Promacta (eltrombopag)

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1 Promacta (eltrombopag) Policy Number: Last Review: 5/2018 Origination: 6/2013 Next Review: 5/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Promacta (eltrombopag) when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered The use of Promacta may be considered medically necessary for the following: 1. Treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia purpura. Approve Promacta if the patient meets the following criteria (a, b, and c): a) The agent is prescribed by, or after consultation with, a hematologist; AND b) The patient is 18 years of age; AND c) The patient meets ONE of the following conditions (i, ii, or iii): i. The patient has tried corticosteroids; OR ii. The patient has tried IVIG; OR iii. The patient has undergone splenectomy Promacta is indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. 1 The safety and efficacy of Promacta in pediatric patients have not been established. The pivotal trials with Promacta involved adults who had tried at least one primary ITP therapy (e.g., corticosteroids, immunoglobulins); approximately 40% of patients had undergone splenectomy. 1 Evidence-based practice guidelines for immune thrombocytopenia from ASH (published in 2011), recommends corticosteroids or IVIG as firstline treatment for adults; splenectomy is recommended for patients who have failed corticosteroid therapy. Thrombopoietin receptor agonists are recommended for adults at risk of bleeding who relapse following splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy. At this time recommendations for use of thrombopoietin receptor agonists in children with ITP cannot be made; clinical trials have been initiated. 2. Treatment of thrombocytopenia in patients with chronic hepatitis C to allow for initiation and maintenance of interferon-based therapy. Approve Promacta if the patient meets the following criteria (a, b, c, and d): a) Promacta is prescribed by, or after consultation with, either a gastroenterologist, a hepatologist, or a physician that specializes in infectious disease; AND b) The patient has low platelet counts (e.g., < 75,000 mm 3 ); AND c) The patient has chronic HCV infection and is a candidate for hepatitis C therapy (e.g., Pegasys or PegIntron plus ribavirin, with or without direct-acting antiviral agents [i.e., Victrelis {boceprevir capsules}, Incivek {telaprevir tablets]); AND d) The patient is aged 18 years. Promacta is indicated for the treatment of thrombocytopenia in patients with CHC to allow the initiation and maintenance of interferon-based therapy. It should only be used in patients with CHC whose

2 degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. Patients in the trials were adults with CHC who were receiving either PegIntron or Pegasys, along with ribavirin, and platelet counts were < 75 x 10 9 /L. Use of Promacta allowed approximately 95% of patients to initiate CHC therapy and a statistically significantly greater proportion of patients given Promacta achieved SVR. In the professional opinion of specialized physicians, these criteria have been adopted. 3. Aplastic Anemia. Approve Promacta for 12 months if the patient meets the following criteria (a, b and c): a) The patient has low platelet counts at baseline (pretreatment) [e.g., < 30,000 mm 3 ]; AND b) Promacta is prescribed by, or after consultation with, a hematologist; AND c) That patient had tried one immunosuppressant therapy (e.g., cyclosporine, mycophenolate moefetil, sirolimus, Atgam [lymphocyte immune globulin, anti-thymocyte globulin [equine] sterile solution for intravenous use only]). Promacta is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1 The data that led to approval of Promacta involved patients who had an insufficient response to at least one prior immunosuppressive therapy and with low initial platelet counts ( 30 x 10 9 /L). 1,10-11 Other immunosuppressive therapies used in aplastic anemia include cyclosporine, Atagam, mycophenolate moefetil, and sirolimus In the professional opinion of specialized physicians, these criteria have been adopted. When Policy Topic is not covered The use of Promacta is considered investigational for all other indications including: Thrombocytopenia in myelodysplastic syndrome (MDS). There are limited data that describe the use of Promacta for thrombocytopenia associated with MDS. Current recommendations from the National Comprehensive Cancer Network (NCCN) (Version ) do not mention the use of thrombopoietin receptor agonists (e.g., Promacta) in the management of thrombocytopenia in MDS. 7 Considerations Promacta requires prior authorization through the pharmacy services area. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Not Applicable Promacta, a thrombopoietin receptor agonist, has three indications. 1 Promacta is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. 1 Promacta is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Promacta is also indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C (CHC) to allow initiation and maintenance of interferon-based therapy. Promacta should only be used in those with ITP whose degree of thrombocytopenia and clinical condition increase the bleeding risk. Promacta should be used only in patients with CHC whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. The safety and efficacy of Promacta have not been established in combination with direct-acting antiviral agents indicated for the treatment of CHC genotype 1 infection. Promacta has a boxed warning regarding the risk for hepatic decompensation in patients with CHC. Promacta should be given on an empty stomach (1 hour before or 2 hours after a meal) and allow at least a 4-hour interval between the agent and other medications, calcium-rich food, or supplements containing polyvalent cations (e.g., iron). 1 For chronic ITP the starting dose is 50 mg once daily (QD)

