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Aranesp Syringe（阿法达贝泊汀预充式注射器）

2015-05-02 07:28:38 作者：新特药房来源：互联网浏览次数：194 文字大小：【大】【中】【小】

简介： 英文药名: Aranesp Syringe(darbepoetin alfa) 中文药名: 阿法达贝泊汀预充式注射器生产厂家: Amgen Inc药品介绍阿法达贝泊汀(darbepoetinal—fa)，在美国和欧洲的商标名分别为Aranesp和Nespo。阿 ...

关键字：阿法达贝泊汀 darbepoetin alfa 药品商标名Aranesp Syringe 用于治疗慢性肾病相关贫血

英文药名: Aranesp Syringe(darbepoetin alfa)

中文药名: 阿法达贝泊汀预充式注射器

生产厂家: Amgen Inc
药品介绍
阿法达贝泊汀(darbepoetinal—fa)，在美国和欧洲的商标名分别为Aranesp和Nespo。阿法达贝泊汀实是阿法依泊汀的改进型产品，其结构较之阿法依泊汀的重要差异在于它带有两个含烃链唾液酸，故半衰期无论是静脉、抑或皮下注射都延长了2倍，十分有利于简化给药方案，临床上可每2周、甚或每3周用药1次。
慢性肾病属进行性和不可逆疾病，它以肾损害和肾功能下降为特征。慢性肾病的最常见症状之一即为贫血，后者是因衰竭了的肾脏不再能够生产足量的促红细胞生成素、由此使得红血细胞生产和血红蛋白水平减少所致。贫血会严重影响患者的日常健康和生活质量，其具体表现包括疲劳、虚弱、呼吸短促、注意力分散、精神混乱、头晕或晕厥、皮肤苍白、心跳加快和反复感冒等。贫血还可致使发展潜在致死性的心血管疾病，此在全部慢性肾病人群中的流行率高至35～40％。
达贝阿法依泊汀于2001年首次获得欧盟批准，用于治疗11岁及以上儿童至成人的慢性肾病相关贫血。2002年，达贝阿法依泊汀又获准治疗正接受化疗之成人实体瘤患者贫血。2003年，此适应证的适用对象获准扩展至正接受化疗之成人非骨髓性恶性肿瘤癌症人群的有症状贫血治疗。2004年，达贝阿法依泊汀又获准可以每3周1次给药频率治疗正接受化疗之成人非骨髓性恶性肿瘤癌症患者贫血及能以每月1次剂量间隔方案治疗尚未进行透析之慢性肾病人群贫血。2006年，达贝阿法依泊汀标签再被更新至允许正进行透析之慢性肾病个体自每周1～3次给药重组人DNA促红细胞生成素类药物切换到每2周1次给药达贝阿法依泊汀疗法。
美国FDA发布警告, 阿法达贝泊汀(darbepoetin alfa,商品名Aranesp)对非化疗引起的癌症病人的贫血无效,不能减少其需要的红细胞输注率及改善疲乏症状,且增加死亡率。
阿法达贝泊汀是一种蛋白,与肾脏分泌的促红细胞生成素作用相似,通过刺激骨髓,促进红细胞生成。2001年被FDA批准用于治疗慢性肾功能衰竭引起的贫血,2002年获准用于非骨髓性恶性肿瘤化疗所致贫血患者。
临床上,阿法达贝泊汀有时被用于非化疗引起的贫血患者,为了验证其有效性和安全性,一项大型、多中心、随机、安慰剂对照的研究被进行,该研究共纳入989例未接受化疗或放疗的活动期恶性肿瘤患者,60%的患者为疾病晚期。
结果显示,阿法达贝泊汀组16周内红细胞输注率为18%,而安慰组剂为24%,两组比较无统计学差异(P=0.15;危险比0.89);治疗组绝对死亡率高于安慰剂组(49%对46%;风险比1.25)。
因此,FDA告诫医务人员,阿法达贝泊汀的适应人群为因化疗所致贫血及产品说明书的适应证,而不应标签外用药。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Aranesp safely and effectively. See full prescribing information for Aranesp.
Aranesp® ( darbepoetin alfa)
injection, for intravenous or subcutaneous use
Initial U.S. Approval: 2001
WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE See full prescribing information for complete boxed warning.
Chronic Kidney Disease:
In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1).
No trial has identified a hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks.
Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).
Cancer:
ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (Table 3, 5.3).
Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Aranesp to patients with cancer (5.2).
Use the lowest dose to avoid RBC transfusions (2.3).
Use ESAs only for anemia from myelosuppressive chemotherapy (1.2).
ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3).
Discontinue following the completion of a chemotherapy course (2.3).
RECENT MAJOR CHANGES
Dosage and Administration:
Patients on Cancer Chemotherapy (2.3)                                       12/2013
INDICATIONS AND USAGE
Aranesp is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia due to:
• Chronic Kidney Disease (CKD) in patients on dialysis and patients not on dialysis (1.1).
• The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy (1.2).
Limitations of Use
Aranesp has not been shown to improve quality of life, fatigue, or patient well-being (1.3).
Aranesp is not indicated for use:
• In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy (1.3).
• In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.3).
• As a substitute for RBC transfusions in patients who require immediate correction of anemia (1.3).
DOSAGE AND ADMINISTRATION
Recommended starting dose for CKD patients on dialysis (2.2):
0.45 mcg/kg intravenously or subcutaneously weekly, or
0.75 mcg/kg intravenously or subcutaneously every 2 weeks
Intravenous route is recommended for patients on hemodialysis
Recommended starting dose for patients with CKD not on dialysis (2.2):
0.45 mcg/kg intravenously or subcutaneously at 4 week intervals
Recommended starting dose for cancer patients on chemotherapy (2.3):
2.25 mcg/kg subcutaneously weekly or
500 mcg subcutaneously every 3 weeks
DOSAGE FORMS AND STRENGTHS
Single-dose vials: 25, 40, 60, 100, 200, 300, and 500 mcg/1 mL, and 150 mcg/0.75 mL (3)
Single-dose prefilled syringes: 10 mcg/0.4mL, 25 mcg/0.42 mL,
40 mcg/0.4 mL,
60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL,
200 mcg/0.4 mL,
300 mcg/0.6 mL, and 500 mcg/1 mL (3)
CONTRAINDICATIONS
Uncontrolled hypertension (4)
Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs (4)
Serious allergic reactions to Aranesp (4)
