ADVERSE REACTIONS
Immunogenicity
As with all therapeutic proteins, there is the 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 EPOGEN® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.
There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to EPOGEN®, in controlled clinical trials.
Where reported, 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
In double-blind, placebo-controlled studies involving over 300 patients with CRF, the events reported in greater than 5% of patients treated with EPOGEN® during the blinded phase were:
Percent of Patients Reporting Event | Event | Patients Treated With EPOGEN® | Placebo-treated Patients |
| (n = 200) | (n = 135) |
| Hypertension | 24% | 19% |
| Headache | 16% | 12% |
| Arthralgias | 11% | 6% |
| Nausea | 11% | 9% |
| Edema | 9% | 10% |
| Fatigue | 9% | 14% |
| Diarrhea | 9% | 6% |
| Vomiting | 8% | 5% |
| Chest Pain | 7% | 9% |
| Skin Reaction | 7% | 12% |
| (Administration Site) |
| Asthenia | 7% | 12% |
| Dizziness | 7% | 13% |
| Clotted Access | 7% | 2% |
Significant adverse events of concern in patients with CRF treated in double-blind, placebo-controlled trials occurred in the following percent of patients during the blinded phase of the studies:
| Seizure | 1.1% | 1.1% |
| CVA/TIA | 0.4% | 0.6% |
| MI | 0.4% | 1.1% |
| Death | 0% | 1.7% |
In the US EPOGEN® studies in adult patients on dialysis (over 567 patients), the incidence (number of events per patient-year) of the most frequently reported adverse events were: hypertension (0.75), headache (0.40), tachycardia (0.31), nausea/vomiting (0.26), clotted vascular access (0.25), shortness of breath (0.14), hyperkalemia (0.11), and diarrhea (0.11). Other reported events occurred at a rate of less than 0.10 events per patient per year.
Events reported to have occurred within several hours of administration of EPOGEN® were rare, mild, and transient, and included injection site stinging in dialysis patients and flu-like symptoms such as arthralgias and myalgias.
In all studies analyzed to date, EPOGEN® administration was generally well-tolerated, irrespective of the route of administration.
Pediatric CRF Patients: In pediatric patients with CRF on dialysis, the pattern of most adverse events was similar to that found in adults. Additional adverse events reported during the double-blind phase in >10% of pediatric patients in either treatment group were: abdominal pain, dialysis access complications including access infections and peritonitis in those receiving peritoneal dialysis, fever, upper respiratory infection, cough, pharyngitis, and constipation. The rates are similar between the treatment groups for each event.
Hypertension: Increases in blood pressure have been reported in clinical trials, often during the first 90 days of therapy. On occasion, hypertensive encephalopathy and seizures have been observed in patients with CRF treated with EPOGEN®. When data from all patients in the US phase 3 multicenter trial were analyzed, there was an apparent trend of more reports of hypertensive adverse events in patients on dialysis with a faster rate of rise of hematocrit (greater than 4 hematocrit points in any 2-week period). However, in a double-blind, placebo-controlled trial, hypertensive adverse events were not reported at an increased rate in the group treated with EPOGEN® (150 Units/kg TIW) relative to the placebo group.
Seizures: There have been 47 seizures in 1010 patients on dialysis treated with EPOGEN® in clinical trials, with an exposure of 986 patient-years for a rate of approximately 0.048 events per patient-year. However, there appeared to be a higher rate of seizures during the first 90 days of therapy (occurring in approximately 2.5% of patients) when compared to subsequent 90-day periods. The baseline incidence of seizures in the untreated dialysis population is difficult to determine; it appears to be in the range of 5% to 10% per patient-year.34-36
Thrombotic Events: In clinical trials where the maintenance hematocrit was 35 ± 3% on EPOGEN®, clotting of the vascular access (A-V shunt) has occurred at an annualized rate of about 0.25 events per patient-year, and other thrombotic events (eg, myocardial infarction, cerebral vascular accident, transient ischemic attack, and pulmonary embolism) occurred at a rate of 0.04 events per patient-year. In a separate study of 1111 untreated dialysis patients, clotting of the vascular access occurred at a rate of 0.50 events per patient-year. However, in CRF patients on hemodialysis who also had clinically evident ischemic heart disease or congestive heart failure, the risk of A-V shunt thrombosis was higher (39% vs 29%, p < 0.001), and myocardial infarctions, vascular ischemic events, and venous thrombosis were increased, in patients targeted to a hematocrit of 42 ± 3% compared to those maintained at 30 ± 3% (see WARNINGS).
