Committee Approval Date: May 9, 2014 Next Review Date: May 2015

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1 Medication Policy Manual Policy No: dru180 Topic: Promacta, eltrombopag Date of Origin: May 8, 2009 Committee Approval Date: May 9, 2014 Next Review Date: May 2015 Effective Date: June 1, 2014 IMPTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Eltrombopag (Promacta ) is an oral medication used to increase platelets. dru180.5 Page 1 of 9

2 Policy/Criteria I. Most contracts require prior authorization of eltrombopag prior to coverage. Eltrombopag may be considered medically necessary when criteria A or B are met. A. A diagnosis of chronic idiopathic thrombocytopenia purpura (ITP), also known as immune thrombocytopenia, made by, or in consultation with, a hematologist. AND 1. Patient is at risk of spontaneous bleeding as demonstrated in chart notes by either one of the following criteria 1 or 2 below: a. Platelet count less than 20,000/mm 3. b. Platelet count less than 30,000/mm 3 accompanied by symptoms of bleeding. AND 2. Treatment with at least one the following ITP treatments was ineffective or not tolerated: a. Adequate course of systemic corticosteroids (e.g., prednisone 1 to 2 mg/kg for 2 to 4 weeks, or pulse dexamethasone 40 mg daily for 4 days). b. Immunoglobulin therapy. c. Splenectomy. B. The member has thrombocytopenia associated with hepatitis C (HCV) and is unable to initiate or maintain interferon (IFN) therapy due to platelet count less than 75,000/mm 3, and a Child-Pugh level A (score 5-6). (See Appendix B) II. Administration, Quantity Limitations, and Authorization Period A. RegenceRx considers eltrombopag to be a self-administered medication. B. When prior authorization is approved, eltrombopag may be authorized for an initial period of 12 weeks. dru180.5 Page 2 of 9

3 C. When prior authorization is approved, eltrombopag may be authorized in quantities of up to one tablet per day, 1. Not to exceed 75 mg per day for treatment of chronic ITP 2. Not to exceed 100 mg per day for the treatment of thrombocytopenia associated with HCV. D. Continued authorization or re-authorization (after the initial 12 week period) shall be reviewed at least every six months to confirm that current medical necessity criteria are met and that the medication is effective: 1. For chronic ITP: the patient s recent (within the last 90 days) platelet count is either: a. Equal to or greater than 30,000/mm 3 but not more than 150,000/mm 3. b. Less than 30,000/mm 3 but platelet counts have increased from baseline accompanied with a resolution of previous bleeding. 2. For thrombocytopenia associated with HCV: The patient remains on interferon/ribavirin therapy and platelet count is less than 400,000/ mm 3. III. Eltrombopag is considered investigational when used for all other conditions, including, but not limited to: A. Acute thrombocytopenia. B. Low platelet counts secondary to other conditions or diseases (including, but not limited to, cancer, HIV, and myelodysplastic syndrome). C. Drug-induced thrombocytopenia [e.g., chemotherapy, heparin (HIT)]. [1] D. Thrombocytopenia secondary to disseminated intravascular coagulation, hemangiomas, or platelet loss (massive bleeding). E. Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). F. In combination with direct-acting antivirals, such as HCV protease inhibitors or polymerase inhibitors, including but not limited to telaprevir (Incivek), boceprevir (Victrelis ), simeprevir (Olysio) or sofosbuvir (Sovaldi). G. In patients with evidence of decompensated liver disease with Child-Pugh score > 6 (class B and C), history of ascites, or hepatic encephalopathy. H. Thrombocytopenia associated with chronic liver disease (CLD), other than for initiation of HCV interferon therapy. dru180.5 Page 3 of 9

4 Position Statement Summary - Eltrombopag is a thrombopoietin (TPO) receptor agonist, used to increase platelet production in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. [2,3] - It has only been studied in patients for whom traditional treatments have been ineffective. Steroids and/or splenectomy are considered first-line treatments of choice for chronic ITP. Other treatments include immune globulin therapy (IVIG), WinRho, rituximab, danazol, chemotherapy (e.g., cyclophosphamide, vincristine) and azathioprine. [4] - A normal platelet count in a healthy person is between 150,000 and 400,000/mm 3. The goal of treatment for chronic ITP should be to maintain a safe platelet count to decrease risks for bleeding, not to achieve a normal platelet count. [4] - Risk of spontaneous bleeding increases as platelet counts drops below 20,000/mm 3. [4] - Considering the slow time to response of TPO receptor agonists and frequent platelet lability in refractory ITP patients, ongoing use of eltrombopag may be indicated for patients with platelets well above the critical threshold, such as over 30,000 but less than 150,000/mm 3. - Due to risk of rare but serious side effects and uncertain long term benefit, eltrombopag should only be reserved for very refractory patients when other treatments options have been ineffective. - Eltrombopag is also used to treat thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Safety and efficacy of eltrombopag has not been established for use in combination with direct-acting antivirals, such as protease inhibitors or polymerase inhibitors. [2] - Eltrombopag may be covered in doses up to 75 mg per day for treatment of ITP and up to 100 mg per day for treatment of thrombocytopenia associated with HCV. Clinical Efficacy Chronic ITP - Eltrombopag has been proven in clinical studies to be more effective for increasing platelets than placebo. [2,3,5] Eltrombopag may increase platelet counts; however, its effectiveness past 6 months is uncertain. Because the risk of bleeding is only prominent when platelet count drops below 20,000/mm 3, it is difficult to quantify the clinical benefit of treatment when half of the patients in the studies had platelet count above 20,000/mm 3 at baseline. dru180.5 Page 4 of 9

