Promacta

PROMACTA is a thrombopoietin receptor agonist indicated:

• for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. (
  1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia

  PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
  )
• for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. (
  1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection

  PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
  )
• in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. (
  1.3 Treatment of Severe Aplastic Anemia

  • PROMACTA is indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia.
  • PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
  )
• for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. (
  1.3 Treatment of Severe Aplastic Anemia

  • PROMACTA is indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia.
  • PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
  )

• PROMACTA is not indicated for the treatment of patients with myelodysplastic syndrome (MDS). (
  1.4 Limitations of Use

  • PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes (MDS)
    [see Warnings and Precautions (5.3)]
    .
  • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
  )
• Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. (
  1.4 Limitations of Use

  • PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes (MDS)
    [see Warnings and Precautions (5.3)]
    .
  • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
  )

• Take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg). Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. (
  2.4 Administration

  Administration of Tablets and Oral Suspension:

  Take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg). Take PROMACTA at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc

  [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]

  .

  Do not split, chew, or crush tablets and mix with food or liquids.

  Preparation of the Oral Suspension:

  Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration of PROMACTA for oral suspension.

  Administer the oral suspension immediately after preparation.

  Discard any suspension not administered within 30 minutes after preparation

  .

  Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension.

  For details on preparation and administration of the suspension, including the recommended duration of use of each oral dosing syringe

  [see Instructions for Use]

  .
  ,
  7.1 Polyvalent Cations (Chelation)

  Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids.

  Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of PROMACTA due to chelation

  [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]

  .
  ,
  12.3 Pharmacokinetics

  Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC_0-INFthan the tablet formulation.

  Absorption

  Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.

  Effect of Food

  A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC_0-INFby approximately 59% and C_maxby 65% and delayed T_maxby 1 hour. The decrease in exposure is primarily due to the high calcium content.

  A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.

  The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC_0-INFand C_maxin healthy adult subjects is presented in Table 14.

  Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal^ain Healthy Adult Subjects

  a372 calories, 9 g fat, and 448 mg calcium.
  Timing of eltrombopag for oral suspension dose	Mean (90% CI) reduction in plasma eltrombopag AUC0-INF	Mean (90% CI) reduction in plasma eltrombopag Cmax
  With a high-calcium, moderate-fat, moderate-calorie meal	75% (71%, 88%)	79% (76%, 82%)
  2 hours after the high-calcium, moderate-fat, moderate-calorie meal	47% (40%, 53%)	48% (40%, 54%)
  2 hours before the high-calcium, moderate-fat, moderate-calorie meal	20% (9%, 29%)	14% (2%, 25%)

  Distribution

  The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study.

  In vitro

  studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.

  Elimination

  The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.

  Metabolism:

  Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine.

  In vitro

  studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

  Excretion

  : 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 approximately 20% of the dose; unchanged eltrombopag is not detectable in urine.

  Specific Populations

  Ethnicity

  Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects

  [see Dosage and Administration (2.1, 2.3)]

  .

  Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.

  Hepatic Impairment

  Following a single dose of PROMACTA (50 mg), plasma eltrombopag AUC_0-INFwas 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC_0-INFwas approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects.

  Chronic Liver Disease

  Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC_(0-τ)and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC_(0-τ)values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects.

  Chronic Hepatitis C

  Patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC_(0-τ)values as compared with healthy subjects, and AUC_(0-τ)increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC_(0-τ)compared with healthy subjects. This clinical trial did not evaluate protein-binding effects.

  Renal Impairment

  Following a single dose of PROMACTA (50 mg), the average total plasma eltrombopag AUC_0-INFwas 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.

  Pediatric Patients

  The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC_(0-τ)values as compared with non-Asian patients.

  Plasma eltrombopag AUC_(0-τ)and C_maxin pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15.

  Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters^ain Patients With ITP (Normalized to a Once-daily 50-mg Dose)

  aPK parameters presented as geometric mean (95% CI). bBased on population PK post-hoc estimates.
  	Cmax b	AUC(0-τ) b
  Age	(mcg/mL)	(mcg·hr/mL)
  Adults (n = 108)	7.03	101
  	(6.44, 7.68)	(91.4, 113)
  12 to 17 years (n = 62)	6.80	103
  	(6.17, 7.50)	(91.1, 116)
  6 to 11 years (n = 68)	10.3	153
  	(9.42, 11.2)	(137, 170)
  1 to 5 years (n = 38)	11.6	162
  	(10.4, 12.9)	(139, 187)

  Drug Interaction Studies

  Clinical Studies

  Effect of Drugs on Eltrombopag

  Effect of Polyvalent Cation-containing Antacids on Eltrombopag:

  The coadministration of a single dose of PROMACTA (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC_0-INFand C_maxby approximately 70%. The contribution of sodium alginate to this interaction is not known.