WARNINGS AND PRECAUTIONS
Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using Aranesp to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1).
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer (5.2 and 5.3).
Hypertension: Control hypertension prior to initiating and during treatment with Aranesp (5.4).
Seizures: Aranesp increases the risk for seizures in patients with CKD (5.5). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.5).
PRCA: If severe anemia and low reticulocyte count develop during Aranesp treatment, withhold Aranesp and evaluate for PRCA (5.7).
ADVERSE REACTIONS
Patients with CKD: Adverse reactions in ≥ 10% of Aranesp-treated patients in clinical studies were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension (6.1).
Cancer Patients Receiving Chemotherapy: Adverse reactions in ≥ 1% of Aranesp-treated patients in clinical studies were abdominal pain, edema, and thrombovascular events (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy Surveillance Program is available (8.1).
Nursing Mothers: Exercise caution when Aranesp is administered to a nursing woman (8.3).
Pediatric Use: Safety and efficacy not established in the initial treatment of anemic patients with CKD, in the transition from another erythropoietin in patients with CKD who are less than 1 year of age, or in pediatric patients with cancer (8.4).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Anemia Due to Chronic Kidney Disease
Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis.
1.2 Anemia Due to Chemotherapy in Patients With Cancer
Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
1.3 Limitations of Use
Aranesp has not been shown to improve quality of life, fatigue, or patient well-being.
Aranesp is not indicated for use:
In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
As a substitute for RBC transfusions in patients who require immediate correction of anemia [see Clinical Pharmacology (12.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Evaluation of Iron Stores and Nutritional Factors
Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Aranesp [see Warnings and Precautions (5.10)].
2.2 Patients with Chronic Kidney Disease
In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1)]. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies (14)].
For all patients with CKD
When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Aranesp by 25% or more as needed to reduce rapid responses.
For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
For patients who do not respond adequately over a 12-week escalation period, increasing the Aranesp dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Aranesp if responsiveness does not improve.
For patients with CKD on dialysis:
Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL.
If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Aranesp.
The recommended starting dose is 0.45 mcg/kg intravenously or subcutaneously as a weekly injection or 0.75 mcg/kg once every 2 weeks as appropriate. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis:
Consider initiating Aranesp treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Aranesp, and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions.
The recommended starting dose is 0.45 mcg/kg body weight intravenously or subcutaneously given once at four week intervals as appropriate.
When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.3).
Refer patients who self-administer Aranesp to the Instructions for Use [see Patient Counseling Information (17)].
Conversion from Epoetin alfa to Aranesp in patients with CKD on dialysis
Aranesp is administered less frequently than epoetin alfa.
Administer Aranesp once weekly in patients who were receiving epoetin alfa 2 to 3 times weekly.
Administer Aranesp once every 2 weeks in patients who were receiving epoetin alfa once weekly.
Estimate the starting weekly dose of Aranesp for adults and pediatric patients on the basis of the weekly epoetin alfa dose at the time of substitution (see Table 1). Maintain the route of administration (intravenous or subcutaneous injection).
Table 1. Estimated Aranesp Starting Doses (mcg/week) for Patients With CKD on Dialysis Based on Previous Epoetin alfa Dose (Units/week)