3 for most patients; for patients of East Asian ancestry or patients with mild, moderate or severe hepatic insufficiency, the starting dose is 25 mg QD. For those of East Asian ancestry with hepatic impairment consider an initial dose of 12.5 mg QD. Adjust the dose to achieve and maintain a platelet count 50 x 10 9 /L to reduce the bleeding risk. Do not exceed a daily dose of 75 mg. It is recommended to discontinue Promacta if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the maximum dose. 1 For CHC-associated thrombocytopenia, initiate Promacta at 25 mg QD for all patients. Adjust the dose in 25-mg increments every 2 weeks to achieve a target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg daily and discontinue Promacta when antiviral therapy is discontinued. For patients with severe aplastic anemia, initiate Promacta at 50 mg QD. Consider a lower initial dose (25 mg QD) in patients with hepatic impairment or in those of East Asian ancestry. Performed dose adjustments based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, which may take up to 16 weeks after Promacta initiation. Use the lowest dose of Promacta to achieve and maintain a hematologic response. If a hematologic response is not achieved after 16 weeks of therapy, consider Promacta discontinuation. Rationale ITP Two studies assessed the clinical efficacy and safety of Promacta in patients with chronic ITP who had a platelet count < 30 x 10 9 /L and who had tried at least one prior ITP therapy. 1-2 Promacta was administered for 6 weeks. The primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of < 30 x 10 9 /L to 50 x 10 9 /L during the treatment period. One multicenter, double-blind study randomized 114 patients in a 2:1 ratio to Promacta 50 mg QD (with a possible increase to 75 mg QD) or placebo, in addition to standard-of-care therapy. There were 73 patients in the Promacta group and 37 in the placebo group that were involved in the efficacy analysis; Day 43 results for patient response were 59% (n = 43/73) and 16% (n = 6/37), respectively (P < 0.001). 1-2 Patients given Promacta had less bleeding during the study compared with patients given placebo (P = 0.021). 2 In another multicenter, double-blind study, 117 adults with ITP were randomized in a 1:1:1:1 ratio to placebo or one of three dosage regimens of Promacta (30, 50 or 75 mg QD). 1,3 Among those receiving Promacta 50 mg QD, 70% (n = 19/27) responded compared with 11% (n = 3/27) given placebo; bleeding events during treatment occurred in 7% and 14%, respectively. 1,3 A Phase III, double-blind, placebo-controlled trial 1,4 in adults with previously treated ITP for more than 6 months duration who had baseline platelet counts < 30 x 10 9 /L were randomized in a 2:1 ratio to standard-of-care treatment plus Promacta 50 mg QD (n = 135) or placebo (n = 62) for 6 months. The Promacta dose could be adjusted based on individual platelet counts. The primary endpoint was achieving a platelet count 50 x 10 9 /L and 400 x 10 9 /L. A total of 106 patients given Promacta (79%) responded to treatment at least once during the study compared with 17 patients (28%) in the placebo group. A sustained platelet response (platelet count 50 x 10 9 /L and 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period without rescue medication use) was obtained by 60% given Promacta vs. 10% of patients given placebo. 1 Other benefits have also been noted for Promacta (e.g., fewer patients required rescue therapy, less clinically significant bleeding). 1,4 Extension studies have also been performed with Promacta; 210 patients have completed 12 months of therapy and 138 have undergone 24 months of therapy. 1 CHC-Associated Thrombocytopenia Two randomized, double-blind, placebo-controlled trials assessed the efficacy and safety of Promacta for the treatment of adult patients with CHC. 1 Patients in Trial 1 used Pegasys (peginterferon alfa-2a injection) plus ribavirin for antiviral treatment and Trial 2 used PegIntron (peginterferon alfa-2b injection) plus ribavirin. In both studies, patients with a platelet count of < 75 x 10 9 /L were included. The median patient age was 52 years in both trials and 74% of patients were Caucasian. In total, 69% of patients were hepatitis C virus (HCV) genotypes 1, 4, and 6. Approximately 30% of patients had been previously treated with interferon and ribavirin. Median baseline platelet counts were approximately 60 x 10 9 /L in both treatment groups. The trials involved two phases that included a preantiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase,