In patients treated with commercial EPOGEN®, there have been rare reports of serious or unusual thromboembolic events including migratory thrombophlebitis, microvascular thrombosis, pulmonary embolus, and thrombosis of the retinal artery, and temporal and renal veins. A causal relationship has not been established.
Allergic Reactions: There have been no reports of serious allergic reactions or anaphylaxis associated with EPOGEN® administration during clinical trials. Skin rashes and urticaria have been observed rarely and when reported have generally been mild and transient in nature.
There have been rare reports of potentially serious allergic reactions including urticaria with associated respiratory symptoms or circumoral edema, or urticaria alone. Most reactions occurred in situations where a causal relationship could not be established. Symptoms recurred with rechallenge in a few instances, suggesting that allergic reactivity may occasionally be associated with EPOGEN® therapy. If an anaphylactoid reaction occurs, EPOGEN® should be immediately discontinued and appropriate therapy initiated.
Zidovudine-treated HIV-infected Patients
In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse events with an incidence of ≥ 10% in either patients treated with EPOGEN® or placebo-treated patients were:
Percent of Patients Reporting Event | Event | Patients Treated With
EPOGEN®
(n = 144) | Placebo-treated
Patients
(n = 153) |
| | |
| Pyrexia | 38% | 29% |
| Fatigue | 25% | 31% |
| Headache | 19% | 14% |
| Cough | 18% | 14% |
| Diarrhea | 16% | 18% |
| Rash | 16% | 8% |
| Congestion, Respiratory | 15% | 10% |
| Nausea | 15% | 12% |
| Shortness of Breath | 14% | 13% |
| Asthenia | 11% | 14% |
| Skin Reaction, Medication Site | 10% | 7% |
| Dizziness | 9% | 10% |
In the 297 patients studied, EPOGEN® was not associated with significant increases in opportunistic infections or mortality.23 In 71 patients from this group treated with EPOGEN® at 150 Units/kg TIW, serum p24 antigen levels did not appear to increase.25 Preliminary data showed no enhancement of HIV replication in infected cell lines in vitro.23
Peripheral white blood cell and platelet counts are unchanged following EPOGEN® therapy.
Allergic Reactions: Two zidovudine-treated HIV-infected patients had urticarial reactions within 48 hours of their first exposure to study medication. One patient was treated with EPOGEN® and one was treated with placebo (EPOGEN® vehicle alone). Both patients had positive immediate skin tests against their study medication with a negative saline control. The basis for this apparent pre-existing hypersensitivity to components of the EPOGEN® formulation is unknown, but may be related to HIV-induced immunosuppression or prior exposure to blood products.
Seizures: In double-blind and open-label trials of EPOGEN® in zidovudine-treated HIV-infected patients, 10 patients have experienced seizures.23 In general, these seizures appear to be related to underlying pathology such as meningitis or cerebral neoplasms, not EPOGEN® therapy.