Previous Weekly Epoetin alfa Dose (Units/week) Aranesp Dose (mcg/week)

Adult Pediatric

< 1,500 6.25 *

1,500 to 2,499 6.25 6.25

2,500 to 4,999 12.5 10

5,000 to 10,999 25 20

11,000 to 17,999 40 40

18,000 to 33,999 60 60

34,000 to 89,999 100 100

≥ 90,000 200 200
For pediatric patients receiving a weekly epoetin alfa dose of < 1,500 Units/week, the available data are insufficient to determine an Aranesp conversion dose.
Conversion from Epoetin alfa to Aranesp in patients with CKD not on dialysis
The dose conversion depicted in Table 1 does not accurately estimate the once monthly dose of Aranesp.
2.3 Patients on Cancer Chemotherapy
Initiate Aranesp in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
Use the lowest dose of Aranesp necessary to avoid RBC transfusions.
Recommended Starting Dose
The recommended starting dose and schedules are:
2.25 mcg/kg every week subcutaneously until completion of a chemotherapy course
500 mcg every 3 weeks subcutaneously until completion of a chemotherapy course
Dose Adjustment

Dose Adjustment Weekly Schedule Every 3 Week Schedule

If hemoglobin increases greater than 1 g/dL in any 2-week period or

If hemoglobin reaches a level needed to avoid RBC transfusion
Reduce dose by 40% Reduce dose by 40%

If hemoglobin exceeds a level needed to avoid RBC transfusion

Withhold dose until hemoglobin approaches a level where RBC transfusions may be required

Reinitiate at a dose 40% below the previous dose

Withhold dose until hemoglobin approaches a level where RBC transfusions may be required

Reinitiate at a dose 40% below the previous dose

If hemoglobin increases by less than 1 g/dL and remains below 10 g/dL after 6 weeks of therapy Increase dose to 4.5 mcg/kg/week No dose adjustment

If there is no response as measured by hemoglobin levels or if RBC transfusions are still required after 8 weeks of therapy

Following completion of a chemotherapy course
Discontinue Aranesp Discontinue Aranesp
2.4 Preparation and Administration
The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Do not shake. Do not use Aranesp that has been shaken or frozen.
Protect vials and prefilled syringes from light.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration.
Discard unused portion of Aranesp in vials or prefilled syringes. Do not re-enter vial.
Do not dilute Aranesp and do not administer in conjunction with other drug solutions.
3 DOSAGE FORMS AND STRENGTHS
Aranesp is available as a polysorbate-containing solution.
Single-dose vials: 25, 40, 60, 100, 200, 300, and 500 mcg Aranesp/1 mL, and 150 mcg Aranesp/0.75 mL
Single-dose prefilled syringes: 10 mcg/0.4 mL, 25 mcg Aranesp/0.42 mL,
40 mcg Aranesp/0.4 mL,
60 mcg Aranesp/0.3 mL, 100 mcg Aranesp/0.5 mL, and
150 mcg Aranesp/0.3 mL,
200 mcg Aranesp/0.4 mL, 300 mcg Aranesp/0.6 mL, and
500 mcg Aranesp/1 mL
4 CONTRAINDICATIONS
Aranesp is contraindicated in patients with:
Uncontrolled hypertension [see Warnings and Precautions (5.4)].
Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs [see Warnings and Precautions (5.7)].
Serious allergic reactions to Aranesp [see Warnings and Precautions (5.8)].
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism
In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL), Aranesp and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
Using Aranesp to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
In controlled clinical trials of patients with cancer, Aranesp and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2.
Table 2: Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients With CKD

Normal Hematocrit Study (NHS)
(N = 1265)
CHOIR
(N = 1432)
TREAT
(N = 4038)

Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009

Population CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL

Hemoglobin Target; Higher vs. Lower (g/dL) 14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0

Median (Q1, Q3) Achieved Hemoglobin level (g/dL) 12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) 13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6) 12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)

Primary Endpoint All-cause mortality or non-fatal MI All-cause mortality, MI, hospitalization for CHF, or stroke All-cause mortality, MI, myocardial ischemia, heart failure, and stroke

Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 - 1.56) 1.34 (1.03 - 1.74) 1.05 (0.94 - 1.17)

Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke

Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 - 1.54) 1.48 (0.97 - 2.27) 1.92 (1.38 - 2.68)
Patients with Chronic Kidney Disease
Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR = 1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p = 0.03].
TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either Aranesp treatment or a matching placebo. Placebo group patients also received Aranesp when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of Aranesp treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with Aranesp treatment (see Table 2), but the risk of stroke was increased nearly two-fold in the Aranesp-treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the Aranesp treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among Aranesp-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
Patients with Cancer
An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
In a randomized, placebo-controlled study (Study 1 in Table 3 [see Warnings and Precautions (5.3)]) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Patients Having Surgery
Aranesp is not approved for reduction of RBC transfusions in patients scheduled for surgical procedures.
An increased incidence of DVT in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received epoetin alfa and standard of care (SOC) treatment (n = 340) or SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group).
Increased mortality was observed in a randomized, placebo-controlled study of epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.
5.2 Prescribing and Distribution Program for Aranesp in Patients With Cancer
In order to prescribe and/or dispense Aranesp to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program requirements. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prior to each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.
5.3 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer
ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 3). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8).
Table 3. Randomized, Controlled Studies With Decreased Survival and/or Decreased Locoregional Control

Q1= 25th percentile

Study/Tumor/(n) Hemoglobin Target Hemoglobin(Median;
Q1, Q3*) Primary Efficacy Outcome Adverse Outcome for
ESA- containing Arm

Chemotherapy

Study 1
Metastatic breast
cancer
(n = 939) 12-14 g/dL 12.9 g/dL;12.2, 13.3 g/dL 12-month overall survival Decreased 12-month survival

Study 2
Lymphoid malignancy
(n = 344)
13-15 g/dL (M)
13-14 g/dL (F) 11 g/dL;9.8, 12.1 g/dL Proportion of patients achieving a hemoglobin response Decreased overall survival

Study 3
Early breast
cancer
(n = 733) 12.5-13 g/dL
13.1 g/dL;
12.5, 13.7 g/dL Relapse-free and overall survival
Decreased 3-year relapse-free and overall survival

Study 4
Cervical cancer
(n = 114) 12-14 g/dL 12.7 g/dL;
12.1, 13.3 g/dL Progression-free and overall survival and locoregional control Decreased 3-year progression-free and overall survival and locoregional control

