Darbepoetin Alfa Injection (Aranesp)

Utilization Review Policy

Subject: darbepoetin alfa injection (Aranesp®)

Date revised: 12/2/2009

Description

Darbepoetin alfa is an erythoid stimulating agent (ESA) that is approved by the Food and Drug Administration (FDA) for the following indications. Anemia with chronic renal failure (CRF). Anemia with non-myeloid malignancies due to chemotherapy.

Darbepoetin alfa is given intravenously (IV) or subcutaneously (SC). Darbepoetin is available in single-dose vials in two solutions, an albumin solution and a polysorbate solution. Darbepoetin alfa is also available in single-dose prefilled syringes. The products are available in various strengths.

Indications, Medically Necessary

1. Anemia in CRF: Indicated for the treatment of anemia associated with CRF in patients (adults and children) who meet all of the following criteria.

 Hb level is ≤ 10.0 g/dL for therapy initiation. Note: For patients currently receiving darbepoetin alfa or epoetin alfa (Epogen, Procrit), hemoglobin (Hb) should be ≤ 12.0 g/dL.

Dosing in CRF: The starting dose for adults is 0.45 mcg/kg body weight SC or IV as a single injection once weekly. Alternatively, in patients not receiving dialysis, in adults an initial dose of 0.75 mcg/kg may be administered SC as a single injection once every 2 weeks. The use of darbepoetin alfa in pediatric CRF patients as the initial treatment to correct anemia has not been studied. However, for adult and pediatric patients receiving a weekly epoetin alfa dose of ≥ 1,500 units/week, conversion doses from epoetin alfa to darbepoetin alfa are available (refer to the package insert). The dose is individualized to achieve and maintain Hb within the range of 10.0 to 12.0 g/dL. Refer to the package insert regarding titration of darbepoetin alfa.1

Initial approval/extended approval in CRF: For patients initiating therapy, approval is for 3 months. Patients are evaluated for a response

12/2/2009 1 darbepoetin alfa injection (Aranesp)

after 3 months. Approve for an additional six months if a Hb response is achieved and Hb ≤ 12.0 g/dL. For patients not responding, despite dose titrations during the first 3 months, discontinue darbepoetin alfa and evaluate and treat for other causes of anemia. In some patients, Hb may not increase but stay the same and not decrease further. This may be interpreted as a response. For patients on maintenance therapy, approve for 6 months if the patient continues to respond and if Hb ≤ 12.0 g/dL. Afterwards, continue to approve darbepoetin alfa at 6 month intervals if the patient is responding and Hb ≤ 12.0 g/dL. Duration of therapy in CRF: Use may be indefinite as long as patient has CRF.

Labs/Diagnostics required: Monitor Hb regularly. Iron status must be evaluated (for example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin saturation [TSAT], bone marrow biopsy) before initiating therapy and as needed during treatment.

Waste management: Single-dose vials and syringes are available in many different strengths. The dose should be calculated and the number of vials/syringes needed assessed. Refer to the package insert for more information. http://www.aranesp.com/professional/crf/full_prescribing_info/pi.jsp

Exclusions: CRF. Also see below.  Use beyond 3 months in the absence of response in CRF patients.

2. Anemia due to cancer chemotherapy: Indicated for anemia in non-myeloid malignancies due to chemotherapy in patients (adults and children) who meet all of the following criteria.

 Hb levels ≤ 10.0 g/dL for therapy initiation, and Note: For patients currently receiving darbepoetin alfa or epoetin alfa (Procrit, Epogen), Hb should be ≤ 12.0 g/dL.

 Patient is currently receiving myelosuppressive chemotherapy, and (Note: myelosuppressive chemotherapy regimens associated with an increased risk of anemia are listed in the National Comprehensive Cancer Network [NCCN] guidelines.2 These references may not be a complete list, as new regimens are being developed).

 Darbepoetin alfa is being prescribed by a hematologist or oncologist, and

 Patient has a metastatic, non-myeloid malignancy and the anticipated outcome is not cure, and

 Absolute iron deficiency has been excluded (serum ferritin < 30 ng/dL and transferrin saturation < 15%).

