Aranesp Side Effects, and Drug Interactions - Darbepoetin Alfa

Aranesp Side Effects, and Drug Interactions - Darbepoetin Alfa

SIDE EFFECTS

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.

In all studies, the most frequently reported serious adverse reactions with Aranesp^® were vascular access thrombosis, congestive heart failure, sepsis, and cardiac arrhythmia. The most commonly reported adverse reactions were infection, hypertension, hypotension, myalgia, headache, and diarrhea, (see WARNINGS: Cardiovascular Events, Hemoglobin, and Rate of Rise of Hemoglobin, and Hypertension). The most frequently reported adverse reactions 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 hypotension, hypertension, fever, myalgia, nausea, and chest pain.

The data described below reflect exposure to Aranesp^® in 1598 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 = 775).

The rates of adverse events and association with Aranesp^® are best assessed in the results from studies in which Aranesp^® was used to stimulate erythropoiesis in patients anemic at study baseline (n = 348), and, in particular, the subset of these patients in randomized controlled trials (n = 276). Because there were no substantive differences in the rates of adverse reactions between these subpopulations, or between these subpopulations and the entire population of patients treated with Aranesp^®, data from all 1598 patients were pooled.

The population encompassed an age range from 18 to 91 years. Fifty-seven percent of the patients were male. The percentages of Caucasian, Black, Asian, and Hispanic patients were 83%, 11%, 3%, and 1%, respectively. The median weekly dose of Aranesp^® was 0.45 mcg/kg (25^th, 75^th percentiles: 0.29, 0.66 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 1 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 2.

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 data described below reflect the exposure to Aranesp^® in 873 cancer patients. 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 3). Except for those events listed in Tables 3 and 4, 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.

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 (21%) patients than in patients who received placebo (10%).

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Aranesp^® has not been adequately determined. Radioimmunoprecipitation assays were performed on sera from 1534 CRF and 833 cancer patients treated with Aranesp^® in clinical studies. High-titer antibodies were not detected in patients with CRF, but assay sensitivity may be inadequate to reliably detect lower titers. Antibodies were detected by radioimmunoprecipitation in sera from three cancer patients; neutralizing activity, possibly related to antibodies, was detected in one of these three patients. There was no evidence of PRCA in that patient (see WARNINGS: Pure Red Cell Aplasia).

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including 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.

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