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.

12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production.

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 complet

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

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1) ] . One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5) ] . Eltrombopag inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST and bilirubin prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration (2.1 , 2.2) ] . Consider contacting the Poison Help line (1­-800-222-1222) or a medical toxicologist for additional overdose management recommendations.