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Chronic Renal Failure:

Cancer:

(See WARNINGS: Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence , INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.)

Aranesp is an erythropoiesis stimulating protein, closely related to erythropoietin, 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 two additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The additional carbohydrate chains increase the approximate molecular weight of the glycoprotein from 30,000 to 37,000 daltons. Aranesp is formulated as a sterile, colorless, preservative-free protein solution for intravenous or subcutaneous administration.

Single-dose vials are available containing 25, 40, 60, 100, 150, 200, 300, or 500 mcg of Aranesp.

Single-dose prefilled syringes and prefilled SureClick™ autoinjectors are available containing 25, 40, 60, 100, 150, 200, 300, or 500 mcg of Aranesp. Each prefilled syringe is equipped with a needle guard that covers the needle during disposal.

Single-dose vials, prefilled syringes and autoinjectors are available in two formulations that contain excipients as follows:

Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with progenitor stem cells to increase red blood cell (RBC) production. Production of endogenous erythropoietin is impaired in patients with chronic renal failure (CRF), and erythropoietin deficiency is the primary cause of their anemia. Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with Aranesp (see DOSAGE AND ADMINISTRATION ). In patients with cancer receiving concomitant chemotherapy, the etiology of anemia is multifactorial.

The pharmacokinetics of Aranesp were studied in patients with CRF receiving or not receiving dialysis and cancer patients receiving chemotherapy.

Following intravenous administration in CRF patients 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 of 21 hours. The terminal half-life of Aranesp was approximately 3-fold longer than that of Epoetin alfa when administered intravenously.

Following subcutaneous administration of Aranesp to CRF patients (receiving or not receiving dialysis), absorption was slow and peak concentrations occurred at 48 hours (range: 12 to 72 hours). In CRF patients receiving dialysis, the average half-life was 46 hours (range: 12 to 89 hours), and in CRF patients not receiving dialysis, the average half-life 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 CRF patients receiving dialysis after subcutaneous administration was 37% (range: 30% to 50%).

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 terminal half-life was 74 hours (range: 24 to 144 hours). Peak concentrations were observed at 90 hours (range: 71 to 123 hours) after a dose of 2.25 mcg/kg, and 71 hours (range: 28 to 120 hours) after a dose of 6.75 mcg/kg. When administered on a once every 3 week schedule, 48-hour post-dose 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 < 2-fold increase in blood levels when compared to the initial dose.

Aranesp pharmacokinetics were studied in 12 pediatric CRF patients (age 3-16 years) receiving or not receiving dialysis. Following a single intravenous or subcutaneous Aranesp dose, Cmax and half-life were similar to those obtained in adult CRF patients on dialysis. Following a single subcutaneous dose, the average bioavailability was 54% (range: 32% to 70%), which was higher than that obtained in adult CRF patients on dialysis.

The safety and effectiveness of Aranesp have been assessed in a number of multicenter studies. Two studies eva luated the safety and efficacy of Aranesp for the correction of anemia in adult patients with CRF, and three studies (2 in adults and 1 in pediatric patients) assessed the ability of Aranesp to maintain hemoglobin concentrations in patients with CRF who had been receiving other recombinant erythropoietins.

Once Weekly Aranesp Starting Dose

In two open-label studies, Aranesp or Epoetin alfa was administered for the correction of anemia in CRF patients who had not been receiving prior treatment with exogenous erythropoietin. Study N1 eva luated CRF patients receiving dialysis; Study N2 eva luated 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 is lower than the target range of these studies. See DOSAGE AND ADMINISTRATION for recommended clinical hemoglobin target.) 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 two products.

In Study N1, the hemoglobin target 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).

Once Every 2 Week Aranesp Starting Dose

In two single arm studies (N3 and N4), Aranesp was administered for the correction of anemia in CRF 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 11-13 g/dL) was achieved by 85% (95% CI: 77%, 93%) of the 75 patients treated with Aranesp.

Two adult studies (N5 and N6) and one pediatric study (N7) were conducted in patients with CRF who had been receiving other recombinant erythropoietins. 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 for recommended clinical hemoglobin target.) CRF patients who had been receiving stable doses of other recombinant erythropoietins were randomized to Aranesp, or to continue 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.