Radiotherapy Alone

Study 5
Head and neck
cancer
(n = 351)
≥15 g/dL (M)
≥14 g/dL (F) Not available Locoregional progression-free survival Decreased 5-year locoregional progression-free and overall survival

Study 6
Head and neck
cancer
(n = 522) 14-15.5 g/dL Not available Locoregional disease control Decreased locoregional disease control

No Chemotherapy or Radiotherapy

Study 7
Non-small cell
lung cancer
(n = 70) 12-14 g/dL Not available Quality of life Decreased overall survival

Study 8
Non-myeloid
malignancy
(n = 989) 12-13 g/dL
10.6 g/dL;
9.4, 11.8 g/dL RBC transfusions Decreased overall survival
Q3= 75th percentile
Decreased Overall Survival
Study 1 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Study 2 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).
Decreased Progression-free Survival and Overall Survival
Study 3 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
Study 4 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
Study 5 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
Decreased Locoregional Control
Study 6 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
5.4 Hypertension
Aranesp is contraindicated in patients with uncontrolled hypertension. In Aranesp clinical studies, approximately 40% of patients with CKD required initiation or intensification of antihypertensive therapy during the early phase of treatment. Hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Aranesp.
Appropriately control hypertension prior to initiation of and during treatment with Aranesp. Reduce or withhold Aranesp if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].
5.5 Seizures
Aranesp increases the risk of seizures in patients with CKD. During the first several months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.
5.6 Lack or Loss of Hemoglobin Response to Aranesp
For lack or loss of hemoglobin response to Aranesp, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions (5.7)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Aranesp therapy [see Dosage and Administration (2.2)].
5.7 Pure Red Cell Aplasia
Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp is not approved).
If severe anemia and low reticulocyte count develop during treatment with Aranesp, withhold Aranesp and evaluate patients for neutralizing antibodies to erythropoietin. Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies. Permanently discontinue Aranesp in patients who develop PRCA following treatment with Aranesp or other erythropoietin protein drugs. Do not switch patients to other ESAs.
5.8 Serious Allergic Reactions
Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp. Immediately and permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
5.9 Dialysis Management
Patients may require adjustments in their dialysis prescriptions after initiation of Aranesp. Patients receiving Aranesp may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.
5.10 Laboratory Monitoring
Evaluate transferrin saturation and serum ferritin prior to and during Aranesp treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [see Dosage and Administration (2.1)]. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1)]
Increased mortality and/or increased risk of tumor progression or recurrence in Patients With Cancer [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Seizures [see Warnings and Precautions (5.5)]
PRCA [see Warnings and Precautions (5.7)]
Serious allergic reactions [see Warnings and Precautions (5.8)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
Patients with Chronic Kidney Disease
Adult Patients
Adverse reactions were determined based on pooled data from 5 randomized, active-controlled studies of Aranesp with a total of 1357 patients (Aranesp 766, epoetin alfa 591). The median duration of exposure for patients receiving Aranesp was 340 days, with 580 patients exposed for greater than 6 months and 360 patients exposed for greater than 1 year. The median (25th, 75th percentiles) weight-adjusted dose of Aranesp was 0.50 mcg/kg (0.32, 0.81). The median (range) age for patients administered Aranesp was 62 years (18 to 88). In the Aranesp group, 55% were male, 72% were white, 83% were receiving dialysis, and 17% were not receiving dialysis.
Table 4 lists adverse reactions occurring in ≥ 5% of patients treated with Aranesp.
Table 4. Adverse Reactions Occurring in ≥ 5% of Patients with CKD

Adverse Reaction Patients Treated With Aranesp (n = 766)

Hypertension 31%

Dyspnea 17%

Peripheral edema 17%

Cough 12%

Procedural hypotension 10%

Angina pectoris 8%

Vascular access complications 8%

Fluid overload 7%

Rash/Erythema 5%

Arteriovenous graft thrombosis 5%
Rates of adverse reactions with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these studies.
Pediatric Patients
Aranesp was administered to 81 pediatric patients with CKD who had stable hemoglobin concentrations while previously receiving epoetin alfa [see Clinical Studies (14.1)]. In this study, the most frequently reported serious adverse reactions with Aranesp were hypertension and convulsions. The most commonly reported adverse reactions were hypertension, injection site pain, rash, and convulsions. Aranesp administration was discontinued because of injection site pain in 2 patients and moderate hypertension in a third patient.
Studies have not evaluated the effects of Aranesp when administered to pediatric patients as the initial treatment for the anemia associated with CKD.
Cancer Patients Receiving Chemotherapy
Adverse reactions were based on data from a randomized, double-blind, placebo-controlled study of Aranesp in 597 patients (Aranesp 301, placebo 296) with extensive stage small cell lung cancer (SCLC) receiving platinum-based chemotherapy. All patients were white, 64% were male, and the median age was 61 years (range: 28 to 82 years); 25% of the study population were from North America, Western Europe, and Australia. Patients received Aranesp at a dose of 300 mcg or placebo weekly for 4 weeks then every 3 weeks for a total of 24 weeks, and the median duration of exposure was 19 weeks (range: 1 to 26 weeks).
Adverse reactions were also based on data from 7 randomized, double-blind, placebo-controlled studies, including the SCLC study described above, that enrolled 2112 patients (Aranesp 1203, placebo 909) with non-myeloid malignancies. Most patients were white (95%), male (52%), and the median age was 63 years (range: 18 to 91 years); 73% of the study population were from North America, Western Europe, and Australia. Dosing and schedules varied by study from once weekly to once every 4 weeks, and the median duration of exposure was 12 weeks (range: 1 to 27 weeks).
Table 5. Thrombovascular Adverse Reactions in Patients Receiving Chemotherapy

