HMO: Medical (provider setting); Rx (out patient) PPO/CDHP: Rx

BENEFIT DESCRIPTION AND LIMITATIONS OF COVERAGE ITEM: PRODUCT LINES: COVERED UNDER: DESCRIPTION: CPT/HCPCS Code: Company Supplying: Setting: Epogen, Procrit (epoetin alfa, injection) Commercial HMO/PPO/CDHP HMO: Medical (provider setting); Rx (out patient) PPO/CDHP: Rx Erythropoietin, an endogenous glycoprotein produced by the kidneys, serves the physiologic function of stimulating erythropoiesis. Epoetin alfa, a 165-amino-acid glycoprotein manufactured by recombinant DNA technology, has the same biological effects as endogenous erythropoietin. J0885, J0886, Q4081 Amgen; Ortho Biotech Intravenous (IV) or subcutaneous (SC) Coverage Criteria: Express Scripts, Inc. monograph dated 8/03/2011 Approval Period: As stated by indication Recommended Authorization Criteria WARNING: Epoetin alfa is contraindicated in patients with uncontrolled hypertension, hypersensitivity to mammalian cell-derived products, and known hypersensitivity to albumin (human). The epoetin alfa labeling also has a warning regarding increased mortality, serious CV events, thromboembolic events and stroke. Patients with CRF had an increased risk of death, serious CV events and stroke when ESAs were given to a target Hb level 13.0 g/dl in clinical trials. Patients with CRF and an insufficient Hb response to ESA therapy may be at a greater risk for CV events and mortality compared with other patients. ESAs increased the risk for death and serious CV events in controlled clinical trials of patients with cancer. These events included myocardial infarction (MI), stroke, congestive heart failure (HF), and hemodialysis vascular access thrombosis. A rate of Hb rise of > 1.0 g/dl over 2 weeks may contribute to these risks. Coverage of epoetin alfa is recommended in those who meet the following criteria listed below. FDA-Approved Indications 1. Patients with CKD. A. Patients on dialysis. Approve for 6 months if Hb < is 10.0 g/dl for initial therapy. If the patient has been previously receiving epoetin alfa or darbepoetin alfa, approve only if Hb is 11.0 g/dl. B. Patients not on dialysis. Approve for 6 months if Hb is < 10.0 g/dl, regardless of whether this is initial therapy or the patient has been receiving epoetin alfa or darbepoetin alfa. These recommendations for initiating and stopping therapy for CKD patients based on Hb values are derived from the FDA-approved dosing information for darbepoetin. The recommendation for the duration of therapy is based on the professional opinion of specialized physicians reviewing the data. 1

2. Anemic patients with HIV who are receiving zidovudine. Approve for 12 months for HIV patients who are receiving zidovudine therapy if Hb is 10.0 g/dl or endogenous erythropoietin levels are 500 munits/ml for therapy initiation. If the patient has previously been receiving epoetin alfa, approve only if Hb is 12.0 g/dl. Therapy with epoetin alfa is not recommended if Hb is > 12.0 g/dl in any situation. Epoetin alfa is FDA-approved for this condition and has been shown to elevate or maintain Hb and/or Hct and to decrease transfusions in this patient population. Patients with baseline endogenous serum erythropoietin levels 500 munits/ml derived greater benefit of epoetin alfa therapy (e.g., achievement of higher Hct, reduction in transfusion requirements) compared to those with levels greater than this threshold. In addition to data found in the product labeling, a published randomized, multicenter, double-blind, placebo-controlled, 3-month clinical trial involving 63 HIV patients receiving zidovudine supports this data. In the professional opinion of specialized physicians, the criteria of Hb 10.0 g/dl or endogenous erythropoietin levels 500 munits/ml have been adopted. 3. Anemia in cancer patients due to chemotherapy. Approve for 4 months if the patient has anemia due to cancer chemotherapy AND Hb is 10.0 g/dl OR Hb is > 10.0 g/dl but 12 g/dl and the physician anticipates a Hb decrease. Therapy with epoetin alfa is not recommended if Hb is > 12.0 g/dl in any situation. If the patient has previously been receiving epoetin alfa or darbepoetin, approve only if Hb is 12.0 g/dl for 4 months. Epoetin alfa is FDA-approved for the treatment of anemia due to the effect of concomitantly administered chemotherapy and has shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for cancer- and chemotherapy-induced anemia, updated in 2011, recommends assessing for anemia in cancer patients if Hb levels are 11.0 g/dl or for those with a high baseline level that have a Hb drop of 2.0 g/dl. For selected patients treatment should be considered based on FDA guidance. The American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for the use of epoetin alfa and darbepoetin in patients with cancer, updated in 2010, state that ESAs are recommended as a treatment option for patients with chemotherapy-associated anemia and a Hb concentration that has decreased to < 10.0 g/dl to decrease transfusions. The optimal level to initiate ESA therapy in patients with anemia and Hb between 10.0 g/dl and 12.0 g/dl cannot be definitively determined from the available evidence. The product labeling for ESAs states that for cancer patients on chemotherapy, ESAs should be initiated only if Hb is < 10.0 g/dl and if there is a minimum of 2 additional months of planned chemotherapy. Use the lowest epoetin alfa dose necessary to avoid RBC transfusions. In the professional opinion of specialized physicians reviewing the data, the criteria regarding Hb values for initiation and cessation of treatment with epoetin alfa and the duration of therapy have been adopted. 4. Anemic patients (Hb 13.0 g/dl) at high risk for perioperative transfusions (secondary to significant, anticipated blood loss and are scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions). Approve up to 21 days of therapy. 2

