 months
12 years or older: 75 mg orally once a day for 6 months

Increase in ALT or AST greater than 6 x ULN: Discontinue this drug. Once ALT or AST is less than 5 x ULN, reinitiate this drug at the same dose.
Increase in ALT or AST greater than 6 x ULN after reinitiating this drug: Discontinue this drug and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is less than 5 x ULN, reinitiate this drug at a daily dose reduced by 25 mg compared to the previous dose.
If ALT or AST returns to greater than 6 x ULN on the reduced dose: Reduce the daily dose of this drug by 25 mg until ALT or AST is less than 5 x ULN. In pediatric patients less than 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.

REFRACTORY SEVERE APLASTIC ANEMIA:
Mild to Severe Liver Dysfunction (Child-Pugh A, B, or C):
Initial dose: 25 mg orally once a day

GENERAL:
Discontinue eltrombopag if ALT levels increase by at least 3 x ULN in patients with normal liver function or transaminases increase by at least 3 x baseline levels in patients with elevated transaminases pretreatment and where transaminases are:

• Progressively increasing,
• Persistent for at least 4 weeks,
• Accompanied by increased direct bilirubin, or
• Accompanied by clinical symptoms of liver injury or evidence of hepatic decompensation

Treatment may be cautiously restarted if the benefits outweigh the risks, with weekly LFT monitoring during the dose adjustment phase; however, it should be permanently discontinued if LFT abnormalities remain, worsen, or reoccur.

Dose Adjustments

General:

• A period of at least 2 weeks is recommended between dose adjustments in order to see the effect on the

platelet count.

• Excessive platelet count responses necessitate eltrombopag treatment discontinuation.

Thrombocytopenia in Patients with Chronic ITP:
General: Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid
excessive increases in platelet counts during eltrombopag therapy.
Platelet count:

• Less than 50 x 10(9)/L following at least 2 weeks of eltrombopag therapy: Increase daily dose by 25 mg to a maximum of 75 mg per day. For patients taking 12.5 mg once a day, increase the dose to 25 mg once a day before increasing the dose amount by 25 mg.
• Greater than or equal to 200 x 10(9)/L to less than or equal to 400 x 10(9)/L at any time: Decrease the daily dose by 25 mg. For patients taking 25 mg once a day, decrease dose to 12.5 mg once a day.
• Greater than 400 x 10(9)/L: Stop eltrombopag; increase platelet monitoring to twice weekly. Once the platelet count is less than 150 x 10(9)/L, restart eltrombopag at a daily dose reduced by 25 mg. For patients taking 25 mg once a day, restart therapy at 12.5 mg once a day.
• Greater than 400 x 10(9)/L after 2 weeks of therapy at the lowest dose of eltrombopag: Discontinue eltrombopag

Thrombocytopenia in Patients with Chronic Hepatitis C:
General:

• During antiviral therapy, the dose of eltrombopag should be adjusted to avoid dose reductions of peginterferon.
• Eltrombopag should be discontinued when antiviral therapy is discontinued.

Platelet count:

• Less than 50 x 10(9)/L following at least 2 weeks of eltrombopag therapy: Increase daily dose by 25 mg to a maximum of 100 mg per day
• Greater than or equal to 200 x 10(9)/L to less than or equal to 400 x 10(9)/L at any time: Decrease the daily dose by 25 mg
• Greater than 400 x 10(9)/L: Stop eltrombopag; increase platelet monitoring to twice weekly. Once the platelet count is less than 150 x 10(9)/L, restart eltrombopag at a daily dose reduced by 25 mg. For patients taking 25 mg once a day, restart therapy at 12.5 mg once a day.
• Greater than 400 x 10(9)/L after 2 weeks of therapy at lowest dose of eltrombopag: Discontinue eltrombopag

First-line Severe Aplastic Anemia:
Platelet count:

• Greater than 200 x 10(9)/L to less than or equal to 400 x 10(9)/L: Decrease the daily dose by 25 mg every 2 weeks to the lowest dose that maintains a platelet count of at least 50 x 10(9)/L. In pediatric patients less than 12 years of age, decrease the dose by 12.5 mg.
• Greater than 400 x 10(9)/L: Discontinue this drug for 1 week. Once the platelet count is less than 200 x 10(9)/L, reinitiate this drug at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients less than 12 years of age).

Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction): Discontinue this drug but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.

Refractory Severe Aplastic Anemia:
Platelet count:

• Less than 50 x 10(9)/L following at least 2 weeks of this drug: Increase daily dose by 50 mg to a

maximum of 150 mg/day. For patients taking 25 mg once a day, increase the dose to 50 mg once a day before increasing the dose amount by 50 mg.

• Greater than or equal to 200 x 10(9)/L to less than or equal to 400 x 10(9)/L at any time: Decrease the daily dose by 50 mg.
• Greater than 400 x 10(9)/L: Stop this drug for 1 week. Once the platelet count is less than 150 x 10(9)/L, reinitiate therapy at a dose reduced by 50 mg.
• Greater than 400 x 10(9)/L after 2 weeks of therapy at the lowest dose of this drug: Discontinue this drug.

Precautions

US BOXED WARNINGS:

• RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C: In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation.
• RISK OF HEPATOTOXICITY: This drug may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

Safety and efficacy have not been established in patients younger than 1 year with ITP. Safety and efficacy have not been established in patients younger than 2 years for the for the first-line treatment of severe aplastic anemia in combination with horse antithymocyte globulin (h-ATG) and cyclosporine. Safety and efficacy have not been established in patients younger than 18 years with thrombocytopenia associated with chronic hepatitis C and severe aplastic anemia.

Consult WARNINGS section for dosing related precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug should be taken without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods, or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.
• Do not administer more than one dose of eltrombopag within any 24 hour period.
• Do not split, chew, or crush tablets and mix with food or liquids.

Reconstitution/preparation techniques: The manufacturer product information should be consulted.

Monitoring:

• Cardiovascular: Thrombotic/thromboembolic events
• Hematologic: CBC with differentials, including platelet counts
• Hepatic: Hepatic function

General:

• Eltrombopag should not be used in an attempt to normalize platelet counts.
• The prescribing information for concomitant pegylated interferon and ribavirin therapy should be consulted for further information regarding these medicines.