5 - It is uncertain whether the increase in platelets with eltrombopag is sustainable and whether eltrombopag decreases long-term rate of bleeding episodes or other complications in patients with chronic ITP. Low-certainty evidence from one 80-week open-label study in 207 patients with chronic ITP suggests that the effectiveness of eltrombopag may decrease significantly over time. At week 52, only 2 out of 207 patients were able to maintain platelet count >50,000/mm 3 continuously. [2,3] - Effect on overall survival is unknown, given the lack of evidence. [3] - Standard of care therapies are effective for many patients with chronic ITP. * Around one-third of patients may expect a long-term response from treatment with an oral corticosteroid. Corticosteroids should be rapidly tapered and stopped in patients who fail to respond after 4 weeks. [6] * Up to two-thirds of patients with ITP who undergo splenectomy may achieve a normal platelet count, which is often sustained with no additional therapy. [4,6] - There are no studies evaluating the efficacy of eltrombopag compared to other refractory ITP treatment options, such as romiplostim (Nplate). Trials of eltrombopag were conducted in patients refractory to standard treatments, predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine, as well as splenectomy. [2] - Guidelines support the use of eltrombopag in chronic ITP refractory to standard therapies and rescue therapies. [4,5] Thrombocytopenia associated with Hepatitis C [2] - Two randomized-controlled studies for the treatment of thrombocytopenia in adult patients with chronic hepatitis C compare eltrombopag to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin for up to 48 weeks. The primary efficacy endpoint for both trials was sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate interferon therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR. - Eltrombopag was only studied in patients trying to receive interferon therapy. * There is no data on the safety and efficacy of eltrombopag in HCV patients on directacting antivirals, such as HCV protease inhibitors or polymerase inhibitors, including but not limited to telaprevir (Incivek), boceprevir (Victrelis), simeprevir (Olysio) or sofosbuvir (Sovaldi). - Eltrombopag doses should be lowered when platelet levels are between 200,000 and 400, 000/mm 3 and stopped when platelets are over 400,000/m 3. [2] dru180.5 Page 5 of 9

6 * There is insufficient evidence to support the use of eltrombopag in patients with thrombocytopenia associated with chronic liver disease (CLD), in the absence of trying to initiate and maintain interferon therapy for HCV. This includes CLD patients with liver failure and/or cirrhosis and patients undergoing an invasive procedure. [7,8] INVESTIGATIONAL USES - Although eltrombopag has been studied in a variety of other conditions, including but not limited to the conditions listed below, there is insufficient evidence to support its use in those settings. Larger, well-designed trials are needed to confirm preliminary results. [9] Acute thrombocytopenia Low platelet counts secondary to other conditions or diseases, including, but not limited to, cancer, HIV, aplastic anemia, and myelodysplastic syndrome (MDS). [10,11] Drug-induced thrombocytopenia [e.g., chemotherapy, heparin (HIT)] Thrombocytopenia secondary to disseminated intravascular coagulation, hemangiomas, or platelet loss (massive bleeding) Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) Safety [2] - Prescribing information contains a boxed warning regarding risk of hepatotoxicity. There is an increased risk of hepatic decompensation when used in combination with peginterferon and ribavirin in patients with hepatitis C. Existing liver abnormalities may preclude the use of eltrombopag in many hepatitis C patients. Careful liver function test (LFT) monitoring is recommended. - Patients with chronic liver disease require lower initial dose due to increased risk for thromboembolic events (specifically portal vein thrombosis). - Uncommon but serious side effects include: * Bone marrow changes: eltrombopag increases the risk for reticulin deposition within the bone marrow. Clinical studies have not ruled out the possibility that reticulin and other fiber deposition may result in bone marrow fibrosis with cytopenias. * Worsening low blood platelet count: discontinuation of eltrombopag may result in worsened thrombocytopenia than was present prior to eltrombopag therapy and increased risk for bleeding. * High platelet counts and increased risk of blood clots: eltrombopag may increase platelet counts to a level that produces thrombotic/thromboembolic complications. dru180.5 Page 6 of 9