Study N5 was a double-blind study conducted in North America, 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 conducted in Europe and Australia 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 347 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.

Study N7 was an open-label, randomized study, conducted in the United States in pediatric patients from 1 to 18 years of age with CRF receiving or not receiving dialysis. Patients that were stable on Epoetin alfa were randomized to receive either darbepoetin alfa (n = 82) administered once weekly (subcutaneously or intravenously) or to continue receiving Epoetin alfa (n = 42) at the current dose, schedule, and route of administration. A median weekly dose of 0.41 mcg/kg Aranesp (25th, 75th percentiles: 0.25, 0.82 mcg/kg) was required to maintain hemoglobin in the study target range.

Efficacy in patients with anemia due to concomitant chemotherapy was demonstrated based on reduction in the requirement for RBC transfusions.

The safety and effectiveness of Aranesp in reducing the requirement for RBC transfusions in patients undergoing chemotherapy was assessed in a randomized, placebo-controlled, double-blind, multinational study (C1). This study was conducted in anemic (Hgb ≤ 11 g/dL) patients with advanced, small cell or non-small cell lung cancer, who received a platinum-containing chemotherapy regimen. Patients were randomized to receive Aranesp 2.25 mcg/kg (n = 156) or placebo (n = 158) administered as a single weekly SC injection for up to 12 weeks. The dose was escalated to 4.5 mcg/kg/week at week 6, in subjects with an inadequate response to treatment, defined as less than 1 g/dL hemoglobin increase. There were 67 patients in the Aranesp arm who had their dose increased from 2.25 to 4.5 mcg/kg/week, at any time during the treatment period.

Efficacy was determined by a reduction in the proportion of patients who were transfused over the 12-week treatment period. A significantly lower proportion of patients in the Aranesp arm, 26% (95% CI: 20%, 33%) required transfusion compared to 60% (95% CI: 52%, 68%) in the placebo arm (Kaplan-Meier estimate of proportion; p < 0.001 by Cochran-Mantel-Haenszel test). Of the 67 patients who received a dose increase, 28% had a 2 g/dL increase in hemoglobin over baseline, generally occurring between weeks 8 to 13. Of the 89 patients who did not receive a dose increase, 69% had a 2 g/dL increase in hemoglobin over baseline, generally occurring between weeks 6 to 13. On-study deaths occurred in 14% (22/156) of patients treated with Aranesp and 12% (19/158) of the placebo-treated patients.

The safety and effectiveness of once every 3 week Aranesp therapy in reducing the requirement for red blood cell (RBC) transfusions in patients undergoing chemotherapy was assessed in a randomized, double-blind, multinational study (C2). This study was conducted in anemic (Hgb < 11 g/dL) patients with non-myeloid malignancies receiving multicycle chemotherapy. Patients were randomized to receive Aranespat 500 mcg once every 3 weeks (n = 353) or 2.25 mcg/kg (n = 352) administered weekly as a subcutaneous injection for up to 15 weeks. In both groups, the dose was reduced by 40% of the previous dose (e.g., for first dose reduction, to 300 mcg in the once every 3 week group and 1.35 mcg/kg in the once weekly group) if hemoglobin increased by more than 1 g/dL in a 14-day period. Study drug was withheld if hemoglobin exceeded 13 g/dL. In the once every 3 week group, 254 patients (72%) required dose reductions (median time to first reduction at 6 weeks). In the once weekly group, 263 patients (75%) required dose reductions (median time to first reduction at 5 weeks).

Efficacy was determined by a comparison of the Kaplan-Meier estimates of the proportion of patients who received at least one RBC transfusion between day 29 and the end of treatment. Three hundred thirty- five patients in the once every 3 week group and 337 patients in the once weekly group remained on study through or beyond day 29 and were eva luated for efficacy. Twenty-seven percent (95% CI: 22%, 32%) of patients in the once every 3 week group and 34% (95% CI: 29%, 39%) in the weekly group required a RBC transfusion. The observed difference in the transfusion rates (once every 3 week-once weekly) was -6.7% (95% CI: -13.8%, 0.4%).

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).

Anemia With Chronic Renal Failure

Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis.

