Eltrombopag

1 INDICATIONS AND USAGE Eltrombopag for oral suspension 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 for oral suspension 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 for oral suspension 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 ) • for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: • Eltrombopag for oral suspension is 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 for oral suspension 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. Eltrombopag for oral suspension 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 for oral suspension is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag for oral suspension 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 for oral suspension is 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 for oral suspension 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. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION Take eltrombopag for oral suspension without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag for oral suspension 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 for oral suspension at 50 mg once daily for most adult and pediatric patients 6 years and older, and at 25 mg 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 for oral suspension at 25 mg 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 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag for oral suspension 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 for oral suspension 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 for oral suspension 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 for oral suspension and decreased within 1 to 2 weeks after discontinuing eltrombopag for oral suspension [see Clinical Studies (14.1) ] . Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP : Initiate eltrombopag for oral suspension at a dose of 50 mg 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 for oral suspension at a reduced dose of 25 mg 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 for oral suspension at a reduced dose of 25 mg 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 for oral suspension at a reduced dose of 12.5 mg once daily [ see Clinical Pharmacology (12.3 )] . Pediatric Patients with ITP Aged 1 to 5 Years: Initiate eltrombopag for oral suspension at a dose of 25 mg once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment: After initiating eltrombopag for oral suspension, 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 for oral suspension and modify the dosage regimen of eltrombopag for oral suspension based on platelet counts as outlined in Table 1. During therapy with eltrombopag for oral suspension, 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 platel…

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. 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. 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 at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative r…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 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 eltrombopag 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 eltrombopag due to chelation [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]. 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ).

8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.

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 Annora Pharma Private Limited at 1-866-495-1995 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 pa…