Increased Mortality, Serious Cardiovascular and Thromboembolic Events

Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two 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

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.³ 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).⁴

A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST' and ‘ENHANCE' studies) evaluating 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.

Increased Mortality and/or Tumor Progression

Erythropoiesis-stimulating agents, when administered to target a hemoglobin of > 12 g/dL, shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy [Cancer Studies 5 and 6 (DAHANCA 10) in Table 1]. ESAs also shortened survival in patients with metastatic breast cancer (Cancer Study 1) and in patients with lymphoid malignancy (Cancer Study 2) receiving chemotherapy when administered to target a hemoglobin of ≥ 12 g/dL. In addition, ESAs shortened survival in patients with non-small cell lung cancer and in a study enrolling patients with various malignancies who were not receiving chemotherapy or radiotherapy; in these two studies, ESAs were administered to target a hemoglobin of ≥ 12 g/dL (Cancer Studies 7 and 8 in Table 1). Although studies evaluated hemoglobin targets of ≥ 12 g/dL in these tumor types, the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of < 12 g/dL.

Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control

Decreased overall survival

Cancer Study 1 (the ‘BEST' study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). 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).⁴

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. An interim analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was 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).

Hypertension

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

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.

Pure Red Cell Aplasia

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 Aranesp® by subcutaneous administration. Any patient who develops a sudden loss of response to Aranesp®, accompanied by severe anemia and low reticulocyte count, should be evaluated 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 erythropoietic proteins. 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 erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

Albumin (Human)

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.

General

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.

Lack or Loss of Response to Aranesp®

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 B12 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 evaluated 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.

Hematology

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).

Allergic Reactions

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 Requiring Dialysis

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.

Patients Transitioning to Dialysis

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).

Dialysis Management

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.

Laboratory Tests

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 evaluated 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%.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity: The carcinogenic potential of Aranesp® has not been evaluated 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 evaluated (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.

Pregnancy Category C

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.

Nursing Mothers

It is not known whether Aranesp® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aranesp® is administered to a nursing woman.

Pediatric Use

Pediatric CRF Patients

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.

Pediatric Cancer Patients

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

Geriatric Use

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.

REFERENCES

2. Singh AK, Szczech L, Tang KL, et al. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease. N Engl J Med. 2006; 355: 2085-98.

3. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998; 339: 584-590.

4. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study. JCO. 2005; 23(25): 1-13.

5. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant Human Erythropoietins and Cancer Patients: Updated Meta-Analysis of 57 Studies Including 9353 Patients. J Natl Cancer Inst. 2006; 98: 708-14.

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