Anemia With Non-Myeloid Malignancies Due to Chemotherapy

Aranesp is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies. Studies to determine whether Aranesp increases mortality or decreases progression-free/recurrence-free survival are ongoing.

Aranesp is contraindicated in patients with:

Patients with chronic renal failure experienced greater risks for death, serious cardiovascular events, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin levels of 13 g/dL and above in clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. Aranesp and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.

In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group [Hazard Ratio (HR) 1.3, 95% CI: 1.0, 1.7, p = 0.03].

In a randomized, double-blind, placebo-controlled study of 4038 patients, there was an increased risk of stroke when Aranesp was administered to patients with anemia, type 2 diabetes, and CRF who were not on dialysis. Patients were randomized to Aranesp treatment targeted to a hemoglobin level of 13 g/dL or to placebo. Placebo patients received Aranesp only if their hemoglobin levels were less than 9 g/dL. A total of 101 patients receiving Aranesp experienced stroke compared to 53 patients receiving placebo (5% vs. 2.6%; HR 1.92, 95% CI: 1.38, 2.68; p < 0.001).

Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to Epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. Higher mortality (35% vs. 29%) was observed in the 634 patients randomized to a target hemoglobin of 14 g/dL than in the 631 patients assigned a target hemoglobin of 10 g/dL. The reason for the increased mortality observed in this study is unknown; however, 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.

An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents. In patients with cancer who received Aranesp, pulmonary emboli, thrombophlebitis, and thrombosis occurred more frequently than in placebo controls (see ADVERSE REACTIONS: Cancer Patients Receiving Chemotherapy , Table 5 ).

In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 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 an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed 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).

A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the 'BEST' and 'ENHANCE' studies) eva luating 9353 patients with cancer compared ESAs plus RBC transfusion with RBC transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk (RR) of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.

An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed. In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received Epoetin alfa and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events.

Increased mortality was observed in a randomized placebo-controlled study of Epoetin alfa in adult patients who were undergoing coronary artery bypass 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 four deaths were associated with thrombotic events.

Aranespis not approved for reduction in allogeneic RBC transfusions in patients scheduled for surgical procedures.

Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).

Decreased overall survival:

Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke ). 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 two 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).

Cancer Study 2 was a Phase 3, double-blind, randomized (Aranesp vs. placebo) study 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 Aranesp as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, 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 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Cancer Study 8 was a Phase 3, double-blind, randomized (Aranesp vs. placebo), 16-week study 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 Aranesp treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased progression-free survival and overall survival:

Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which Aranesp was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. After a median follow-up of approximately 3 years the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate were lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the Aranesp-treated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized 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 transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events 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).

Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobins of 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 a median of 406 days Epoetin beta vs. 745 days placebo. 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:

Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to Aranesp with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving Aranesp (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving Aranesp (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Aranesp to patients with cancer. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prescribers and patients must provide written acknowledgment of a discussion of the risks associated with Aranesp.

Patients with uncontrolled hypertension should not be treated with Aranesp; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anemia with Aranesp or Epoetin alfa. In Aranesp clinical trials, approximately 40% of patients with CRF required initiation or intensification of antihypertensive therapy during the early phase of treatment when the hemoglobin was increasing. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with Aranesp or Epoetin alfa.

Special care should be taken to closely monitor and control blood pressure in patients treated with Aranesp. During Aranesp therapy, patients should be advised of the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control by pharmacologic or dietary measures, the dose of Aranesp should be reduced or withheld (see DOSAGE AND ADMINISTRATION ). A clinically significant decrease in hemoglobin may not be observed for several weeks.

Seizures have occurred in patients with CRF participating in clinical trials of Aranesp and Epoetin alfa. During the first several months of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. While the relationship between seizures and the rate of rise of hemoglobin is uncertain, it is recommended that the dose of Aranesp be decreased if the hemoglobin increase exceeds 1 g/dL in any 2‑week period.

Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp. This has been reported predominantly in patients with CRF receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon and ribavirin. Any patient who develops a sudden loss of response to Aranesp, accompanied by severe anemia and low reticulocyte count, should be eva luated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response to Aranesp ). If anti-erythropoietin antibody-associated anemia is suspected, withhold Aranesp and other ESAs. Contact Amgen (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies. Aranesp should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other ESAs as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity ).

