Anemias:
Indications for: PROMACTA
First-line treatment of severe aplastic anemia in patients ≥2yrs, in combination with standard immunosuppressive therapy. Severe aplastic anemia in adults who have had insufficient response to immunosuppressive therapy.
Limitations of Use:
Not indicated for the treatment of myelodysplastic syndromes (MDS).
Clinical Trials:
First-Line Treatment of Severe Aplastic Anemia
In a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]), the concomitant use of Promacta with h-ATG and cyclosporine was evaluated in 153 patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. All patients received Promacta in 3 sequential cohorts and an extension of the third cohort.
The starting dose of Promacta for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians).
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Cohort 1 (n=30): Promacta on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine
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Cohort 2 (n = 31): Promacta on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine
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Cohort 3 + Extension cohort [Promacta D1-M6 cohort] (n = 92): Promacta on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months)
The efficacy of Promacta in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109 /L and hemoglobin > 10 g/dL.
The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively.
Pediatric Patients: There were 34 patients 2 to 16 years of age who enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.
Refractory Severe Aplastic Anemia
The approval was based on data from a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) that evaluated Promacta in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109 /L. Patients received an initial dose of 50 mg once daily for 2 weeks then increased over 2-week periods up to a maximum dose of 150 mg once daily.
The efficacy was evaluated by the hematologic response after 12 weeks. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109 /L. Promacta was discontinued after 16 weeks if no hematologic response was observed.
Results showed that 40% (n=17/43) of patients achieved hematologic response. Among the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days.
Adult Dosage:
Take without a meal or with a meal low in calcium (≤50mg). First-line treatment: if baseline ALT/AST levels >6×ULN, do not initiate until baseline transaminases <5×ULN. ≥12yrs: initially 150mg once daily for 6 months. Hepatic impairment or East-/Southeast-Asian ancestry: reduce initial dose by 50%. Refractory: initially 50mg once daily. Hepatic impairment or East-/Southeast-Asian ancestry: initially 25mg once daily. Titrate dose by 50mg increments every 2 weeks as needed to maintain platelet count ≥50×109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling.
Children Dosage:
<2yrs: not established. Take without a meal or with a meal low in calcium (≤50mg). If baseline ALT/AST levels >6×ULN, do not initiate until baseline transaminases <5×ULN. First-line treatment (2–5yrs): initially 2.5mg/kg once daily; (6–11yrs): initially 75mg once daily. Treat for 6 months. Hepatic impairment or East-/Southeast-Asian ancestry: reduce initial dose by 50%. Monitoring, dose adjustment, and discontinuation: see full labeling.
Boxed Warning:
Risk for hepatic decompensation in patients with chronic hepatitis C. Risk of hepatotoxicity.
PROMACTA Warnings/Precautions:
Increased risk of hepatic decompensation in patients with chronic hepatitis C in combination with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Increased risk of severe hepatotoxicity; monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (for first-line treatment of aplastic anemia, monitor at baseline, every other day while hospitalized, and every 2 weeks during therapy; see full labeling); discontinue if ALT ≥3×ULN in those with normal liver function or ≥3× baseline (or >5×ULN, whichever is lower) in those with pre-treatment transaminase elevations and are progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or symptoms/evidence of hepatic injury/decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of death and progression of MDS to acute myeloid leukemia (AML). Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Asian ancestry. Advise females of reproductive potential to use effective contraception during and for ≥7 days after stopping treatment. Pregnancy. Nursing mothers: not recommended.
See Also:
PROMACTA Classification:
Thrombopoietin receptor agonist.
PROMACTA Interactions:
Potentiates substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Separate dosing by at least 2hrs before or 4hrs after food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2).
Adverse Reactions:
Anemia, nausea, pyrexia, increased ALT, cough, fatigue, headache, diarrhea; hepatotoxicity, thrombotic/thromboembolic complications, cataracts.
Drug Elimination:
The plasma elimination half-life of eltrombopag is ~21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.
The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for ~20% of the dose; unchanged eltrombopag is not detectable in urine.