Epoetin alfa is not indicated for anemic patients who are willing to donate autologous blood. Epoetin alfa is FDA-approved for use in this condition and several trials support this use. In a multicenter, double-blind, placebo-controlled, parallel group trial 17 patients undergoing major orthopedic surgery of the hip or knee were randomized to receive epoetin alfa 300 IU/kg SC (n = 112), epoetin alfa 100 IU/kg SC (n = 101) or placebo (n = 103) for 15 consecutive days starting 10 days prior to, on the day of, and for 4 days after major orthopedic surgery of the hip or knee. Patients with a baseline Hb of > 10.0 to 13.0 g/dl who received epoetin alfa experienced a statistically significant decrease in the number of units transfused and the percentage of patients given transfusions in this subgroup who received epoetin alfa 300 IU/kg SC was reduced. Other Uses with Supportive Evidence 5. Anemia associated with myelodysplastic syndrome (MDS). Approve for 6 months for therapy initiation if Hb is 12.0 g/dl. Therapy with epoetin alfa is not recommended if Hb is > 12.0 g/dl in any situation. If the patient has previously been receiving darbepoetin or epoetin alfa, approve only if Hb is 12.0 g/dl. An additional 6 months of epoetin alfa may be allowed if Hb is 12.0 g/dl. Data are available regarding use of epoetin alfa in patients with MDS. Response rates vary among the populations studied but benefits have been noted. Clinical practice guidelines from NCCN (updated in 2011) state that epoetin has a role in select patient populations with MDS. Epoetin has been studied as a single agent, as well as with other hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF]). The treatment of MDS is largely supportive as it can be highly resistant to conventional chemotherapy and because patients are often elderly and cannot tolerate chemotherapy. Due to the safety issues that have surfaced, the guidelines suggest that ESAs be used in the management of symptomatic anemia in MDS patients but to aim for a target Hb 12.0 g/dl. In the professional opinion of specialized physicians reviewing the data, the criteria regarding Hb 12.0 g/dl and the duration of therapy have been adopted. 6. Anemia associated with use of ribavirin therapy for hepatitis C (in combination with interferon or pegylated interferon alfa 2a/2b products with or without direct-acting antiviral agents [i.e., boceprevir capsules {Victrelis }, telaprevir tablets {Incivek }]). Approve for 12 months of therapy if Hb is 10.0 g/dl. If the patient has previously been receiving epoetin alfa, approve only if Hb is 12.0 g/dl. Therapy with epoetin alfa is not recommended if Hb is > 12.0 g/dl in any situation. Interferon alfa 2a or alfa 2b with ribavirin and pegylated interferon alfa 2a or alfa 2b with ribavirin are used in the treatment of hepatitis C; epoetin alfa has been effective in treating anemia caused by these therapies. Two trials, one open-label, randomized trial and the other a double-blind, placebo-controlled trial, have demonstrated that administering epoetin alfa to patients (with < Hb 12.0 g/dl) receiving these interferontype products led to increases in Hb levels and allowed more patients to tolerate the recommended ribavirin dosages compared with a group receiving standard care. A recent review noted that ESA therapy is generally initiated in patients receiving interferon alfa plus ribavirin therapy in patients with Hb levels < 10.0 g/dl when accompanied by qualitative complaints of fatigue. The pivotal trials with boceprevir allowed for administration of erythropoietin. One study stated that the use of erythropoietin was recommended when Hb dropped to < 10.0 g/dl; however, use was at the investigator s discretion. Erythropoietin was to be stopped if Hb rebounded to 12.0 g/dl. In the professional opinion of specialized physicians reviewing the data, the Hb criteria have been adopted. 7. Anemia in HIV-infected patients. Approve for 12 months of therapy initiation if Hb is 10.0 g/dl or endogenous erythropoietin levels are 500 munits/ml. If the patient 3

