NESP Adverse Reactions

Adverse Events in CRF Patients: Data from Clinical Studies: Darbepoetin alfa was well tolerated in clinical studies involving 1578 patients, with an exposure of 942 patient years. The adverse events reported are typical sequelae of CRF and are not necessarily attributable to darbepoetin alfa therapy. The adverse events reported in ≥5% of patients treated with darbepoetin alfa compared with r-HuEPO are shown in Table 9. Adverse events reported in <5% of patients treated with darbepoetin alfa that are considered to be of interest are shown in Table 10. The incidence of deaths was 7% in the darbepoetin alfa-treated patients and 6% in the r-HuEPO-treated patients.
The data described in Table 11 reflect exposure to darbepoetin alfa and placebo in 4,023 patients who received at least one dose of investigational product from the TREAT study; a randomised placebo controlled clinical study in adult CRF patients not on dialysis with type 2 diabetes (see PRECAUTIONS). (See Tables 9 and 10.)

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Treatment-related events were defined as those occurring in >0.5% of patients treated with darbepoetin alfa (n=1598) and / or occurring in ≥0.2% compared to r-HuEPO (n=600).
Subject incidence: 1 to 10%: Hypertension, injection site pain, headache, thrombosis vascular access.
<1%: Fatigue, anaemia, pruritus, dizziness, hypotension, nausea, arrhythmia, influenza-like symptoms, somnolence, dyspnoea, chest pain, convulsions, abdominal pain, epistaxis.
Thrombotic Events in CRF Patients: Vascular access thrombosis occurred in CRF clinical studies at an annualised rate of 0.19 events per patient year of darbepoetin alfa therapy and 0.40 events per patient year of r-HuEPO. Rates of thrombotic events (e.g., vascular access thrombosis, venous thrombosis and pulmonary emboli) with darbepoetin alfa therapy were similar to those observed in r-HuEPO therapy in these studies. (See Table 11.)

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Adverse Events in Cancer Patients: Data from Clinical Studies: The darbepoetin alfa clinical program included evaluation of a total of 1087 patients with cancer receiving chemotherapy in double-blind, placebo-controlled or open-label, active-controlled (r-HuEPO) studies of up to 6 months duration. Death, primarily due to disease progression, occurred on study in 9% of darbepoetin alfa, 10% of placebo, and 13% of r-HuEPO subjects. Common adverse events reported by the treating physicians as severe are shown in Table 12. (See Table 12.)

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The data in Table 13 reflect the adverse events reported in at least 5% of cancer patients treated with darbepoetin alfa and receiving concomitant chemotherapy in these controlled studies. In general, adverse experiences reported in clinical trials with darbepoetin alfa in patients with cancer receiving chemotherapy were consistent with the underlying disease and its treatment with chemotherapy. (See Table 13.)

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Clinically significant adverse reactions occurring in <1% of cancer patients treated with darbepoetin alfa include: injection site reaction, headache, myalgia, arthralgia and thromboembolic events.
In clinical trials of darbepoetin alfa (n=873) versus placebo (n=221), one adverse reaction was reported in ≥1% of cancer patients: Injection site pain (darbepoetin alfa 4% versus placebo 3%).
Thrombotic Events in Cancer Patients: In cancer patients, the incidence of thrombotic events was 6% for darbepoetin alfa, 5% for r-HuEPO and 4% for placebo. The following events were reported more frequently in darbepoetin alfa-treated patients than in placebo controls, but at a rate comparable to r-HuEPO: pulmonary embolism, thromboembolism, thrombosis and thrombophlebitis (deep and/or superficial).
Adverse Events in Anaemia with Myelodysplastic Syndrome: Adverse reactions including laboratory data abnormalities were reported in 18 (34.6%) of 52 patients including 31 Japanese patients in the safety analysis set of international joint study (phase 2 study). The major adverse reactions were diarrhoea in 2 cases (3.8%), blood alkaline phosphatase increased in 2 cases (3.8%), hyperuricaemia in 2 cases (3.8%), folate deficiency in 2 cases (3.8%), headache in 2 cases (3.8%) and hypertension in 2 cases (3.8%). [Data at the time of approval of additional indication.]
Adverse Events, All Patients: Post-marketing Experience: Cases of convulsions have been rarely reported in patients with CRF receiving darbepoetin alfa.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Radioimmuno-precipitation (RIP) assays were performed on sera from 1534 CRF patients and 833 cancer patients treated with darbepoetin alfa in clinical studies. Antibodies were not detected in the CRF patients; however reactivity, not considered antibody-related was detected in 3 cancer patients. The patients responded to darbepoetin alfa therapy and there was no evidence of PRCA.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Antibody positivity in an assay may also be influenced by sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to darbepoetin alfa with the incidence of antibodies to other products may be misleading.
Rarely, serious allergic reactions have been reported with darbepoetin alfa (see PRECAUTIONS).
Severe cutaneous reactions including blistering, skin exfoliation, Erythema multiforme and Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) have been reported in patients treated with darbepoetin alfa (see PRECAUTIONS).
Cases of PRCA associated with neutralising antibodies to erythropoietin have been reported in patients receiving NESP (see Pure Red Cell Aplasia under PRECAUTIONS).