Dosing in anemia due to cancer chemotherapy: Various doses have been used. Initial and some maximum doses are listed below for adults.  darbepoetin alfa 2.25 mcg/kg weekly SC (increase darbepoetin alfa up to 4.5 mcg/kg weekly SC).1  darbepoetin alfa 500 mcg every 3 weeks by SC injection.1  darbepoetin alfa 100 mcg fixed dose every week by SC injection (increase darbepoetin alfa up to 150-200 mcg fixed dose every week by SC injection).2  darbepoetin alfa 200 mcg fixed dose every 2 weeks by SC injection (increase darbepoetin alfa up to 300 mcg fixed dose every 2 weeks by SC injection).2  darbepoetin alfa 300 mcg fixed dose every 3 weeks by SC injection (increase up to 500 mcg fixed dose every 3 weeks by SC injection).2 Note: Doses are not established in children. Darbepoetin alfa 2.25 mcg/kg SC (given at a two week interval, followed by 2.25 mcg/kg SC once weekly) has been studied in a phase 1, pharmacokinetic study involving pediatric patients with chemotherapy-induced anemia.3 The dose for all patients should be adjusted to maintain the lowest Hb level sufficient to avoid red blood cell transfusions. Discontinue darbepoetin alfa if after 8-9 weeks of therapy there is no response as measured by Hb levels or if transfusions are still required.

Initial approval/extended approval in anemia due to cancer chemotherapy: Approve for an initial 2 months to monitor for Hb values and check the appropriate doses. Darbepoetin alfa should be discontinued after 8 weeks of therapy if there is no response as measured by Hb levels or if transfusions are still required; evaluate and treat for other causes of anemia.1 In some patients, Hb may not increase but stay the same and not decrease further. This may be interpreted as a response. If the patient has a response after 8 weeks (2 months), approve at 4 month intervals if the patient is still receiving

chemotherapy during this time frame (plus within six weeks after chemotherapy discontinuation). At each 4-month interval, assure that Hb values are ≤ 12.0 g/dL at all times, otherwise therapy should be discontinued or withheld. Discontinue darbepoetin alfa when chemotherapy treatment is complete and anemia has resolved, usually within 6 weeks.2

Labs/Diagnostics required: After dose adjustment, the Hb should be assessed weekly for at least 4 weeks until it has been determined that the Hb has stabilized in response to the dose change. The Hb should be monitored at regular intervals. Iron status should be evaluated (for example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin saturation [TSAT], bone marrow biopsy) before initiating therapy and as needed during treatment. Hb should always be ≤ 12.0 g/dL for continuation of therapy.

Exclusions: anemia due to cancer chemotherapy. See also below.  Use beyond 8-9 weeks in the absence of response or in those receiving transfusions.  Continued use when chemotherapy treatment is complete and anemia has resolved (usually within 6 weeks of the last dose of chemotherapy).  Absolute iron deficiency (serum ferritin < 30 ng/dL and transferrin saturation < 15%).  Use is not indicated for patients when the anticipated outcome is cure.

3. Anemia in myelodysplastic syndromes (MDS): Indicated for the treatment of anemia associated with MDS in adults who meet all of the following criteria. [NOT FDA-APPROVED INDICATION]

 Hb levels ≤ 12.0 g/dL for therapy initiation, and

 Serum erythropoietin levels ≤ 500 mU/mL, and

 Darbepoetin alfa is prescribed by a hematologist or an oncologist.

Dosing in MDS: The dose of darbepoetin alfa is 150-300 mcg SC once per week.4

Initial approval/extended approval in MDS: For patients initiating therapy, approval is for 4 months. Patients are evaluated for an erythroid response after 4 months. Approve for an additional six months if an erythroid response is achieved (increase in Hb or a decrease in transfusions) and Hb ≤ 12.0 g/dL. For patients not responding, despite dose titrations and/or concomitant use of granulocyte colony stimulating factor (G-CSF) during the first 4 months, discontinue darbepoetin alfa and evaluate and treat for other causes of anemia. For patients on maintenance therapy, approve for 4 months if the patient continues to have an erythroid response and if Hb ≤ 12.0 g/dL. Afterwards, continue to approve darbepoetin alfa at 4- month intervals if the patient has had an erythroid response and Hb ≤ 12.0 g/dL.

Duration of therapy in MDS: may be indefinite as long as the patient has MDS.

Labs/Diagnostics required in MDS: Evaluate for erythroid response (Hb increase and/or a decrease in transfusions) regularly. Iron status should be evaluated (for example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin saturation [TSAT], bone marrow biopsy) before initiating therapy and as needed during treatment.

Exclusions: MDS. See also below.  Serum erythropoietin levels > 500 mU/mL.  Use beyond 4 months in the absence of an erythroid response in MDS patients.  Use in children (aged < 18 years).