  Effect of HIV Protease Inhibitors on Eltrombopag:

  The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of PROMACTA (100 mg) decreased plasma eltrombopag AUC_0-INFby 17%.

  Effect of HCV Protease Inhibitors on Eltrombopag:

  The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC_0-INFor C_maxto a significant extent.

  Effect of Cyclosporine on Eltrombopag:

  The coadministration of a single dose of PROMACTA (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC_0-INFby 18% to 24% and C_maxby 25% to 39%.

  Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag:

  The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag.

  Effect of Eltrombopag on Other Drugs

  Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates:

  The coadministration of multiple doses of PROMACTA (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans.

  Effect of Eltrombopag on Rosuvastatin:

  The coadministration of multiple doses of PROMACTA (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC_0-INFby 55% and C_maxby 103%.

  Effect of Eltrombopag on HCV Protease Inhibitors:

  The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC_0-INFor C_maxto a significant extent.

  In vitro

  Studies

  Eltrombopag Effect on Metabolic Enzymes

  Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.

  Eltrombopag Effect on Transporters

  Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP.
  )
  
• Persistent or Chronic ITP:
  Initiate PROMACTA at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10⁹/L. Do not exceed 75 mg per day. (
  2.1 Persistent or Chronic Immune Thrombocytopenia

  Use the lowest dose of PROMACTA to achieve and maintain a platelet count greater than or equal to 50 x 10⁹/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts

  [see Warnings and Precautions (5.4)].

  In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting PROMACTA and decreased within 1 to 2 weeks after discontinuing PROMACTA

  [see Clinical Studies (14.1)]

  .

  Initial Dose Regimen:

  Adult and Pediatric Patients 6 Years and Older with ITP:

  Initiate PROMACTA at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C).

  For patients of East-/Southeast-Asian ancestry with ITP, initiate PROMACTA at a reduced dose of 25 mg orally once daily

  [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

  For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate PROMACTA at a reduced dose of 25 mg orally once daily

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  .

  For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating PROMACTA at a reduced dose of 12.5 mg orally once daily

  [see Clinical Pharmacology (12.3)]

  .

  Pediatric Patients with ITP Aged 1 to 5 Years:

  Initiate PROMACTA at a dose of 25 mg orally once daily

  [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  .

  Monitoring and Dose Adjustment:

  After initiating PROMACTA, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10⁹/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 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 1. During therapy with PROMACTA, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter.

  When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring.

  Table 1. Dose Adjustments of PROMACTA in Patients With Persistent or Chronic Immune Thrombocytopenia

  Platelet count result	Dose adjustment or response
  < 50 x 109/L following at least 2 weeks of PROMACTA	Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
  ≥ 200 x 109/L to ≤ 400 x 109/L at any time	Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
  > 400 x 109/L	Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
  > 400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTA	Discontinue PROMACTA.

  In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating PROMACTA or after any subsequent dosing increase, wait 3 weeks before increasing the dose.

  Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with PROMACTA. Do not administer more than one dose of PROMACTA within any 24-hour period.

  Discontinuation:

  Discontinue PROMACTA if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with PROMACTA at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of PROMACTA

  [see Warnings and Precautions (5.2, 5.6) and Drug Interactions (7.5)]

  . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of PROMACTA.
  ,
  8.6 Hepatic Impairment

  Patients With Persistent or Chronic ITP and Severe Aplastic Anemia

  Reduce the initial dose of PROMACTA in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C)

  [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]

  .

  In a clinical trial in patients with severe aplastic anemia 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 PROMACTA for the first-line treatment of severe aplastic anemia, reduce the initial dose

  [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]

  .

  Patients With Chronic Hepatitis C

  No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment

  [see Clinical Pharmacology (12.3)]

  .
  ,
  8.7 Ethnicity

  Reduce the initial dose of PROMACTA for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia

  [see Dosage and Administration (2.1, 2.3), Clinical Pharmacology (12.3)]

  . No reduction in the initial dose of PROMACTA is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C

  [see Clinical Pharmacology (12.3)]

  .
  )
  
• Chronic Hepatitis C-associated Thrombocytopenia:
  Initiate PROMACTA at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. (
  2.2 Chronic Hepatitis C-Associated Thrombocytopenia

  Use the lowest dose of PROMACTA to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts

  [see Warnings and Precautions (5.4)]

  . In clinical trials, platelet counts generally began to rise within the first week of treatment with PROMACTA

  [see Clinical Studies (14.2)]

  .