Generic Drug Availability:
NO
How Supplied:
Tabs 12.5mg, 25mg, 75mg—30; 50mg—14, 30; Oral susp kit—1 (30 pkts w. supplies)
Bleeding disorders:
Indications for: PROMACTA
Thrombocytopenia in adult and pediatric patients ≥1year with persistent or chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Should be used only in ITP patients whose degree of thrombocytopenia and clinical condition increase the risk of bleeding. Thrombocytopenia in adults with chronic hepatitis C to allow initiation and maintenance of interferon-based therapy. Should be used only in chronic hepatitis C patients whose degree of thrombocytopenia prevents starting or limiting ability to maintain interferon-based therapy.
Limitations of Use:
Not indicated for the treatment of myelodysplastic syndromes (MDS). Safety and efficacy not established in combination with direct-acting antiviral agents without interferon for chronic hepatitis C infection.
Clinical Trials:
First-Line Treatment of Severe Aplastic Anemia
In a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]), the concomitant use of Promacta with h-ATG and cyclosporine was evaluated in 153 patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. All patients received Promacta in 3 sequential cohorts and an extension of the third cohort.
The starting dose of Promacta for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians).
-
Cohort 1 (n=30): Promacta on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine
-
Cohort 2 (n = 31): Promacta on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine
-
Cohort 3 + Extension cohort [Promacta D1-M6 cohort] (n = 92): Promacta on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months)
The efficacy of Promacta in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109 /L and hemoglobin > 10 g/dL.
The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively.
Pediatric Patients: There were 34 patients 2 to 16 years of age who enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.
Refractory Severe Aplastic Anemia
The approval was based on data from a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) that evaluated Promacta in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109 /L. Patients received an initial dose of 50 mg once daily for 2 weeks then increased over 2-week periods up to a maximum dose of 150 mg once daily.
The efficacy was evaluated by the hematologic response after 12 weeks. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109 /L. Promacta was discontinued after 16 weeks if no hematologic response was observed.
Results showed that 40% (n=17/43) of patients achieved hematologic response. Among the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days.
Adults and Children:
Take without a meal or with a meal low in calcium (≤50mg). ITP: <1yr: not established; 1–5yrs: initially 25mg once daily; ≥6yrs: initially 50mg once daily. Hepatic impairment or East-/Southeast-Asian ancestry: initially 25mg once daily. East-/Southeast-Asian ancestry with hepatic impairment: consider initiating at 12.5mg once daily. Titrate to maintain platelet count ≥50×109/L; max 75mg once daily. Chronic hepatitis C-associated thrombocytopenia: initially 25mg once daily. Titrate dose by 25mg increments every 2 weeks as needed to achieve target platelet counts; max 100mg/day. Monitoring, dose adjustment, and discontinuation: see full labeling.
Boxed Warning:
Risk for hepatic decompensation in patients with chronic hepatitis C. Risk of hepatotoxicity.
PROMACTA Warnings/Precautions:
Increased risk of hepatic decompensation in patients with chronic hepatitis C in combination with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Increased risk of severe hepatotoxicity; monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (for first-line treatment of aplastic anemia, monitor at baseline, every other day while hospitalized, and every 2 weeks during therapy; see full labeling); discontinue if ALT ≥3×ULN in those with normal liver function or ≥3× baseline (or >5×ULN, whichever is lower) in those with pre-treatment transaminase elevations and are progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or symptoms/evidence of hepatic injury/decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of death and progression of MDS to acute myeloid leukemia (AML). Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Asian ancestry. Advise females of reproductive potential to use effective contraception during and for ≥7 days after stopping treatment. Pregnancy. Nursing mothers: not recommended.
See Also:
PROMACTA Classification:
Thrombopoietin receptor agonist.
PROMACTA Interactions:
Potentiates substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Separate dosing by at least 2hrs before or 4hrs after food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2).
Adverse Reactions:
Anemia, nausea, pyrexia, increased ALT, cough, fatigue, headache, diarrhea; hepatotoxicity, thrombotic/thromboembolic complications, cataracts.
Drug Elimination:
The plasma elimination half-life of eltrombopag is ~21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.
The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for ~20% of the dose; unchanged eltrombopag is not detectable in urine.
Generic Drug Availability:
NO
How Supplied:
Tabs 12.5mg, 25mg, 75mg—30; 50mg—14, 30; Oral susp kit—1 (30 pkts w. supplies)