SCLC Study All Placebo-controlled
Studies

Adverse Reaction Aranesp
(n = 301) Placebo
(n = 296) Aranesp
(n = 1203) Placebo
(n = 909)

Thromboembolic Adverse Reactions, n (%) 24 (8.0%) 13 (4.4%) 73 (6.1%) 37 (4.1%)

Arterial 10 (3.3%) 3 (1.0%) 15 (1.2%) 5 (0.6%)

Myocardial infarction 5 (1.7%) 0 7 (0.6%) 2 (0.2%)

Venous 14 (4.7%) 10 (3.4%) 60 (5.0%) 32 (3.5%)

Pulmonary embolism 5 (1.7%) 3 (1.0%) 16 (1.3%) 6 (0.7%)

Cerebrovascular disorders* 14 (4.7%) 9 (3.0%) 20 (1.7%) 17 (1.9%)

Cerebrovascular disorders” encompasses CNS hemorrhages and cerebrovascular accidents (ischemic and hemorrhagic). Events in this category may also be included under “thromboembolic adverse reactions.”
In addition to the thrombovascular adverse reactions, abdominal pain and edema occurred at a higher incidence in patients taking Aranesp compared to patients on placebo. Among all placebo-controlled studies, abdominal pain (13.2% vs. 9.4%) and edema (12.8% vs. 9.7%) were reported more frequently in patients receiving Aranesp compared to the placebo group. In the SCLC study the incidence of abdominal pain (10.3% vs. 3.4%) and edema (5.6% vs. 5.1%) in the Aranesp-treated patients compared to those receiving placebo.
6.2 Postmarketing Experience
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postmarketing use of Aranesp:
Seizures [see Warnings and Precautions (5.5)]
PRCA [see Warnings and Precautions (5.7)]
Serious allergic reactions [see Warnings and Precautions (5.8)]
6.3 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.7)].
In clinical studies, the percentage of patients with antibodies to Aranesp was examined using the Biacore® assay. Sera from 1501 patients with CKD and 1159 cancer patients were tested. At baseline, prior to Aranesp treatment, binding antibodies were detected in 59 patients (4%) with CKD and 36 cancer patients (3%). During Aranesp therapy (range: 22 to 177 weeks), a follow-up sample was taken. One additional patient with CKD and 8 additional cancer patients developed antibodies capable of binding Aranesp. None of the patients had antibodies capable of neutralizing the activity of Aranesp or endogenous erythropoietin at baseline or at end of study. No clinical sequelae consistent with PRCA were associated with the presence of these antibodies.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No formal drug interaction studies have been conducted with Aranesp.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Aranesp use in pregnant women. In animal reproduction and developmental toxicity studies, Aranesp increased early post-implantation loss. Use Aranesp during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When Aranesp was administered intravenously to healthy pregnant rats and rabbits, there was no evidence of embryofetal toxicity or other adverse outcomes at the intravenous doses tested, up to 20 mcg/kg/day. This animal dose level of 20 mcg/kg/day is approximately 20-fold higher than the clinical recommended starting dose, depending on the patient’s treatment indication. Slightly reduced fetal weights were observed when healthy rat and rabbit mothers received doses of 1 mcg/kg or more. This dose of 1 mcg/kg is near the clinical recommended starting dose. While no adverse effects on uterine implantation occurred in animals, there was an increase in early post-implantation loss in animal fertility studies. It is not clear whether the increased post-implantation loss reflects a drug effect on the uterine environment or on the conceptus. No significant placental transfer of Aranesp was detected.
In a peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation throughout pregnancy and lactation. The lowest dose tested, 0.5 mcg/kg, did not cause fetal toxicity; this dose is approximately equivalent to the clinical recommended starting dose. At maternal doses of 2.5 mcg/kg and higher, pups had decreased fetal body weights, which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation [see Nonclinical Toxicology (13.3)].
Women who become pregnant during Aranesp treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.
8.3 Nursing Mothers
It is not known whether Aranesp is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aranesp is administered to a nursing woman.
8.4 Pediatric Use
Pediatric Patients with CKD
Aranesp safety and efficacy were similar between adults and pediatric patients with CKD who were over 1 year of age when patients were transitioned from treatment with epoetin alfa to Aranesp [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Aranesp safety and efficacy have not been established in the initial treatment of anemic pediatric patients with CKD or in the transition from another erythropoietin to Aranesp in pediatric CKD patients less than 1 year of age.
Pediatric Cancer Patients
The safety and efficacy of Aranesp in pediatric cancer patients have not been established.
8.5 Geriatric Use
Of the 1801 patients with CKD in clinical studies of Aranesp, 44% were age 65 and over, while 17% were age 75 and over. Of the 873 patients in clinical studies receiving Aranesp and concomitant cancer chemotherapy, 45% were age 65 and over, while 14% were age 75 and over. No differences in safety or efficacy were observed between older and younger patients.
10 OVERDOSAGE
Aranesp overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Aranesp dosage and/or with phlebotomy, as clinically indicated [see Pharmacodynamics (12.2)]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.4)].
11 DESCRIPTION
Aranesp (darbepoetin alfa) is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Aranesp is a 165-amino acid protein that differs from recombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons.
Aranesp is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 ± 0.2).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
12.2 Pharmacodynamics
Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with Aranesp.
12.3 Pharmacokinetics
Adult Patients with CKD
The pharmacokinetics of Aranesp were studied in patients with CKD receiving or not receiving dialysis and cancer patients receiving chemotherapy.
Following intravenous administration of Aranesp to patients with CKD receiving dialysis, Aranesp serum concentration-time profiles were biphasic, with a distribution half-life of approximately 1.4 hours and a mean terminal half-life (t1/2) of 21 hours. The t1/2 of Aranesp was approximately 3-fold longer than that of epoetin alfa when administered intravenously.