Aranesp is supplied in two formulations with different excipients, one containing polysorbate 80 and another containing albumin (human), a derivative of human blood (see DESCRIPTION ). Based on effective donor screening and product manufacturing processes, Aranesp formulated with albumin carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

The safety and efficacy of Aranesp therapy have not been established in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia, thalassemia, porphyria).

The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.

A lack of response or failure to maintain a hemoglobin response with Aranesp doses within the recommended dosing range should prompt a search for causative factors. Deficiencies of folic acid, iron, or vitamin B should be excluded or corrected. Depending on the clinical setting, intercurrent infections, inflammatory or malignant processes, osteofibrosis cystica, occult blood loss, hemolysis, severe aluminum toxicity, and bone marrow fibrosis may compromise an erythropoietic response. In the absence of another etiology, the patient should be eva luated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia ). See DOSAGE AND ADMINISTRATION : Chronic Renal Failure Patients , Dose Adjustment for management of patients with an insufficient hemoglobin response to Aranesp therapy.

Sufficient time should be allowed to determine a patient’s responsiveness to a dosage of Aranesp before adjusting the dose. Because of the time required for erythropoiesis and the RBC half-life, an interval of 2 to 6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontinuation) and a significant change in hemoglobin.

In order to prevent the hemoglobin from exceeding the recommended target range (10 to 12 g/dL) or rising too rapidly (greater than 1 g/dL in 2 weeks), the guidelines for dose and frequency of dose adjustments should be followed (see WARNINGS and DOSAGE AND ADMINISTRATION ).

There have been rare reports of potentially serious allergic reactions, including skin rash and urticaria, associated with Aranesp. Symptoms have recurred with rechallenge, suggesting a causal relationship exists in some instances. If a serious allergic or anaphylactic reaction occurs, Aranesp should be immediately and permanently discontinued and appropriate therapy should be administered.

Patients with CRF not yet requiring dialysis may require lower maintenance doses of Aranesp than patients receiving dialysis. Though CRF patients not on dialysis generally receive less frequent monitoring of blood pressure and laboratory parameters than dialysis patients, CRF patients not on dialysis may be more responsive to the effects of Aranesp, and require judicious monitoring of blood pressure and hemoglobin. Renal function and fluid and electrolyte balance should also be closely monitored.

During the transition period onto dialysis, hemoglobin and blood pressure should be monitored carefully and patients may need to have their maintenance doses adjusted to maintain hemoglobin levels within the range of 10 to 12 g/dL (see DOSAGE AND ADMINISTRATION: Maintenance Dose ).

Therapy with Aranesp results in an increase in RBCs and a decrease in plasma volume, which could reduce dialysis efficiency; patients who are marginally dialyzed may require adjustments in their dialysis prescription.

After initiation of Aranesp therapy, the hemoglobin should be determined weekly until it has stabilized and the maintenance dose has been established (see DOSAGE AND ADMINISTRATION ). After a dose adjustment, the hemoglobin should be determined weekly for at least 4 weeks, until it has been determined that the hemoglobin has stabilized in response to the dose change. The hemoglobin should then be monitored at regular intervals.

In order to ensure effective erythropoiesis, iron status should be eva luated for all patients before and during treatment, as the majority of patients will eventually require supplemental iron therapy. Supplemental iron therapy is recommended for all patients whose serum ferritin is below 100 mcg/L or whose serum transferrin saturation is below 20%.

Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS ). Patients should be informed of the possible side effects of Aranesp and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Aranesp treatment, dietary and dialysis prescriptions, and the importance of judicious monitoring of blood pressure and hemoglobin concentration should be stressed.

In those rare cases where it is determined that a patient can safely and effectively administer Aranesp at home, appropriate instruction on the proper use of Aranesp should be provided for patients and their caregivers. Patients should be instructed to read the Aranesp Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients and caregivers should also be cautioned against the reuse of needles, syringes, prefilled SureClick™ autoinjectors, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes, autoinjectors, and needles should be made available to the patient. Patients should be informed that the needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex.

No formal drug interaction studies of Aranesp have been performed.