7 * Worsening hematologic conditions: romiplostim may increase the risk for hematological malignancies, especially in patients with myelodysplastic syndrome. - More common adverse reactions are nausea, vomiting, menorrhagia, myalgia, paresthesia, cataract, dyspepsia, ecchymosis, thrombocytopenia, increased ALT/AST and conjunctival hemorrhage. - Drug interactions and the overall safety of eltrombopag have not been evaluated in patients receiving direct-acting antivirals for hepatitis C, such as boceprevir (Victrelis) and telaprevir (Incivek). These medications are part of standard of care treatment for the most common HCV genotype (genotype 1). - Both thrombopoietin receptor agonists, eltrombopag and romiplostim, have a Risk Evaluation and Mitigation Strategy (REMS) program for the risk of bone marrow fibrosis, thromboembolic events, and hematologic malignancy. Risk for hepatotoxicity is also included in the eltrombopag program, and risk for worsening thrombocytopenia and bleeding after treatment discontinuation is included in the romiplostim program. [12] Dosing [2] - The initial dose of eltrombopag for most chronic ITP patients is 50 mg once daily. Maximum dose is 75 mg daily and adjusted based on clinical response (platelet count and bleeding). - Initial response to romiplostim for ITP is usually seen within 7 to 28 days, with a peak response in 14 to 90 days. [4] - The initial dose of eltrombopag HCV-associated thrombocytopenia is 25 mg once daily. Maximum dose is 100 mg daily and adjusted based on response of platelet count, to allow initiation of antiviral therapy. - The safety and effectiveness of higher doses have not been established. dru180.5 Page 7 of 9

8 Appendix A: American Society of Hematology Criteria for the Diagnosis of Chronic Immune Thrombocytopenic Purpura : Diagnosis of Exclusion [2] - History compatible with the diagnosis of chronic ITP - Normal physical examination findings except for signs of thrombocytopenia (petechiae, purpura, or mucosal bleeding); no adenopathy or splenomegaly - Complete blood count showing isolated thrombocytopenia with large platelets but no anemia unless bleeding or immune hemolysis is present - Bone marrow examination showing normal or increased numbers of megakaryocytes (not required for diagnosis unless unusual manifestation or age >60 yr.) - No clinical or laboratory evidence for other causes of thrombocytopenia Appendix B: Child-Pugh Classification Of Severity Of Liver Disease Child-Pugh Classification Points A: well-compensated disease 5 to 6 B: significant functional compromise 7 to 9 C: decompensated disease 10 to 15 Points Assigned Parameter Ascites Absent Slight Moderate Bilirubin (mg/dl) < 2 2 to 3 > 3 Albumin (g/dl) > to 3.5 < 2.8 Prothrombin Time Seconds over control 1 to 3 4 to 6 >6 INR < to 2.3 > 2.3 Encephalopathy None Grade 1 to 2 Grade 3 to 4 dru180.5 Page 8 of 9

9 Cross References Immune Globulin Replacement Therapy (IVIG, SQ), RegenceRx Medication Policy Manual, Policy No. dru020 Rituxan, rituximab, RegenceRx Medication Policy Manual, Policy No. dru214 Nplate, romiplostim, RegenceRx Medication Policy Manual, Policy No. dru162 References 1. Kellum, A, Jagiello-Gruszfeld, A, Bondarenko, IN, Patwardhan, R, Messam, C, Mostafa Kamel, Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin Oct;26(10): PMID: Promacta (eltrombopag) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; February Zeng, Y, Duan, X, Xu, J, Ni, X. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura. Cochrane Database Syst Rev. 2011(7):CD PMID: Neunert, C, Lim, W, Crowther, M, et al. The American Society of Hematology (ASH) 2011 evidence-based practice guideline for immune thrombocytopenia. Blood Apr 21;117(16): PMID: National Institute for Health and Clinical Evidence (NICE). NICE technology appraisal 293 (TA293). Eltrombopag for treating chronic immune (idiopathic) thrombocytopenic purpura(itp). Issued: July [cited March 19, 2014]; Available from: 6. British Committee for Standards in Haematology General Haematology Task, F. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol Feb;120(4): PMID: Afdhal, NH, Giannini, EG, Tayyab, G, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med Aug 23;367(8): PMID: Aguilar, C. Potential usefulness of thrombopoietin receptor agonists in haemophiliacs with thrombocytopaenia due to chronic liver disease. Blood Coagul Fibrinolysis Apr;24(3): PMID: Clinicaltrials.gov. [cited (updated periodically)]; Available from: Marsh, JC, Kulasekararaj, AG. Management of the refractory aplastic anemia patient: what are the options? Blood Nov 21;122(22): PMID: Townsley, DM, Desmond, R, Dunbar, CE, Young, NS. Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes. International journal of hematology Jul;98(1): PMID: Nplate (romiplostim) for subcutaneous injection [package insert]. thousand Oaks, CA: Amgen, Inc.; February 2014 dru180.5 Page 9 of 9