Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis.

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.

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.

•       In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.

•       As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Evaluate the iron status in all patients before and during treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy.  

Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Aranesp. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.

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.

Aranesp is administered less frequently than epoetin alfa.

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).

*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.

Refer to Table 1. The dose conversion depicted in Table 1 does not accurately estimate the once monthly dose of Aranesp.

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.

The recommended starting dose and schedules are:

Self-Administration of the Prefilled Syringe

The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 3.

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 3), 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.

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.

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.

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).

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. 129 days; HR 1.84; p = 0.04).

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. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).

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. At the time of clinical data cutoff, the median progression-free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), 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%). At the final analysis, 1653 deaths were reported (79.8% of subjects in the epoetin alfa plus SOC group and 77.8% of subjects in the SOC group). Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).

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. 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 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. 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 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. 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).

In a randomized, double-blind, placebo-controlled study to demonstrate non-inferiority of overall survival for Aranesp compared to placebo in patients with anemia receiving chemotherapy for the treatment of advanced stage non-small cell lung cancer (NSCLC), a total of 2549 adult patients who were expected to receive ≥ 2 cycles of myelosuppressive chemotherapy and with a hemoglobin (Hb) ≤ 11.0 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. The median OS for Aranesp versus placebo was 9.5 and 9.3 months, respectively (stratified hazard ratio 0.92; 95% CI: 0.84–1.01). The median PFS was 4.4 and 4.2 months, respectively (stratified hazard ratio 0.96; 95% CI: 0.87–1.05). Aranesp did not demonstrate superiority to placebo for OS or PFS. 

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.

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.

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.

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.

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.

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.

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.

Table 5 lists adverse reactions occurring in ≥ 5% of patients treated with Aranesp.

Rates of adverse reactions with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these studies.

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).

* “Cerebrovascular disorders” encompasses central nervous system (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.

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.

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

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.

Consider the benefits and risks of Aranesp for the mother and possible risks to the fetus when prescribing Aranesp to a pregnant woman.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

When Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days 6 to 15) and rabbits (gestational days 6 to 18), 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 rat and rabbit mothers received doses of 1 mcg/kg or more, causing exaggerated pharmacological effects in both the rat and rabbit dams. This dose of 1 mcg/kg is near the clinical recommended starting dose. While no adverse effects on uterine implantation occurred in animals, in a rat fertility study, there was an increase in early post-implantation loss at doses equal to or greater than 0.5 mcg/kg, administered 3 times weekly. 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 observed in rats; placental transfer was not evaluated in rabbits.

In a peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation (day 6) throughout pregnancy and lactation (day 23). 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. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Aranesp related effects were apparent for their offspring (F2 generation fetuses).

There is no information regarding the presence of Aranesp in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Aranesp and any potential adverse effects on the breastfed child from Aranesp or from the underlying maternal condition.

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

Aranesp contains darbepoetin alfa, which is not a controlled substance.

In animal studies, darbepoetin alfa did not distribute to the CNS nor produce behavioral effects that are consistent with CNS activity.

Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.

Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with Aranesp.

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

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.

The carcinogenic potential of Aranesp has not been evaluated in long-term animal studies. In toxicity studies of approximately 6 months duration in rats and dogs, no tumorigenic or unexpected mitogenic responses were observed in any tissue type.

Aranesp increased the incidence of post-implantation losses in rats. Male and female rats received intravenous doses prior to and during mating; then females were treated 3 times weekly during the first trimester of gestation (gestation days 1, 3, 5, and 7). No effect on reproductive performance, fertility, or sperm assessment parameters were detected at any of the doses evaluated (up to 10 mcg/kg, administered 3 times weekly). The dose of 10 mcg/kg is more than 10-fold higher than the clinical recommended starting dose. An increase in post-implantation fetal loss was seen at doses equal to or greater than 0.5 mcg/kg, administered 3 times weekly. The dose of 0.5 mcg/kg is approximately equivalent to the clinical recommended starting dose. Signs of exaggerated pharmacology were not observed in the mother receiving 0.5 mcg/kg or less, but were observed at 2.5 mcg/kg and higher.

In early clinical studies conducted in patients with CKD 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).

Aranesp use has not been demonstrated in controlled clinical trials to improve quality of life, fatigue, or patient well-being.

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 patients with CKD 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.

Study N8 was a double-blind, randomized, controlled study in 114 pediatric patients from 1 to 18 years of age receiving darbepoetin alfa. In this study, pediatric patients with CKD receiving or not receiving dialysis who were anemic (hemoglobin [Hb] < 10.0 g/dL) and not being treated with an erythropoiesis stimulating agent (ESA) received darbepoetin alfa weekly or once every 2 weeks for the correction of anemia. 

The primary efficacy endpoint was proportion of patients having hemoglobin corrected to ≥ 10.0 g/dL at any time point after the first dose without receiving any red blood cell transfusions after randomization and within 90 days prior to the Hb measurement.  For pediatric patients receiving QW dosing, 98% (95% CI: 91%-100%), had hemoglobin concentrations corrected to ≥ 10 g/dL. For those receiving Q2W dosing, 84% (95% CI: 72%-92%), had hemoglobin concentrations corrected to ≥ 10 g/dL. The study was designed to assess the safety and effectiveness of Aranesp but not to support conclusions regarding comparisons between the 2 regimens.

Conversion from Other Recombinant Erythropoietins

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 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). 

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 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).