Following subcutaneous administration of Aranesp to patients with CKD (receiving or not receiving dialysis), absorption was slow and Cmax occurred at 48 hours (range: 12 to 72 hours). In patients with CKD receiving dialysis, the average t1/2 was 46 hours (range: 12 to 89 hours), and in patients with CKD not receiving dialysis, the average t1/2 was 70 hours (range: 35 to 139 hours). Aranesp apparent clearance was approximately 1.4 times faster on average in patients receiving dialysis compared to patients not receiving dialysis. The bioavailability of Aranesp in patients with CKD receiving dialysis after subcutaneous administration was 37% (range: 30% to 50%).
Pediatric Patients with CKD
Aranesp pharmacokinetics was studied in 12 pediatric patients (age 3 to 16 years) with CKD receiving or not receiving dialysis. Following a single intravenous or subcutaneous Aranesp dose, Cmax and t1/2 were similar to those obtained in adult patients with CKD on dialysis. Following a single subcutaneous dose, the average bioavailability was 54% (range: 32% to 70%), which was higher than that obtained in adult patients with CKD on dialysis.
Adult Cancer Patients
Following the first subcutaneous dose of 6.75 mcg/kg (equivalent to 500 mcg for a 74-kg patient) in patients with cancer, the mean t1/2 was 74 hours (range: 24 to 144 hours) and Cmax was observed at 71 hours (range: 28 to 120 hours). When administered on a once every 3 week schedule, 48-hour postdose Aranesp levels after the fourth dose were similar to those after the first dose.
Over the dose range of 0.45 to 4.5 mcg/kg Aranesp administered intravenously or subcutaneously on a once weekly schedule and 4.5 to 15 mcg/kg administered subcutaneously on a once every 3 week schedule, systemic exposure was approximately proportional to dose. No evidence of accumulation was observed beyond an expected less than 2-fold increase in blood levels when compared to the initial dose.
14 CLINICAL STUDIES
Clinical studies in the nephrology and chemotherapy-induced anemia clinical programs are designated with the prefixes “N” and “C”, respectively.
14.1 Patients With Chronic Kidney Disease
Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion
In early clinical studies conducted in CKD patients on dialysis, ESAs have been shown to reduce the use of RBC transfusions. These studies enrolled patients with mean baseline hemoglobin levels of approximately 7.5 g/dL and ESAs were generally titrated to achieve a hemoglobin level of approximately 12 g/dL. Fewer transfusions were given during the ESA treatment period when compared to a pre-treatment interval.
In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).
Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion
In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered Aranesp to target a hemoglobin of 13 g/dL compared to the control arm in which Aranesp was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of an ESA to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions (5.1)].
ESA Effects on quality of life
Aranesp use has not been demonstrated in controlled clinical trials to improve quality of life, fatigue, or patient well-being.
ESA Effects on rates of death and other serious cardiac adverse events
Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions (5.1)].
Other ESA trials
Two studies evaluated the safety and efficacy of the de novo use of Aranesp for the correction of anemia in adult patients with CKD, and 3 studies (2 in adults and 1 in pediatric patients) assessed the ability of Aranesp to maintain hemoglobin concentrations in patients with CKD who had been receiving other recombinant erythropoietins.
De Novo Use of Aranesp
Once Weekly Aranesp Starting Dose
In 2 randomized, open-label studies, Aranesp or epoetin alfa was administered for the correction of anemia in patients with CKD who had not been receiving prior treatment with exogenous erythropoietin. Study N1 evaluated CKD patients receiving dialysis; Study N2 evaluated patients not requiring dialysis. In both studies, the starting dose of Aranesp was 0.45 mcg/kg administered once weekly. The starting dose of epoetin alfa was 50 Units/kg 3 times weekly in Study N1 and 50 Units/kg twice weekly in Study N2. When necessary, dosage adjustments were instituted to maintain hemoglobin in the study target range of 11 to 13 g/dL. (Note: The recommended hemoglobin target range is lower than the target range of these studies [see Dosage and Administration (2.2)].) The primary efficacy endpoint was the proportion of patients who experienced at least a 1 g/dL increase in hemoglobin concentration to a level of at least 11 g/dL by 20 weeks (Study N1) or 24 weeks (Study N2). The studies were designed to assess the safety and effectiveness of Aranesp but not to support conclusions regarding comparisons between the 2 products.
In Study N1, the primary efficacy endpoint was achieved by 72% (95% CI: 62%, 81%) of the 90 patients treated with Aranesp and 84% (95% CI: 66%, 95%) of the 31 patients treated with epoetin alfa. The mean increase in hemoglobin over the initial 4 weeks of Aranesp treatment was 1.1 g/dL (95% CI: 0.82 g/dL, 1.37 g/dL).
In Study N2, the primary efficacy endpoint was achieved by 93% (95% CI: 87%, 97%) of the 129 patients treated with Aranesp and 92% (95% CI: 78%, 98%) of the 37 patients treated with epoetin alfa. The mean increase in hemoglobin from baseline through the initial 4 weeks of Aranesp treatment was 1.38 g/dL (95% CI: 1.21 g/dL, 1.55 g/dL).
In 2 single-arm studies (N3 and N4), Aranesp was administered for the correction of anemia in CKD patients not receiving dialysis. In both studies, the starting dose of Aranesp was 0.75 mcg/kg administered once every 2 weeks.
In Study N3 (study duration of 18 weeks), the hemoglobin goal (hemoglobin concentration ≥ 11 g/dL) was achieved by 92% (95% CI: 86%, 96%) of the 128 patients treated with Aranesp.
In Study N4 (study duration of 24 weeks), the hemoglobin goal (hemoglobin concentration of 11 to 13 g/dL) was achieved by 85% (95% CI: 77%, 93%) of the 75 patients treated with Aranesp.
Conversion from Other Recombinant Erythropoietins
Two studies of adults (N5 and N6) and 1 study in pediatric patients (N7) were conducted in patients who had been receiving other recombinant erythropoietins for treatment of the anemia due to CKD. The studies compared the abilities of Aranesp and other erythropoietins to maintain hemoglobin concentrations within a study target range of 9 to 13 g/dL in adults and 10 to 12.5 g/dL in pediatric patients. (Note: The recommended hemoglobin target is lower than the target range of these studies [see Dosage and Administration (2.2)].) Patients who had been receiving stable doses of other recombinant erythropoietins were randomized to Aranesp or continued with their prior erythropoietin at the previous dose and schedule. For patients randomized to Aranesp, the initial weekly dose was determined on the basis of the previous total weekly dose of recombinant erythropoietin.
