General

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.

Immunogenicity

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.

Chronic Renal Failure Patients

Adult Patients

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: Increase Mortality, Serious Cardiovascular and Thromboembolic Events 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 evaluated 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®.

Table 2. Adverse Events Occurring in ≥ 5% of CRF Patients

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

Table 3. Percent Incidence of Other Clinically Significant Events in CRF Patients

Pediatric Patients

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 evaluated the effects of Aranesp® when administered to pediatric patients as the initial treatment for the anemia associated with CRF.

Thrombotic Events

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.

Cancer Patients Receiving Chemotherapy

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 evaluated 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.

Table 4. Adverse Events Occurring in ≥ 5% of Patients Receiving Chemotherapy

Table 5. Incidence of Other Clinically Significant Adverse Events in Patients Receiving Chemotherapy

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.

Thrombotic and Cardiovascular Events

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%).

No formal drug interaction studies of Aranesp® have been performed.

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