Carcinogenicity: The carcinogenic potential of Aranesp has not been eva luated in long-term animal studies. Aranesp did not alter the proliferative response of non-hematological cells in vitro or in vivo. In toxicity studies of approximately 6 months duration in rats and dogs, no tumorigenic or unexpected mitogenic responses were observed in any tissue type. Using a panel of human tissues, the in vitro tissue binding profile of Aranesp was identical to Epoetin alfa. Neither molecule bound to human tissues other than those expressing the erythropoietin receptor.

Mutagenicity: Aranesp was negative in the in vitro bacterial and CHO cell assays to detect mutagenicity and in the in vivo mouse micronucleus assay to detect clastogenicity.

Impairment of Fertility: When administered intravenously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected at any doses eva luated (up to 10 mcg/kg/dose, administered 3 times weekly). An increase in post implantation fetal loss was seen at doses equal to or greater than 0.5 mcg/kg/dose, administered 3 times weekly.

When Aranesp was administered intravenously to rats and rabbits during gestation, no evidence of a direct embryotoxic, fetotoxic, or teratogenic outcome was observed at doses up to 20 mcg/kg/day. The only adverse effect observed was a slight reduction in fetal weight, which occurred at doses causing exaggerated pharmacological effects in the dams (1 mcg/kg/day and higher). No deleterious effects on uterine implantation were seen in either species. No significant placental transfer of Aranesp was observed in rats. An increase in post implantation fetal loss was observed in studies assessing fertility (see PRECAUTIONS:Carcinogenesis, Mutagenesis, and Impairment of Fertility: Impairment of Fertility ).

Intravenous injection of Aranesp to female rats every other day from day 6 of gestation through day 23 of lactation at doses of 2.5 mcg/kg/dose and higher resulted in offspring (F1 generation) with decreased body weights, which correlated with a low incidence of deaths, as well as delayed eye opening and delayed preputial separation. No adverse effects were seen in the F2 offspring.

There are no adequate and well-controlled studies in pregnant women. Aranesp should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

A study of the conversion from Epoetin alfa to Aranesp among pediatric CRF patients over 1 year of age showed similar safety and efficacy to the findings from adult conversion studies (see CLINICAL PHARMACOLOGY and CLINICAL STUDIES ). Safety and efficacy in the initial treatment of anemic pediatric CRF patients or in the conversion from another erythropoietin to Aranesp in pediatric CRF patients less than 1 year of age have not been established.

The safety and efficacy of Aranesp in pediatric cancer patients have not been established.

Of the 1801 CRF patients in clinical studies of Aranesp, 44% were age 65 and over, while 17% were age 75 and over. Of the 873 cancer patients in clinical studies receiving Aranesp and concomitant chemotherapy, 45% were age 65 and over, while 14% were age 75 and over. No overall differences in safety or efficacy were observed between older and younger patients.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Aranesp cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving Aranesp (see WARNINGS: Pure Red Cell Aplasia ) during post-marketing experience.

In clinical studies, the percentage of patients with antibodies to Aranesp was examined using the BIAcore assay. Sera from 1501 CRF patients and 1159 cancer patients were tested. At baseline, prior to Aranesp treatment, binding antibodies were detected in 59 (4%) of CRF patients and 36 (3%) of cancer patients. While receiving Aranesp therapy (range 22-177 weeks), a follow-up sample was taken. One additional CRF patient and eight 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 across products within this class (erythropoietic proteins) may be misleading.

In all studies, the most frequently reported serious adverse events with Aranesp were infection, congestive heart failure, angina pectoris/cardiac chest pain, thrombosis vascular access, and cardiac arrhythmia/cardiac arrest. The most frequently reported adverse events resulting in clinical intervention (e.g., discontinuation of Aranesp, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were infection, hypertension, hypotension, and muscle spasm. See WARNINGS : Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke and Hypertension

The data described below reflect exposure to Aranesp in 1801 CRF patients, including 675 exposed for at least 6 months, of whom 185 were exposed for greater than 1 year. Aranesp was eva luated in active-controlled (n = 823) and uncontrolled studies (n = 978). These data include a pooled analysis of CRF patients not on dialysis and dialysis patients who were studied for the correction of anemia and maintenance of hemoglobin.

