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Procrit

"The U.S. Food and Drug Administration approved a risk management program to inform healthcare providers and their patients about the risks of a class of drugs called Erythropoiesis-Stimulating Agents (ESAs). For patients with cancer, the program "...

Procrit

Side Effects
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SIDE EFFECTS

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 PROCRIT® (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 PROCRIT® (epoetin alfa) , 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 PROCRIT® (epoetin alfa) during the blinded phase were:

Percent of Patients Reporting Event

Event Patients Treated With PROCRIT®
(n = 200)
Placebo-treated Patients
(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 (Administration Site) 7% 12%
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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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, PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) . 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 PROCRIT® (epoetin alfa) (150 Units/kg TIW) relative to the placebo group.

Seizures: There have been 47 seizures in 1010 patients on dialysis treated with PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) , 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 PROCRIT® (epoetin alfa) , 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) therapy. If an anaphylactoid reaction occurs, PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) or placebo-treated patients were:

Percent of Patients Reporting Event

Event Patients Treated With PROCRIT®
(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, PROCRIT® (epoetin alfa) was not associated with significant increases in opportunistic infections or mortality.23 In 71 patients from this group treated with PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) and one was treated with placebo (PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) or placebo-treated patients were as indicated below:

Percent of Patients Reporting Event

Event Patients Treated With PROCRIT®
(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%
* Statistically significant

Although some statistically significant differences between patients being treated with PROCRIT® (epoetin alfa) and placebo-treated patients were noted, the overall safety profile of PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) ) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 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 PROCRIT® (epoetin alfa) 300 U/kg
(n = 112)a
Patients Treated With PROCRIT® (epoetin alfa) 100 U/kg
(n = 101)a
Placebo-treated Patients
(n = 103)a
Patients Treated With PROCRIT® (epoetin alfa) 600 U/kg
(n = 73)b
Patients Treated With PROCRIT® (epoetin alfa) 300 U/kg
(n = 72)b
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%c 0%c
Dyspepsia 9% 11% 6% 7% 8%
Anxiety 7% 2% 11% 11% 4%
Edema 6% 11% 8% 11% 7%
a Study including patients undergoing orthopedic surgery treated with PROCRIT® (epoetin alfa) or placebo for 15 days
b Study including patients undergoing orthopedic surgery treated with PROCRIT® (epoetin alfa) 600 Units/kg weekly x 4 or 300 Units/kg daily x 15
c Determined by clinical symptoms

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 PROCRIT® (epoetin alfa) 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).

Read the Procrit (epoetin alfa) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No evidence of interaction of PROCRIT® (epoetin alfa) with other drugs was observed in the course of clinical trials.

REFERENCES

17. deAndrade JR and Jove M. Baseline Hemoglobin as a Predictor of Risk of Transfusion and Response to Epoetin alfa in Orthopedic Surgery Patients. Am. J. of Orthoped. 1996;25 (8):533-542.

18. Goldberg MA and McCutchen JW. A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin alfa in Patients Undergoing Major Orthopedic Surgery. Am. J. of Orthoped. 1996;25 (8):544-552.

19. Faris PM and Ritter MA. The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopedic Operation. J. Bone and Joint Surgery. 1996;78-A:62-72.

23. Ortho Biologics, Inc., data on file.

25. Fischl M, Galpin JE, Levine JD, et al. Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine. NEJM. 1990;322:1488-1493.

26. Laupacis A. Effectiveness of Perioperative Recombinant Human Erythropoietin in Elective Hip Replacement. Lancet. 1993;341:1228-1232.

34. Raskin NH, Fishman RA. Neurologic Disorders in Renal Failure (First of Two Parts). NEJM. 1976;294:143-148.

35. Raskin NH and Fishman RA. Neurologic Disorders in Renal Failure (Second of Two Parts). NEJM. 1976;294:204-210.

36. Messing RO, Simon RP. Seizures as a Manifestation of Systemic Disease. Neurologic Clinics. 1986;4:563-584.

Read the Procrit Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/20/2012
This monograph has been modified to include the generic and brand name in many instances.

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