Erythropoiesis Stimulating Agents (ESA)

Policy Number: Original Effective Date: MM.04.008 04/15/2007 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST 03/01/2013 Section: Prescription Drugs Place(s) of Service: Home; Office; Outpatient

I. Description

Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor that regulates hemoglobin levels in response to changes in the blood oxygen concentration. Erythropoiesis- stimulating agents (ESAs) are produced using recombinant DNA technologies and have pharmacologic properties similar to EPO. The primary clinical use of ESAs is in patients with chronic anemia.

II. Criteria/Guidelines A. Epoetin alfa and darbepoetin alfa are covered (subject to Limitations/Exclusions and Administrative Guidelines) for the following: 1. Treatment of anemia associated with chronic kidney disease, (pre-treatment hemoglobin is less than 10g/dL.) with or without the use of dialysis until hemoglobin reaches a target of 10 to 11 g/dL. 2. Treatment of anemia (pre-treatment hemoglobin is less than (10g/dL) in AZT-treated HIV infected patients, when the dose of AZT is equal to or less than 4,200 mg per week and the patient's pre-treatment endogenous erythropoietin level is less than or equal to 500 mUnits/mL. The maximum dosage of erythropoietin should not exceed a total of 60,000 units per week. 3. Treatment of anemia due to the effects of concomitantly administered chemotherapy in patients with non-myeloid malignancies. 4. Treatment of anemia (pre-treatment hemoglobin is greater than 10 to less than or equal to 13 g/dL) in patients scheduled to undergo elective, non-cardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions. Treatment is indicated for patients at

Erythropoiesis Stimulating Agents 2

high risk for peri-operative transfusions with significant, anticipated blood loss, for example, for patients expected to lose greater than two units of blood. The maximum dosage of erythropoietin should not exceed a total of 60,000 units per week 5. Treatment of patients following allogeneic bone marrow transplantation. 6. Treatment of anemia (pre-treatment hematocrit less than 32 percent) in low birth weight infants at doses of erythropoietin up to 1,000 units per week. 7. Treatment of limited acute severe anemia (pre-treatment hemoglobin less than or equal to 8g/dL) when a blood transfusion would otherwise be needed, such as with blood loss after trauma, at erythropoietin doses up to a total of 60,000 units per week. 8. Treatment of patients with anemia associated with the management of hepatitis C with a combination of ribavirin and interferon alfa at a dose of erythropoietin up to a total of 60,000 units per week. One of the following criteria must be met: a. The patient's hemoglobin is less than 11.0 g/dL; or b. The patient has a co-morbid condition, e.g., cirrhosis, CHF, COPD requiring treatment of mild to moderate anemia. 9. Treatment of patients to increase the capacity for donation for future autologous transfusion prior to elective surgery. This medication has been found effective in females, patients with low packed-cell volumes due to anemia or small body size, and patients requiring donation of greater than or equal to four units of blood. B. Epoetin alfa and darbepoetin alfa are covered (subject to Limitations/Exclusions and Administrative Guidelines) with precertification for the following conditions: 1. Initial treatment of anemia in patients with International Prognostic Scoring System low or intermediate-1 risk myelodysplastic syndrome (MDS) (see Appendix) with pre-treatment hemoglobin of less than or equal to 10 g/dL or transfusion dependency and erythropoietin level of less than or equal to 500 mU/ml (500 U/L). 2. Initial treatment of anemia in patients with chronic disease (other than chronic kidney disease) characterized by a pre-treatment hemoglobin of less than or equal to 10 g/dL or transfusion dependency when iron deficiency has been ruled out (generally, transferrin saturation is at least 20 percent and ferritin at least 100 ng/mL). The maximum dosage of erythropoietin should not exceed a total of 60,000 units per week. 3. Continuation of treatment of anemia in patients with a chronic disease (other than chronic kidney disease) or MDS when there is a response to therapy, i.e., increase in hemoglobin or a decrease in transfusion dependency. C. Peginesatide (Omontys) is covered (subject to Limitations/Exclusions and Administrative Guidelines) for the treatment of anemia associated with chronic kidney disease in adults on dialysis.

III. Limitations/Exclusions ESAs are not covered for the treatment of anemia associated with malignancy, or the anemia of cancer, in patients with solid tumors who are not receiving chemotherapy.