has previously been receiving epoetin alfa, approve only if Hb is 12.0 g/dl. Therapy with epoetin alfa is not recommended if Hb is > 12.0 g/dl in any situation. Anemia can be a common complication of HIV infection due to the disease process itself or due to antiretroviral therapy. Some evidence suggests that use of epoetin alfa has been shown to increase Hb, decrease transfusion requirements and improve quality of life parameters in several trials. The Anemia in HIV Working-group made recommendations, published in 2004, which state that epoetin alfa therapy is recommended if Hb is < 13.0 g/dl in men and < 12.0 g/dl in women. In the professional opinion of specialized physicians reviewing the data, the criteria of requiring Hb 10.0 g/dl or endogenous erythropoietin levels 500 munits/ml have been adopted. Other Uses with Supportive Evidence Case-by-Case Consideration 8. Anemia of chronic disease/anemia of chronic inflammation (e.g., anemia in inflammatory bowel disease [ulcerative colitis, Crohn s disease], rheumatoid arthritis, systemic lupus erythematosus). Patients will be evaluated by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. A short trial of epoetin alfa (3 months) may be authorized to determine responsiveness and improvement in clinical parameters (e.g., increase in Hb). Some patients that may be candidates include those with symptomatic anemia with low Hb (< 10.0 g/dl) who have anemia despite transfusions (e.g., transfusion dependent) or cannot tolerate or undergo transfusions. Other factors that may suggest appropriate treatment with ESAs include those with low erythropoietin levels or failure of other treatment modalities (e.g., iron supplementation). Other causes of anemia should have been ruled out and therapy with epoetin alfa is generally not recommended if Hb is > 12.0 g/dl. Further approval after initial therapy will be determined on a case-by-case basis. ESAs have been used for anemia of chronic disease/inflammation. Some beneficial results regarding parameters related to anemia (e.g., increases in Hb) have been noted. It should be recognized, however, that use of ESAs for anemia of chronic disease/inflammation are not a standard of care and are generally not recommended. 9. Treatment of aplastic anemia. Patients will be evaluated by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. Patients that may be candidates for a trial include those with lower Hb values (< 11.0 g/dl) with symptomatic anemia and if prescribed by a hematologist. A short trial of epoetin alfa (< 1month) to determine efficacy and/or safety may be made by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. Therapy with epoetin alfa is generally not recommended if Hb is > 12.0 g/dl. Further approval after initial therapy will be determined on a caseby-case basis. Although studies are available regarding the use of epoetin alfa in aplastic anemia, 2009 guidelines for the diagnosis and management of aplastic anemia do not recommend routine use. Also, epoetin alfa should not be used as monotherapy or in newly diagnosed patients in an attempt to treat aplastic anemia. 10. Anemia in heart failure (HF). Patients will be evaluated by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. A short trial with epoetin alfa (< 2 months) may be authorized to determine efficacy and/or safety. Patients that may be candidates include those that have more severe heart failure, have a Hb 10.0 g/dl, have anemia despite transfusions or have contraindications to transfusions (e.g., fluid overload). Therapy with epoetin alfa is generally not recommended if Hb is > 12.0 g/dl. Further approval after initial therapy will be determined on a case-by-case basis. Several trials have assessed epoetin alfa in HF and trials with ESAs are ongoing in this patient population. Some benefits have been 4

noted with ESA use, such as an increase in exercise duration and improvement in some quality of life indices. 2009 guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) for the management of HF do not recognize ESAs as a standard of care for HF patients with anemia. Further studies are ongoing. Exclusions Coverage of epoetin alfa is not recommended in the following circumstances: 1. Anemia associated with cancer in patients not on cancer chemotherapy. Epoetin alfa is not indicated in cancer patients who are not receiving cancer chemotherapy. The ASCO/ASH guidelines for the use of epoetin and darbepoetin in adult patients with cancer recommend that ESAs not be used in treatment of anemia associated with malignancy in those who are not receiving concurrent myelosuppressive chemotherapy. 2. Anemia associated with acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) or other myeloid cancers. Epoetin alfa is indicated for use in nonmyeloid cancers when chemotherapy is given. AML and CML are examples of myeloid cancers. 3. Anemia associated with radiotherapy in cancer. Epoetin alfa is not indicated for use in cancer patients who are only given radiation therapy. 4. To enhance athletic performance. Epoetin is not recommended for approval because this indication is excluded from coverage in a typical pharmacy benefit. 5. Anemia in patients due to acute blood loss. Use of epoetin alfa is not appropriate in these types of situations. 6. Non-anemic patients (Hb > 13.0 g/dl) prior to surgery. Although studies have been done that involved non-anemic patients undergoing various surgeries receiving epoetin alfa preoperative and sometimes postoperatively to prevent transfusions or subsequent anemia, the overall benefit of this therapy in those with relatively normal preoperative Hb level is questionable. Epoetin alfa did not statistically significantly decrease the number of patients who underwent transfusions in a double-blind, placebocontrolled trial involving patients (n = 218) scheduled to undergo elective orthopedic hip or knee surgery whose pretreatment Hb was > 13.0 g/dl but 15.0 g/dl. In another small study patients undergoing total hip replacement surgery with normal preoperative Hb levels (most patients had a baseline Hb > 13.0 g/dl) did not have improved Hb levels or a reduction in allogeneic blood transfusions with epoetin use. 7. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. APPROVAL: ENDORSED BY: Pharmacy & Therapeutics Committee Original Date: 7/21/2010 APPROVED BY: Date: 1/18/2012 5