4. Treatment of anemia associated with chronic hepatitis C treatment (e.g., peginterferon/interferon [PEG-Intron, Pegasys]

plus ribavirin therapy): Indicated for the treatment of anemia associated with chronic hepatitis C treatment in adults who meet all of the following criteria. [NOT FDA-APPROVED INDICATION]

 Hb levels ≤ 10.0 g/dL for therapy initiation, and Note: For patients currently receiving darbepoetin alfa or epoetin alfa (Procrit, Epogen), Hb should be ≤ 12.0 g/dL.

 Patient is receiving therapy for the treatment of chronic hepatitis C (e.g., peginterferon alfa/interferon alfa therapy plus ribavirin), and

 Darbepoetin alfa is prescribed by a hepatologist, gastroenterologist, or infectious disease physician who specializes in the management of hepatitis C.

Dosing in anemia due to chronic hepatitis C treatment: The initial dose is darbepoetin alfa 3 mcg/kg once every other week or 0.45 mcg/kg/week, titrating to Hb response (and Hb ≤ 12.0 g/dL).5-6

Initial approval/extended approval in anemia due to chronic hepatitis C treatment: For patients initiating therapy, approval is for 6 months if the duration of the treatment for hepatitis C (peginterferon alfa/interferon alfa plus ribavirin) also is this long (if not, only approve for the duration of the hepatitis C therapy). Patients are evaluated for a Hb response after 6 months. Approve for an additional six months if an increase in Hb is achieved and Hb ≤ 12.0 g/dL. For patients not responding, despite dose titrations, discontinue darbepoetin alfa; evaluate and treat for other causes of anemia. For patients on maintenance therapy, approve for 6 months if the patient continues to have a Hb response and if Hb ≤ 12.0 g/dL. For all patients, therapy with darbepoetin alfa should stop when the treatment with ribavirin for hepatitis C is discontinued (generally one year total).

Duration of therapy in anemia due to chronic hepatitis C treatment: patients can receive darbepoetin alfa therapy only if the patient is also receiving therapy with ribavirin for hepatitis C, which is usually approximately one year for most patients.

Labs/Diagnostics required: Monitor Hb regularly and evaluate for response. Iron status has been evaluated (for example, serum iron, total iron binding capacity, serum ferritin, per cent transferrin saturation [TSAT], bone marrow biopsy) before initiating therapy and as needed during treatment.

Exclusions: anemia due to chronic hepatitis C treatment. See also below.  Anemia in a patient with hepatitis C who is not receiving ribavirin.  Use beyond 6 months in the absence of a Hb response.  Use in children (aged < 18 years).

Exclusions for all:  Continued use when Hb exceeds 12.0 g/dL.  Treatment of cancer-related anemia in those not receiving myelosuppressive chemotherapy.  Darbepoetin alfa is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.  Treatment of anemia in patients with acute myelogenous leukemia or chronic myelogenous leukemias (examples of myeloid cancers).  Use in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia, thalassemia, porphyria).  For reduction in allogeneic red blood cell transfusions in patients scheduled for surgical procedures.  To treat anemia in patients with other risk factors such as iron deficiency, folate deficiency or B12 deficiency, hemolysis, gastrointestinal bleeding, active or occult bleeding.  Patients with uncontrolled hypertension.  Anemia in patients due to acute blood loss.

ABBREVIATIONS CRF = chronic renal failure FDA = Food and Drug Administration ESA = erythroid stimulating agent G-CSF = granulocyte colony-stimulating factor Hb = hemoglobin IV = intravenous

MDS = myelodysplastic syndrome mL = milliliter NCCN = National Comprehensive Cancer Network SC = subcutaneous TSAT = percent transferrin saturation < less than ≤ less than or equal to > greater than ≥ greater than or equal to

REFERENCES 1. Aranesp® for injection [package insert]. Thousand Oaks, CA: Amgen; April 2009. 2. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Cancer- and chemotherapy-induced anemia. V.2.2010. Printed 10/27/2009. 3. Blumer J, Berg S, Adamson PC, et al. Pharmacokinetic evaluation of darbepoetin alfa for the treatment of pediatric patients with chemotherapy-induced anemia. Pediatr Blood Cancer. 2007;49:687-693. 4. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Myelodysplastic syndromes. V.2.2010. Printed 10/27/2009. 5. Younossi ZM, Nader FM, Bai C, et al. A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment. J Viral Hepatitis. 2008;15(5):370-378. 6. Kamar N, Guitard J, Ribes D, et al. A monocentric observational study of darbepoetin alfa in anemic hepatitis-C-virus transplant patients treated with ribavirin. Exp Clin Transplant. 2008;6(4):271-275. Chronic kidney disease  Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584-590.  KDOQI; National Kidney Foundation. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. Am J Kidney Dis. 2006;47(5 Suppl 3):S16-S85.  KDOQI; National Kidney Foundation. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease. 2007 update of the hemoglobin target. Am J Kidney Dis. 2007;50(3):476-530.  KDOQI; National Kidney Foundation. III. Clinical practice recommendations for anemia in chronic kidney disease in children. Am J Kidney Dis. 2006;47(5 Suppl 3):S86-S108.  Pfeffer MA, Burdmann EA, Chen CY, et al, for the TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032.  Pfeffer MA, Burdmann EA, Chen CY, et al, on behalf of the TREAT Investigators. Baseline characteristics in the trial to reduce cardiovascular events with Aranesp Therapy (TREAT). Am J Kidney Dis. 2009;54:59-69.  Singh AK, Szczech L, Tang KL, et al, for the CHOIR investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. Cancer patients receiving chemotherapy  Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomized trials. Lancet. 2009;373:1532-1542.

