Eltrombopag

1 INDICATIONS AND USAGE Eltrombopag 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. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets 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 ) 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 ) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) 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 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are 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. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets 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. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are 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. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are 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.

2 DOSAGE AND ADMINISTRATION Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets 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 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag tablets 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 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets 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 ) First-line Severe Aplastic Anemia: Initiate eltrombopag tablets 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 , 8.7 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets 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 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies (14.1) ] . Initial Dose Regimen Adult and Pediatric Patients 6 Years and Older with ITP Initiate eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /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 eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, 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 Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets 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 10 9 /L to ≤ 400 x 10 9 /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 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /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 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets 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 eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets 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 eltrombopag tablets [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 eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets [see Clinical Studies (14.2) ] . Initial Dose Regimen Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment Adjust the dose of eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets [see Drug Interactions (7.5) ] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2: Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /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 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /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 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. 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. Eltrombopag tablets 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 eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets 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 eltrombopag tablets. Table 3: Recommended Initial Eltrombopag Tablets 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 eltrombopag tablets 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 eltrombopag tablets 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 Tablets 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 Eltrombopag Tablets Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions (5.2) ] . Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5: Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets 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 eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6: Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets 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 tablets 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 eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets 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 eltrombopag tablets [see Clinical Studies (14.3) ] . Initial Dose Regimen Initiate eltrombopag tablets 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 eltrombopag tablets 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 eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7: Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets 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 10 9 /L to ≤ 400 x 10 9 /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 10 9 /L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies (14.3) ] . If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. 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, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions (6.1) ] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.4 Administration Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3) ] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.5) ] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ] . The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1) ] . Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8: Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9: Treatment-related Adverse Reactions ( > 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.4) ] . Pediatric Patients The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10: Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11: Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3) ] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort. Table 12: Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse Reaction Eltrombopag n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%) and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%) and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13: Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing.

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-INF than 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-INF by approximately 59% and C max by 65% and delayed T max by 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. 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 eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was 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 eltrombopag 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 eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 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 max in 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 a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The co-administration of a single-dose of eltrombopag (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-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single-dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag The co-administration of a single-dose of eltrombopag (50 mg) with a single-dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 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 co-administration of multiple-doses of eltrombopag (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 co-administration of multiple-doses of eltrombopag (75 mg once daily for 5 days) with a single-dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to 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.