Epogen Side Effects

Please note - some side effects for Epogen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Epogen - for the Consumer

Epogen

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Epogen:

Constipation; cough; diarrhea; headache; indigestion; joint or muscle aches; nausea; respiratory congestion; sleeplessness; stinging at the injection site; stomach pain; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); calf pain or tenderness; chest pain; confusion; fever, chills, or sore throat; increased fatigue/weakness; fast or irregular heartbeat; irritation at the injection site; numbness or pain of an arm or leg; numbness or tingling of the skin; one-sided weakness; pale skin color; seizures; severe stomach pain; shortness of breath; sudden severe headache, dizziness, vomiting, or fainting; sudden trouble walking or loss of balance; swelling of the fingers, ankles, or legs; unusual tiredness or weakness; vision or speech problems; weight gain.

Epogen Side Effects - for the Professional

Epogen

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® 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:

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:

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%.

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:

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:

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:

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.

Side Effects by Body System

Immunologic

Immunologic side effects including neutralizing antibodies to erythropoietin, in association with pure red cell aplasia (PRCA) or severe anemia (with or without cytopenias) have been reported.

General

Epoetin alfa generally has been well tolerated. A flu-like syndrome has been reported in 5% of patients receiving intravenous injections of epoetin alfa. This syndrome includes low-grade fever, arthralgias, myalgias, and flank pain. These symptoms may be managed by subcutaneous administration or a slower rate of intravenous administration. Many patients receiving epoetin alfa have serious underlying conditions and it is sometimes difficult to discern true drug toxicity from disease activity.

The most frequently reported adverse effects observed in patients on dialysis were hypertension, headache, tachycardia, nausea and vomiting, clotted vascular access, shortness of breath, hyperkalemia, and diarrhea. In zidovudine treated HIV patients, the incidence of epoetin alfa side effects were not statistically significant from those in the placebo group and were consistent with disease progression. Diarrhea and edema occurred at a statistically significant greater incidence (compared to placebo) in cancer patients on chemotherapy.

Cardiovascular

The development or exacerbation of hypertension in patients with chronic renal failure is of concern. Epoetin alfa associated hypertension does not appear to depend on preexisting hypertension and one study suggests a relationship between new onset hypertension and an hematocrit of less than 20%. The mechanism for development of hypertension has not been established, but may be due to increased blood viscosity as red cell production increases or increased peripheral resistance as the anemia is corrected. Therapeutic endpoints should be approached slowly and preexisting hypertension should be controlled prior to initiating therapy.

Cardiovascular side effects have been reported the most frequently. These have included hypertension, myocardial infarction, and tachycardia. Up to 35% of patients with hypertension due to chronic renal failure may require additional antihypertensive medication or an adjustment of an existing regimen.

Deep vein thrombosis has been reported in at least one patient receiving 20,000 units three times a week.

Increased mortality has been observed in cardiac patients (ischemic heart disease or congestive heart failure) on hemodialysis with a target hematocrit of 42% compared to similar patients with a target hematocrit of 30% (mortality rate 35% and 29%, respectively). The incidence of nonfatal myocardial infarctions, vascular access thrombosis, and all other thrombotic events was also increased in patients randomized to the higher target hematocrit. Maintenance of hematocrit levels between 30% and 36% is recommended.

A significant increase in thrombosis and mortality has been associated with the use of epoetin alfa (compared to placebo) in patients without renal failure undergoing coronary bypass surgery. In patients receiving epoetin who are at risk for thrombosis, the risk versus benefit of therapy should be individually evaluated.

Hematologic

Hematologic side effects have included incidences of vascular access thrombosis. All other thrombotic events were increased in cardiac patients randomized to a target hematocrit (HCT) of 42% compared to a target HCT of 30%. Maintenance of HCT levels between 30% and 36% is recommended.

A significant increase in thrombosis and mortality has been associated with the use of epoetin alfa (compared to placebo) in patients without renal failure undergoing coronary bypass surgery. In patients requiring epoetin who are at risk for thrombosis, the risk versus benefit of therapy should be individually evaluated.

Iron deficiency has occurred in most patients due to incorporation of iron into newly synthesized red blood cells. Supplemental iron may be necessary.

Arteriovenous shunt clotting may occur in hemodialysis patients due to increased blood viscosity and decreased bleeding time, however, the incidence does not appear to be greater than in hemodialysis patients not receiving epoetin alfa. Clotting within the dialyzer has resulted in a 25% increase in heparin anticoagulation requirements during hemodialysis.

Iron stores are readily incorporated into new red blood cells as hemoglobin is produced during the acute phase of drug therapy. Iron deficiency diminishes the therapeutic effect of the drug. Iron replacement is necessary in nearly all patients treated with epoetin alfa, and iron status should be evaluated prior to initiating therapy and at regular intervals. A transferrin saturation of less than 20% or a serum ferritin level of less than 100 mcg/L suggests inadequate iron stores and a need for iron replacement therapy.

Nervous system

Nervous system side effects have included headache (15%) and seizures (to 5%).

Seizures have occurred primarily in the first three months of therapy and may have been associated with a increase in hematocrit or blood pressure. Neurologic monitoring and evaluation during epoetin alfa therapy is recommended in patients with a history of seizure activity. Therapeutic endpoints should be approached slowly to minimize seizure risks.

Psychiatric

Psychiatric side effects have rarely included hallucinations among the dialysis patients treated with epoetin alfa.

Oncologic

Oncologic side effects, particularly with myeloid tumors, may occur due to epoetin alfa's growth factor activity.

Erythropoietin receptors have been found to be present on the surface of some malignant cell lines and tumor biopsy specimens. However, there is insufficient data to establish whether use of epoetin products have an adverse effect on time to tumor progression or progression-free survival.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, and diarrhea, but these have not occurred at an incidence significantly greater than reported in placebo groups amongst patients with chronic renal failure and HIV-infected patients treated with zidovudine. Diarrhea occurred at a statistically significant greater incidence (compared to placebo) in cancer patients on chemotherapy.

Dermatologic

Dermatologic side effects have rarely included mild and transient skin rashes and urticaria.

Local

Local side effects of epoetin alfa have included pain at the injection site.

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