4 patients were given open-label Promacta to increase the platelet count to a threshold of 90 x 10 9 /L for Trial 1 and 100 x 10 9 /L for Trial 2. Promacta was given at an initial dose of 25 mg QD for 2 weeks and increased in 25 mg increments over 2 to 3 week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximum time patients could receive open-label Promacta was 9 weeks. Promacta was given in combination with pegylated interferon and ribavirin per their respective prescribing information 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. In total, 95% of patients were able to initiate therapy. In both trials, a significantly greater proportion of patients given Promacta achieved SVR. The results are in Table 1. Of note, the majority of patients given Promacta (76%) maintained a platelet count 50 x 10 9 /L compared to 19% with placebo. A greater proportion of patients on Promacta did not require any antiviral dose reduction as compared with placebo (45% vs. 27%). Table 1. Sustained Virological Response in Adults with CHC on Promacta. 1 Trial 1* Trial 2 Pre-antiviral treatment phase N = 715 N = 805 Percentage of patients who 95% 94% achieved target platelet counts and initiated antiviral therapy Antiviral Treatment Phase Promacta Placebo Promacta Overall Sustained Virological Responseº HCV Genotype 2, 3 HCV Genotype 1, 4, 6 (n = 450) 23% 35% 18% (n = 232) 14% 24% 10% (n = 506) 19% 34% 13% Placebo (n = 253) 13% 25% 7% * Promacta given in combination with Pegasys (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally); Promacta given in Peg-Intron (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally); º P value < 0.05 for Promacta vs. placebo. Severe Aplastic Anemia A single-arm, single-center, open-label, Phase II trial involved 43 patients with severe aplastic anemia who did not have an adequate response to at least one prior immunosuppressive therapy and who had a platelet count 30 x 10 9 /L. 1,10-11 Promacta was given at an initial dose of 50 mg QD for 2 weeks, which was increased over 2-week periods up to a maximum dose of 150 mg QD. The primary endpoint assessed was hematologic response at 12 weeks. Hematologic response was defined as one or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by > 1.5 g/dl, or a reduction in greater than or equal to 4 units of red blood cell transfusions for 8 consecutive weeks; and 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase > 0.5 x 10 9 /L. 1,10-11 Promacta was discontinued after 16 weeks if no hematologic response was noted. The patient population was a median age of 45 years (range, 17 to 77 years), and 56% of patients were male. 1,10 The baseline median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dl, ANC was 0.58 x 10 9 /L and absolute reticulocyte count was 24.3 x 10 9 /L. 1 In total, 86% of patients were red blood cell transfusion dependent and 91% of patients were platelet transfusion dependent. 1 Most patients (84%) had received at least two prior immunosuppressive therapies. 1,10 In total, 40% of patients (n = 17/43) responded. 1,10 In the 17 patients who responded, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days. 1 In an extension phase, eight patients achieved a multi-lineage response; four of these patients subsequently tapered off therapy with Promacta and maintained the response (median follow up: 8.1 months [range, 7.2 to 10.6 months]). Guidelines

5 ITP In 2011 the American Society of Hematology (ASH) published an evidence-based practice guideline for immune thrombocytopenia. 5 First-line treatment for adults include corticosteroids or intravenous immunoglobulin (IVIG). For patients who are unresponsive or relapse after initial corticosteroid therapy splenectomy is recommended. Thrombopoietin receptor agonists are recommended for patients with a bleeding risk who relapse following splenectomy, or have a contraindication to splenectomy and who have failed at least one other therapy. The guidelines also suggest that thrombopoietin receptor agonists be considered for those at risk of bleeding who have failed one line of therapy, such as corticosteroids or IVIG, and who have not undergone splenectomy. Regarding children, the guidelines state that studies of thrombopoetin receptor agonists in children and adolescents have been initiated. No recommendation for the use of such agents can be formed at this time. 5 In 2010, an international consensus report was published regarding the management of primary immune thrombocytopenia. 6 Thrombopoietin receptor agonists are recommended as a second-line therapy after corticosteroids or IVIG. References: 1. Promacta [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; August Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomized, double-blind, placebocontrolled trial. Lancet. 2009;373(9664): Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357: Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomized, phase 3 study. Lancet. 2011;377: Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117: Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115: The NCCN Myelodysplastic Syndromes Clinical Practice Guidelines in Oncology (Version ) National Comprehensive Cancer Network, Inc. Available at: Accessed June 11, Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for the treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3): Afdahl N, Dusheiko GM, Giannini EG, et al. Eltrombopag increases platelet numbers in thrombocytopenia patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology. 2014;146: Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12): Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1): Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012: Marsh JCW, Kulasekararaj AG. Management of the refractory aplastic anemia patients: what are the options? Blood. 2013;122(22): Hartung HD, Olson TS, Bessler M. Acquired aplastic anemia in children. Pediatr Clin North Am. 2013;60(6): Marsh JCW, Ball SE, Cavenagh J, et al, Writing Group: British Committee for Standards in Haematology. Guidelines for the diagnosis and management of aplastic anemia. Br J Haematol. 2009;147: Available at: Accessed on September 2, Atgam [prescribing information]. New York, NY: Pfizer; August Other References Utilized

6 Afdahl NH, Giannini EG, Tayyab G, et al, for the ELEVATE Study Group. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012;367(8): Garnock-Jones KP. Eltrombopag. A review of its use in treatment-refractory primary immune thrombocytopenia. Drugs. 2011;71(10): Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365: Billing Coding/Physician Documentation Information N/A Promacta is considered a pharmacy benefit. Additional Policy Key Words Policy Number: Policy Implementation/Update Information 06/ / / / / /2018 New Policy titled Promacta Reviewed no changes made Reviewed -- For the criteria regarding chronic immune thrombocytopenia purpura, removed the criteria that the patient is not using Promacta in combination with Nplate. Criteria added based on new indication for patients with severe aplastic anemia. Updated references. No changes made No changes made Reviewed Added statement Promacta requires prior authorization through the pharmacy services area State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.