Cancer Patients on Chemotherapy
In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with EPOGEN® or placebo-treated patients were as indicated below:
Percent of Patients Reporting Event | Event | Patients Treated With
EPOGEN®
(n=63) | Placebo-treated
Patients
(n = 68) |
| | |
| Pyrexia | 29% | 19% |
| Diarrhea | 21%
| 7% |
| Nausea | 17% | 32% |
| Vomiting | 17% | 15% |
| Edema | 17% | 1% |
| Asthenia | 13% | 16% |
| Fatigue | 13% | 15% |
| Shortness of Breath | 13% | 9% |
| Parasthesia | 11% | 6% |
| Upper Respiratory Infection | 11% | 4% |
| Dizziness | 5% | 12% |
| Trunk Pain | 3% | 16% |
Although some statistically significant differences between patients being treated with EPOGEN® and placebo-treated patients were noted, the overall safety profile of EPOGEN® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to EPOGEN®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of EPOGEN® was consistent with the progression of advanced cancer.
Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with EPOGEN® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms.
Surgery Patients
Adverse events with an incidence of ≥ 10% are shown in the following table:
Percent of Patients Reporting Event | Event | Patients Treated With
EPOGEN®
300 U/kg
(n = 112)
| Patients Treated With
EPOGEN®
100 U/kg
(n = 101) | Placebo-treated Patients
(n = 103) | Patients Treated With
EPOGEN®
600 U/kg
(n = 73)
| Patients Treated With
EPOGEN®
300 U/kg
(n = 72) |
| Pyrexia | 51% | 50% | 60% | 47% | 42% |
| Nausea | 48% | 43% | 45% | 45% | 58% |
| Constipation | 43% | 42% | 43% | 51% | 53% |
| Skin Reaction, Medication Site | 25% | 19% | 22% | 26% | 29% |
| Vomiting | 22% | 12% | 14% | 21% | 29% |
| Skin Pain | 18% | 18% | 17% | 5% | 4% |
| Pruritus | 16% | 16% | 14% | 14% | 22% |
| Insomnia | 13% | 16% | 13% | 21% | 18% |
| Headache | 13% | 11% | 9% | 10% | 19% |
| Dizziness | 12% | 9% | 12% | 11% | 21% |
| Urinary Tract Infection | 12% | 3% | 11% | 11% | 8% |
| Hypertension | 10% | 11% | 10% | 5% | 10% |
| Diarrhea | 10% | 7% | 12% | 10% | 6% |
| Deep Venous Thrombosis | 10% | 3% | 5% | 0%
| 0% |
| Dyspepsia | 9% | 11% | 6% | 7% | 8% |
| Anxiety | 7% | 2% | 11% | 11% | 4% |
| Edema | 6% | 11% | 8% | 11% | 7% |
Thrombotic/Vascular Events: In three double-blind, placebo-controlled orthopedic surgery studies, the rate of deep venous thrombosis (DVT) was similar among Epoetin alfa and placebo-treated patients in the recommended population of patients with a pretreatment hemoglobin of > 10 g/dL to ≤ 13 g/dL.17,19,26 However, in 2 of 3 orthopedic surgery studies the overall rate (all pretreatment hemoglobin groups combined) of DVTs detected by postoperative ultrasonography and/or surveillance venography was higher in the group treated with Epoetin alfa than in the placebo-treated group (11% vs. 6%). This finding was attributable to the difference in DVT rates observed in the subgroup of patients with pretreatment hemoglobin > 13 g/dL.
In the orthopedic surgery study of patients with pretreatment hemoglobin of > 10 g/dL to ≤ 13 g/dL which compared two dosing regimens (600 Units/kg weekly x 4 and 300 Units/kg daily x 15), 4 subjects in the 600 Units/kg weekly EPOGEN® group (5%) and no subjects in the 300 Units/kg daily group had a thrombotic vascular event during the study period.18
In a study examining the use of Epoetin alfa in 182 patients scheduled for coronary artery bypass graft surgery, 23% of patients treated with Epoetin alfa and 29% treated with placebo experienced thrombotic/vascular events. There were 4 deaths among the Epoetin alfa-treated patients that were associated with a thrombotic/vascular event (see WARNINGS).
|