  Initial Dose Regimen:

  Initiate PROMACTA at a dose of 25 mg orally once daily.

  Monitoring and Dose Adjustment:

  Adjust the dose of PROMACTA in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy.

  During antiviral therapy, adjust the dose of PROMACTA to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with PROMACTA

  [see Drug Interactions (7.5)]

  .

  For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.

  Table 2. Dose Adjustments of PROMACTA in Adults With Thrombocytopenia Due to Chronic Hepatitis C

  Platelet count result	Dose adjustment or response
  < 50 x 109/L following at least 2 weeks of PROMACTA	Increase daily dose by 25 mg to a maximum of 100 mg/day.
  ≥ 200 x 109/L to ≤ 400 x 109/L at any time	Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
  > 400 x 109/L	Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
  > 400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTA	Discontinue PROMACTA.

  Discontinuation:

  The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility.

  PROMACTA should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of PROMACTA

  [see Warnings and Precautions (5.2)]

  .
  )
  
• First-line Severe Aplastic Anemia:
  Initiate PROMACTA orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. (
  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 orally once daily for 6 months
  Pediatric patients 6 to 11 years	75 mg orally once daily for 6 months
  Pediatric patients 2 to 5 years	2.5 mg/kg orally once daily for 6 months

  For patients with severe aplastic anemia of East-/Southeast-Asian ancestry 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 East-/Southeast-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 orally once daily for 6 months
  Pediatric patients 6 to 11 years	37.5 mg orally once daily for 6 months
  Pediatric patients 2 to 5 years	1.25 mg/kg orally 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 ULN Discontinue 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 PROMACTA Discontinue 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 dose Reduce 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 orally once daily.

  For patients with severe aplastic anemia of East-/Southeast-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 orally 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)]

  .
  ,
  8.7 Ethnicity

  Reduce the initial dose of PROMACTA for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia

  [see Dosage and Administration (2.1, 2.3), Clinical Pharmacology (12.3)]

  . No reduction in the initial dose of PROMACTA is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C

  [see Clinical Pharmacology (12.3)]

  .
  )
  
• Refractory Severe Aplastic Anemia:
  Initiate PROMACTA orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10⁹/L. Do not exceed 150 mg per day. (
  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 orally once daily for 6 months
  Pediatric patients 6 to 11 years	75 mg orally once daily for 6 months
  Pediatric patients 2 to 5 years	2.5 mg/kg orally once daily for 6 months

  For patients with severe aplastic anemia of East-/Southeast-Asian ancestry 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 East-/Southeast-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 orally once daily for 6 months
  Pediatric patients 6 to 11 years	37.5 mg orally once daily for 6 months
  Pediatric patients 2 to 5 years	1.25 mg/kg orally 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 ULN Discontinue 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 PROMACTA Discontinue 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 dose Reduce 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 orally once daily.

  For patients with severe aplastic anemia of East-/Southeast-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 orally 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)]

  .
  ,
  8.6 Hepatic Impairment

  Patients With Persistent or Chronic ITP and Severe Aplastic Anemia

  Reduce the initial dose of PROMACTA in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C)

  [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]

  .

  In a clinical trial in patients with severe aplastic anemia 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 PROMACTA for the first-line treatment of severe aplastic anemia, reduce the initial dose

  [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]

  .

  Patients With Chronic Hepatitis C

  No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment

  [see Clinical Pharmacology (12.3)]

  .
  ,
  8.7 Ethnicity

  Reduce the initial dose of PROMACTA for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia

  [see Dosage and Administration (2.1, 2.3), Clinical Pharmacology (12.3)]

  . No reduction in the initial dose of PROMACTA is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C

  [see Clinical Pharmacology (12.3)]

  .
  )
  

• 12.5 mg tablets —– round, biconvex, white, film-coated tablets debossed with “GS MZ1” and 12.5 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid.
• 25 mg tablets —– round, biconvex, orange, film-coated tablets debossed with “GS NX3” and 25 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid.
• 50 mg tablets —– round, biconvex, blue, film-coated tablets debossed with “GS UFU” and 50 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid.
• 75 mg tablets —– round, biconvex, pink, film-coated tablets debossed with “GS FFS” and 75 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid.

• 12.5 mg packet —– contains a reddish-brown to yellow powder for reconstitution.
• 25 mg packet —– contains a reddish-brown to yellow powder for reconstitution.

• Lactation:
  Advise women not to breastfeed during treatment. (
  8.2 Lactation

  Risk Summary

  There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from PROMACTA, breastfeeding is not recommended during treatment.
  )