DESCRIPTION

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 5N‑linked oligosaccharide chains, whereas recombinant human erythropoietin contains3 chains.1 The twoadditional 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 from30,000 to 37,000daltons. 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 500mcg of Aranesp®.

Single-dose prefilled syringes and prefilled SureClick™ autoinjectors are available containing 25, 40, 60, 100, 150, 200, 300, or 500mcg 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:

CLINICAL PHARMACOLOGY

Aranesp® stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Aprimary 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.

CLINICAL STUDIES

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 threestudies (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 twoopen-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. StudyN1 eva luated CRF patients receiving dialysis; StudyN2 eva luated patients not requiring dialysis. In both studies, the starting dose of Aranesp® was 0.45mcg/kg administered once weekly. The starting dose of Epoetin alfa was 50Units/kg 3 times weekly in StudyN1 and 50Units/kg twice weekly in StudyN2. When necessary, dosage adjustments were instituted to maintain hemoglobin in the study target range of 11to 13g/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 1g/dL increase in hemoglobin concentration to a level of at least 11g/dL by 20 weeks (StudyN1) or 24 weeks (StudyN2). The studies were designed to assess the safety and effectiveness of Aranesp® but not to support conclusions regarding comparisons between the two products.

In StudyN1, the hemoglobin target was achieved by 72% (95%CI: 62%, 81%) of the 90patients treated with Aranesp® and 84% (95%CI: 66%, 95%) of the 31patients treated with Epoetin alfa. The mean increase in hemoglobin over the initial 4weeks of Aranesp® treatment was 1.1g/dL (95%CI: 0.82g/dL, 1.37g/dL).

In Study N2, the primary efficacy endpoint was achieved by 93% (95%CI: 87%, 97%) of the 129patients treated with Aranesp® and 92% (95%CI: 78%, 98%) of the 37patients treated with Epoetin alfa. The mean increase in hemoglobin from baseline through the initial 4weeks of Aranesp® treatment was 1.38g/dL (95%CI: 1.21g/dL, 1.55g/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 9to 13g/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.

StudyN5 was a double-blind study conducted in North America, in which 169hemodialysis patients were randomized to treatment with Aranesp® and 338patients continued on Epoetin alfa. StudyN6 was an open-label study conducted in Europe and Australia in which 347patients were randomized to treatment with Aranesp® and 175patients were randomized to continue on Epoetin alfa or Epoetin beta. Of the 347patients randomized to Aranesp®, 92% were receiving hemodialysis and 8%were receiving peritoneal dialysis.

In StudyN5, a median weekly dose of 0.53mcg/kg Aranesp® (25th, 75thpercentiles: 0.30, 0.93mcg/kg) was required to maintain hemoglobin in the study target range. In StudyN6, a median weekly dose of 0.41mcg/kg Aranesp® (25th, 75thpercentiles: 0.26, 0.65mcg/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 1g/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 2g/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 Aranesp® at 500 mcg once every 3 weeks (n = 353) or 2.25mcg/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-Meierestimates 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).

INDICATIONS AND USAGE

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 not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
• Aranesp® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of Aranesp® on progression-free and overall survival(see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).
• Aranesp® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

CONTRIANDICATIONS

Aranesp® is contraindicated in patients with:

• uncontrolled hypertension
• known hypersensitivity to the active substance or any of the excipients

WARNINGS

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].2

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±1g/dL or 10±1g/dL.3 Higher mortality (35% vs. 29%) was observed in the 634patients randomized to a target hemoglobin of 14g/dL than in the 631patients assigned a target hemoglobin of 10g/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 14g/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).4

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.5

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.

Aranesp® is 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).