PROMACTA (Page 2 of 9)

2.3 Severe Aplastic Anemia

First-Line Severe Aplastic Anemia

Initiate PROMACTA concurrently with standard immunosuppressive therapy [see Clinical Studies (14.3)].

Initial Dose Regimen:

The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of PROMACTA.

Table 3. Recommended Initial PROMACTA Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia

Age

Dose Regimen

Patients 12 years and older

150 mg once daily for 6 months

Pediatric patients 6 to 11 years

75 mg once daily for 6 months

Pediatric patients 2 to 5 years

2.5 mg/kg once daily for 6 months

For patients with severe aplastic anemia of 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 PROMACTA dose by 50% as listed in Table 4 [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)].

If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate PROMACTA 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 PROMACTA Dose Regimen for Patients of 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 Anemia

Age

Dose Regimen

Patients 12 years and older

75 mg once daily for 6 months

Pediatric patients 6 to 11 years

37.5 mg once daily for 6 months

Pediatric patients 2 to 5 years

1.25 mg/kg once daily for 6 months

Monitoring and Dose Adjustment for PROMACTA: Perform clinical hematology and liver tests regularly throughout therapy with PROMACTA [see Warnings and Precautions (5.2)].

Modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 5.

Table 5. Dose Adjustments of PROMACTA for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia

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 pediatric patients under 12 years of age, decrease the dose by 12.5 mg.

> 400 x 109 /L

Discontinue PROMACTA for one week. Once the platelet count is < 200 x 109 /L, reinitiate PROMACTA at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).

Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of PROMACTA in the management of elevated liver transaminase levels and thromboembolic events.

Table 6. Recommended Dose Modifications for PROMACTA for ALT or AST Elevations and Thromboembolic Events
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Event

Recommendation

ALT or AST Elevations

Increase in ALT or AST > 6 x ULNDiscontinue PROMACTA. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA at the same dose.

Increase in ALT or AST > 6 x ULN after reinitiating PROMACTADiscontinue PROMACTA and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA 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 doseReduce the daily dose of PROMACTA by 25 mg until ALT or AST is < 5 x ULN.

In pediatric 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., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction)

Discontinue PROMACTA but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.

The total duration of PROMACTA treatment is 6 months.

Refractory Severe Aplastic Anemia

Use the lowest dose of PROMACTA to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting PROMACTA [see Clinical Studies (14.3)].

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

For patients with severe aplastic anemia of Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced dose of 25 mg once daily [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)].

Monitoring and Dose Adjustment: Adjust the dose of PROMACTA in 50-mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 109 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 7.

Table 7. Dose Adjustments of PROMACTA in Patients With Refractory Severe Aplastic Anemia

Platelet Count Result

Dose Adjustment or Response

< 50 x 109 /L following at least 2 weeks of PROMACTA

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.

≥ 200 x 109 /L to ≤ 400 x 109 /L at any time

Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.

> 400 x 109 /L

Stop PROMACTA for 1 week.

Once the platelet count is < 150 x 109 /L, reinitiate therapy at a dose reduced by 50 mg.

> 400 x 109 /L after 2 weeks of therapy at lowest dose of PROMACTA

Discontinue PROMACTA.

For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of PROMACTA may be reduced by 50% [see Clinical Studies (14.3)]. If counts remain stable after 8 weeks at the reduced dose, then discontinue PROMACTA and monitor blood counts. If platelet counts drop to less than 30 x 109 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 109 /L, PROMACTA may be reinitiated at the previous effective dose.

Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with PROMACTA, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of PROMACTA [see Adverse Reactions (6.1)]. Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2)].

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