ARANESP

For adult 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. 75 mcg/kg once every 2 weeks as appropriate. The intravenous route is recommended for patients on hemodialysis.

For adult 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. 45 mcg/kg body weight intravenously or subcutaneously given once at four week intervals as appropriate.

For pediatric patients with CKD :

Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of Aranesp. 75 mcg/kg once every 2 weeks. 2 ) . 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. 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 Refer to Table 1. The dose conversion depicted in Table 1 does not accurately estimate the once monthly dose of Aranesp. 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. 25 mcg/kg every week subcutaneously until completion of a chemotherapy course. 500 mcg every 3 weeks subcutaneously until completion of a chemotherapy course. Table 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. Self-Administration of the Prefilled Syringe Training should aim to demonstrate to those patients and caregivers how to measure the dose of Aranesp, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use for a prefilled syringe.

If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of Aranesp or whether the patient would benefit from a different Aranesp presentation.

If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the Aranesp prefilled syringe, use of the Aranesp vial may be considered.

Patients with Cancer 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 6. 3%) * “Cerebrovascular disorders” encompasses central nervous system (CNS) hemorrhages and cerebrovascular accidents (ischemic and hemorrhagic). ” 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.

2% vs. 8% vs. 7%) were reported more frequently in patients receiving Aranesp compared to the placebo group. 3% vs. 6% vs. 1%) in the Aranesp-treated patients compared to those receiving placebo. 2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of Aranesp.

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. 3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity.

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 patients with cancer were tested. At baseline, prior to Aranesp treatment, binding antibodies were detected in 59 patients (4%) with CKD and 36 patients with cancer (3%).

During Aranesp therapy (range: 22 to 177 weeks), a follow-up sample was taken. One additional patient with CKD and 8 additional patients with cancer developed antibodies capable of binding Aranesp. In two studies of pediatric patients with CKD aged 2-16, 20 of 111 patients with CKD (18%) receiving dialysis and 6 of 69 patients (9%) not receiving dialysis had anti-ESA antibodies at baseline.

During therapy, 4 additional patients receiving dialysis and 4 additional patients not receiving dialysis 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. 6 ) ] .

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. 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.

3 g/dL. The trial was terminated early with adverse safety findings. 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.

1% vs. 001. 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.

2 ) ] ) 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%).

7% vs. 1% vs. 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.

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).

1%] patients). 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. 2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 4).

Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

Table 4. 8 g/dL RBC transfusions Decreased overall survival *Q1 = 25 th percentile Q3 = 75 th percentile † This study did not include a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.

1 ) ] . 7% vs. 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. 012). Study 3 was a randomized, double-blind study (darbepoetin alfa vs.

placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. 82). Study 8 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. 04). Study 9 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. 57). Decreased Progression - free Survival and Overall Survival Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy.

This was a non-inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. 20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs.

56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). 8% of subjects in the SOC group). 18). Study 4 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. 18) and the 3-year relapse-free survival rate was lower (72% vs. 79) in the darbepoetin alfa-treated arm compared to the control arm.

Study 5 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 patients with cervical cancer 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. 91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 42). Study 6 was a randomized, placebo-controlled study in 351 patients with head and neck cancer where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively.

0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms respectively. 02). 5 g/dL or no darbepoetin alfa. 02). 08). 0 g/dL, were randomized 2:1 to Aranesp or placebo and treated to a maximum Hb of 12 g/dL. Non-inferiority of Aranesp versus placebo was shown for overall survival (OS) and progression-free survival (PFS).

The study was designed to rule out a 15% risk increase. 01). 05). Aranesp did not demonstrate superiority to placebo for OS or PFS. 1% placebo). 1 )]. 3 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 ) ] . 4 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. , iron deficiency, infection, inflammation, bleeding). 6 ) ] . 2 )] . 6 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. 7 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. 8 Severe Cutaneous Reactions Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Aranesp) in the post-marketing setting.

Discontinue Aranesp therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected. 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.