 Bohlius J, Wilson J, Seidenfled J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708-714.  Henke M, Laszig R, Rube C, et al. Erythropoetin to treat head and neck cancer patients with anemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet. 2003;362:1255-1260.  Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first- line chemotherapy: a survival study. J Clin Oncol. 2005;23:5960-5972.  Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149.  Smith RE, Aapro MS, Ludwig H, et al. Darbepoetin alfa for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2008;26:1040-1050.  Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs. above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol. 2008;108(2):317-325.  Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ. 2009;180(11):E62-E71.  Wright MR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-1032. Myelodysplastic syndromes [NOT FDA-APPROVED]  Gabrilove J, Paquette R, Lyons RM, et al. Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol. 2008;142(3):379-393.  Giraldo P, Nomdedeu B, Loscertales J, et al. Darbepoetin α for the treatment of anemia in patients with myelodysplastic syndromes. Cancer. 2006;107:2807-2816.  Gotlib J, Lavori P, Quesada S, et al. A phase II intra-patient dose-escalation trial of weight- based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes. Am J Hematol. 2009;84(1):15-20.  Mannone L, Gardin C, Quarre MC, et al, for the Groupe Francais des Myelodysplasies (GFM). High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol. 2006;133:513-519.  Moyo V, Lefebvre P, Duh MS, et al. Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic syndromes: a meta-analysis. Ann Hematol. 2008;87(7):527-536.  Musto P, Lanza F, Balleari E, et al. Darbepoetin alfa for the treatment of anemia in low- intermediate risk myelodysplastic syndromes. Br J Haematol. 2004;128:204-209.  Stasi R, Abruzzese E, Lanzetta G, et al. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1 risk myelodysplastic syndromes. Ann Oncol. 2005;16:1921- 1927. Anemia in hepatitis C [NOT FDA-APPROVED]  Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: an update. Hepatology. 2009;49(4):2335-1374.  McHutchison JG, Lawitz EJ, Schiffman ML, et al, for the IDEAL study team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. Anemia in chronic heart failure [NOT FDA-APPROVED]  Anand IS. Anemia in chronic heart failure. Implications and treatment options. J Am Coll Cardiol. 2008;52(7):501-511.  Ghali JK, Anand IS, Abraham WT, et al, on behalf of the Study of Anemia in Heart Failure Trial (STAMINA-HeFT) group. Randomized, double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117:526-535.

 Jessup, M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice guidelines: developed in collaboration with the international society of heart and lung transplantation. Circulation. 2009;119:1977-2016.  McMurray JJ, Anand IS, Diaz R, et al, RED-HF Committees and Investigators. Design and the reduction of events with darbepoetin alfa in heart failure (RED-HF): a phase III, anaemia correction, morbidity-mortality trial. Eur J Heart Fail. 2009;11(8):795-801.  Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure. A randomized, double- blind, placebo-controlled trial. J Am Coll Cardiol. 2007;49(7):753-762.  Van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo- controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007;28(18):2208-2216. Anemia in inflammatory bowel disease [NOT FDA-APPROVED]  Koutroubakis IE, Karmiris K, Makreas S, et al. Effectiveness of darbepoetin-alfa in combination with intravenous iron sucrose in patients with inflammatory bowel disease and refractory anemia: a pilot study. Eur J Gastroenterol. Hepatol. 2006;18:421-425. Aplastic anemia [NOT FDA-APPROVED]  Marsh JCW, Ball SE, Cavenagh J, et al, for the British Committee for Standards in Haematology. Guidelines for the diagnosis and management of aplastic anemia. Br J Haematol. 2009;147:43-70.

12/2/2009 10