Adult Patients
Study N5 was a double-blind study in which 169 hemodialysis patients were randomized to treatment with Aranesp and 338 patients continued on epoetin alfa. Study N6 was an open-label study in which 347 patients were randomized to treatment with Aranesp and 175 patients were randomized to continue on epoetin alfa or epoetin beta. Of the patients randomized to Aranesp, 92% were receiving hemodialysis and 8% were receiving peritoneal dialysis.
In Study N5, a median weekly dose of 0.53 mcg/kg Aranesp (25th, 75th percentiles: 0.30, 0.93 mcg/kg) was required to maintain hemoglobin in the study target range. In Study N6, a median weekly dose of 0.41 mcg/kg Aranesp (25th, 75th percentiles: 0.26, 0.65 mcg/kg) was required to maintain hemoglobin in the study target range.
Pediatric Patients
Study N7 was an open-label, randomized study conducted in the United States in pediatric patients from 1 to 18 years of age with CKD receiving or not receiving dialysis. Eighty-one patients with hemoglobin concentrations that were stable on epoetin alfa received darbepoetin alfa (subcutaneously or intravenously), and 42 patients continued to receive epoetin alfa at the current dose, schedule, and route of administration. Patients received darbepoetin alfa once weekly if previously receiving epoetin alfa 2 or 3 times weekly or once every other week if previously receiving epoetin alfa weekly. A median weekly dose of 0.41 mcg/kg darbepoetin alfa (25th, 75th percentiles: 0.25, 0.82 mcg/kg) was required to maintain hemoglobin in the study target range.
14.2 Cancer Patients Receiving Chemotherapy
The safety and efficacy of Aranesp was assessed in two multicenter, randomized studies in patients with anemia due to the effect of concomitantly administered cancer chemotherapy. Study C1 was a randomized (1:1), placebo-controlled, double-blind, multinational study conducted in 314 patients where Aranesp was administered weekly. Study C2 was a randomized (1:1), double-blind, double-dummy, active-controlled, multinational study conducted in 705 patients where Aranesp was administered either every week or every 3 weeks. Efficacy was demonstrated by a statistically significant reduction in the proportion of patients receiving RBC transfusions among patients who were on study therapy for more than 28 days.
Study C1
Study C1 was conducted in anemic patients (hemoglobin ≤ 11 g/dL) with non-small cell lung cancer or small cell lung cancer who were scheduled to receive at least 12 weeks of a platinum-containing chemotherapy regimen. Randomization was stratified by tumor type and region (Australia vs. Canada vs. Europe). Patients received Aranesp 2.25 mcg/kg or placebo as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle. Efficacy was determined by a reduction in the proportion of patients who received RBC transfusions between week 5 (day 29) and end of treatment period (12 weeks) in the subset of 297 randomized patients (148 Aranesp and 149 placebo) who were on-study at the beginning of study week 5. All 297 patients were white, 72% were male, 71% had non-small cell histology, and the median age was 62 years (range: 36 to 80). A significantly lower proportion of patients in the Aranesp arm received RBC transfusions during week 5 to the end of treatment compared to patients in the placebo arm (crude percentages: 26% vs. 50%; p < 0.001, based on a comparison of the difference in Kaplan-Meier proportions using the Cochran-Mantel-Haenszel strata-adjusted Chi-square test).
Study C2
Study C2 was conducted in anemic patients (hemoglobin < 11 g/dL) with non-myeloid malignancies receiving chemotherapy. Randomization was stratified by region (Western vs. Central/Eastern Europe), tumor type (lung and gynecological vs. others), and baseline hemoglobin (< 10 vs. ≥ 10 g/dL); all patients received double-dummy placebo and either Aranesp 500 mcg every 3 weeks or Aranesp 2.25 mcg/kg weekly subcutaneous injections for 15 weeks. Only 1 patient was non-white, 55% were female, and the median age was 60 years (range: 20 to 86). One hundred seven patients (16%) had lung or gynecological cancer while 565 (84%) had other tumor types. In both treatment schedules, the dose was reduced by 40% of the previous dose if hemoglobin level increased by more than 1 g/dL in a 14-day period.
Efficacy was determined by a comparison of the proportion of patients who received at least 1 RBC transfusion between week 5 (day 29) and the end of treatment. Three hundred thirty-five patients in the every 3 week dosing arm and 337 patients in the weekly dosing arm remained on study through or beyond day 29 and were evaluable for efficacy. Two hundred thirty-eight patients (71%) in the every 3 week arm and 261 patients (77%) patients in the weekly arm required dose reductions. Twenty-three percent (95% CI: 18%, 28%) of patients in the every 3 week treatment schedule and 28% (95% CI: 24%, 34%) in the weekly schedule received at least 1 RBC transfusion. The observed difference in the RBC transfusion rates (every 3 week minus weekly) was -5.8% (95% CI: -12.4%, 0.8%).
Study C3
Lack of Efficacy in Improving Survival
Study C3 was conducted in patients required to have a hemoglobin concentration ≥ 9 g/dL and ≤ 13 g/dL with previously untreated extensive-stage small cell lung cancer (SCLC) receiving platinum and etoposide chemotherapy. Randomization was stratified by region (Western Europe, Australia/North America, and rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2), and lactate dehydrogenase (below vs. above the upper limit of normal). Patients were randomized to receive Aranesp (n = 298) at a dose of 300 mcg once weekly for the first 4 weeks, followed by 300 mcg once every 3 weeks for the remainder of the treatment period or placebo (n = 298).
This study was designed to detect a prolongation in overall survival (from a median of 9 months to a median of 12 months). For the final analysis, there was no evidence of improved survival (p=0.43, log-rank test).
16 HOW SUPPLIED/STORAGE AND HANDLING
Store at 36°F to 46°F (2°C to 8°C). Do not freeze.
Do not shake. Protect from light; store Aranesp in the carton until use.
Do not use Aranesp that has been shaken or frozen.
Aranesp is available in the following packages:
Single-dose Vial