Erythropoiesis Stimulating Agents 3

IV. Administrative Guidelines A. Precertification is required for the initial three months of treatment for MDS and anemia of chronic disease (other than chronic kidney disease). The following documentation from the medical record must be submitted: 1. Pretreatment hemoglobin of less than or equal to 10 g/dL and/or clinical notes demonstrating transfusion dependency. 2. For MDS; patient has low or intermediate-1 MDS and erythropoietin level of less than or equal to 500 mU/ml (500 U/L) 4. For anemia due to chronic disease: transferrin and ferritin test results. B. Precertification is required for continuation of therapy for up to 12 months. The following documentation from the medical record must be submitted: Laboratory test results demonstrating an increase in hemoglobin and/or clinical notes demonstrating a decrease in transfusion dependency. C. To precertify, complete HMSA's Drug Review Request and mail or fax the form as indicated. D. Precertification is not required to treat conditions noted in II.A.1-9. HMSA reserves the right to perform retrospective review using the above criteria to validate if services rendered met payment determination criteria.

HCPCS Code Description

J0881 Injection, darbepoetin alfa, 1 microgram (non-ESRD use) J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis) J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units J0886 Injection, epoetin alfa, 1000 units (for ESRD on dialysis) J0890 Injection, peginesatide, 0.1 mg ( for ESRD on dialysis) Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis) ICD-9 Codes (requiring Description precertification) 238.72 Low grade myelodysplastic syndrome lesions 238.73 High grade myelodysplastic syndrome lesions 238.74 Myelodysplastic syndrome with 5q deletion 238.75 Myelodysplastic syndrome, unspecified 285.29 Anemia of chronic disease

Erythropoiesis Stimulating Agents 4

ICD-10 codes are provided for your information. These will not become effective until 10/1/2014

ICD-10-CM Code Description D46.0 Refractory anemia without ring sideroblasts, so stated D46.1 Refractory anemia with ring sideroblasts D46.20 Refractory anemia with excess of blasts, unspecified D46.21 Refractory anemia with excess of blasts 1 D46.22 Refractory anemia with excess of blasts 2 D46.a Refractory cytopenia with multilineage dysplasia D46.b Refractory cytopenia with multilineage dysplasia and ring sideroblasts D46.c Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality D46.4 Refractory anemia, unspecified D46.z Other myelodysplastic syndromes D46.9 Myelodysplastic syndrome, unspecified D63.8 Anemia in other chronic diseases classified elsewhere

V. Important Reminder The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician. Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA’s determination as to medical necessity in a given case, the physician may request that HMSA reconsider the application of the medical necessity criteria to the case at issue in light of any supporting documentation.

VI. References 1. Aranesp (darbepoetin alfa) prescribing information. Amgen Inc. Thousand Oaks, CA. Revised 07/2012

Erythropoiesis Stimulating Agents 5

2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Cancer-and Chemotherapy-induced Anemia. Version 1.2013 3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 2 2013. 4. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 Update of Hemoglobin Target. 5. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer. J Clin Oncol. 2010; 28(33); 4996-5010. 6. Rizzo JD, Somerfield MR, Hagerty KL, et al. American Society of Clinical Oncology; American Society of Hematology. Use of epoetin and darbepoetin in patients with cancer: 2007 clinical practice guideline update. J Clin Oncol. 2008; 26(1); 132-149. 7. Thomson Micromedex Healthcare Series: Drugdex Evaluations. Erythropoietin September 12, 2012. 8. Epogen (epoetin alfa) prescribing information. Amgen Inc. Thousand Oaks, CA. Revised 07/2012. 9. Omontys (peginesatide) prescribing information. Affymax Inc. and Takeda Pharmaceuticals America Inc. Palo Alto, CA and Deerfield, IL; March 2012

VII. Appendix

International prognosis scoring system (IPSS) in myelodysplastic syndrome

Score Variable 0 0.5 1.0 1.5 2.0

Bone marrow blasts (percent) <5 5 to 10 - 11 to 20 21 to 30

Karyotypea Good Intermediate Poor - -

Cytopeniasb 0/1 2/3 - - -

Risk group IPSS score

Low 0

Intermediate-1 0.5 to 1.0

Intermediate-2 1.5 to 2.0

High 2.5 to 3.5

Erythropoiesis Stimulating Agents 6

a. Karytope definitions: Good: Normal;-Y; del (5q); del (20q); Poor: Complex (≥3 abnormalities); abnormal chromosome 7 Intermediate: All others b. Cytopenia definitions: Red blood cells: Hemoglobin <10 g/dL (100 g/L) White blood cells: Absolute neutrophil count <1800/microL Platelets: Platelet count <100,000/microL