The population encompassed an age range from 18 to 94 years. Fifty-five percent of the patients were male. The percentages of Caucasian, Black, Asian, and Hispanic patients were 80%, 13%, 3%, and 2%, respectively. The median weekly dose of Aranesp for patients who received either once weekly or once every 2 week administration was 0.44 mcg/kg (25th, 75th percentiles: 0.30, 0.64 mcg/kg).

Some of the adverse events reported are typically associated with CRF, or recognized complications of dialysis, and may not necessarily be attributable to Aranesp therapy. No important differences in adverse event rates between treatment groups were observed in controlled studies in which patients received Aranesp or other recombinant erythropoietins.

The data in Table 2 reflect those adverse events occurring in at least 5% of patients treated with Aranesp.

The incidence rates for other clinically significant events are shown in Table 3.

In Study N7, Aranesp was administered to 81 pediatric CRF patients who had stable hemoglobin concentrations while previously receiving Epoetin alfa (see CLINICAL STUDIES ). In this study, the most frequently reported serious adverse events with Aranesp were catheter sepsis, fever, catheter related infection, chronic renal failure, and vascular access complication. The most commonly reported adverse events were fever, headache, nasopharyngitis, hypertension, hypotension, injection site pain, cough, peritonitis, and vomiting. Aranesp administration was discontinued because of injection site pain in two patients and moderate hypertension in a third patient.

Studies have not eva luated the effects of Aranesp when administered to pediatric patients as the initial treatment for the anemia associated with CRF.

Vascular access thrombosis in hemodialysis patients occurred in clinical trials at an annualized rate of 0.22 events per patient year of Aranesp therapy. Rates of thrombotic events (e.g., vascular access thrombosis, venous thrombosis, and pulmonary emboli) with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these trials; the median duration of exposure was 12 weeks.

The incidence data described below reflect the exposure to Aranesp in 873 cancer patients including patients exposed to Aranesp once weekly (547, 63%), once every 2 weeks (128, 16%), and once every 3 weeks (198, 23%). Aranesp was eva luated in seven studies that were active-controlled and/or placebo-controlled studies of up to 6 months duration. The Aranesp-treated patient demographics were as follows: median age of 63 years (range of 20 to 91 years); 40% male; 88% Caucasian, 5% Hispanic, 4% Black, and 3% Asian. Over 90% of patients had locally advanced or metastatic cancer, with the remainder having early stage disease. Patients with solid tumors (e.g., lung, breast, colon, ovarian cancers) and lymphoproliferative malignancies (e.g., lymphoma, multiple myeloma) were enrolled in the clinical studies. All of the 873 Aranesp-treated subjects also received concomitant cyclic chemotherapy.

The most frequently reported serious adverse events included death (10%), fever (4%), pneumonia (3%), dehydration (3%), vomiting (2%), and dyspnea (2%). The most commonly reported adverse events were fatigue, edema, nausea, vomiting, diarrhea, fever, and dyspnea (see Table 4 ). Except for those events listed in Tables 4 and 5, the incidence of adverse events in clinical studies occurred at a similar rate compared with patients who received placebo and were generally consistent with the underlying disease and its treatment with chemotherapy. The most frequently reported reasons for discontinuation of Aranesp were progressive disease, death, discontinuation of the chemotherapy, asthenia, dyspnea, pneumonia, and gastrointestinal hemorrhage. No important differences in adverse event rates between treatment groups were observed in controlled studies in which patients received Aranesp or other recombinant erythropoietins.

In a randomized controlled trial of Aranesp 500 mcg once every 3 weeks (n = 353) and Aranesp 2.25 mcg/kg once weekly (n = 352), the incidences of all adverse events and of serious adverse events were similar between the two groups.

Overall, the incidence of thrombotic events was 6.2% for Aranesp and 4.1% for placebo. However, the following events were reported more frequently in Aranesp-treated patients than in placebo controls: pulmonary embolism, thromboembolism, thrombosis, and thrombophlebitis (deep and/or superficial). In addition, edema of any type was more frequently reported in Aranesp-treated patients (21%) than in patients who received placebo (10%).

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
• Last Updated: 2nd of March 2011