1 Vial/Pack, 4 Packs/Case 4 Vials/Pack, 10 Packs/Case

200 mcg/1 mL
(NDC 55513-006-01)

300 mcg/1 mL
(NDC 55513-110-01) 25 mcg/1 mL
(NDC 55513-002-04)

40 mcg/1 mL
(NDC 55513-003-04)

60 mcg/1 mL
(NDC 55513-004-04)

100 mcg/1 mL
(NDC 55513-005-04)

150 mcg/0.75 mL
(NDC 55513-053-04)
Single-dose Prefilled Syringe (SingleJect®) with a 27-gauge, ½-inch needle with an UltraSafe® Needle Guard that is manually activated to cover the needle during disposal

1 Syringe/Pack, 4 Packs/Case 4 Syringes/Pack, 10 Packs/Case

200 mcg/0.4 mL
(NDC 55513-028-01)

300 mcg/0.6 mL
(NDC 55513-111-01)

500 mcg/1 mL
(NDC 55513-032-01)
10 mcg/0.4 mL
(NDC 55513-098-04)

25 mcg/0.42 mL
(NDC 55513-057-04)

40 mcg/0.4 mL
(NDC 55513-021-04)

60 mcg/0.3 mL
(NDC 55513-023-04)

100 mcg/0.5 mL
(NDC 55513-025-04)

150 mcg/0.3 mL
(NDC 55513-027-04)
www.oneyao.net
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fd36cb9-c4f6-4167-93c9-8530865db3f9

-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 30mcg/0.6ml 1Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 300微克/0.6毫升/注射器 1注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 60mcg/0.3ml 4Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 60微克/0.3毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 40mcg/0.4ml 4Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 40微克/0.4毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 25mcg/0.42ml 4Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
RANESP 25微克/0.42毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 200mcg/0.4ml 1 Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 200微克/0.4毫升/注射器 1注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
产地英文商品名:
ARANESP 10mcg/0.4ml 4Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 10微克/0.4毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 500mcg/ml 1 Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 500微克/毫升/注射器 1注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 150mcg/0.3ml 4Syringe/Box
原产地英文药品名:
Darbepoetin Alfa
中文参考商品译名:
ARANESP 150微克/0.3毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen
-----------------------------------------------------
产地国家：美国
原产地英文商品名:
ARANESP 100ug/0.5ml 4 Syringe/Box
原产地英文药品名:
Darbepoetin alfa ln polysorbat
中文参考商品译名:
ARANESP 100微克/0.5毫升/注射器 4注射器/盒
中文参考药品译名:
达依泊汀 a ln polysorbat
生产厂家中文参考译名:
安进公司
生产厂家英文名:
Amgen