"The U.S. Food and Drug Administration is alerting health care providers and patients of a voluntary nationwide recall of all lots of Omontys Injection by Affymax, Inc., of Palo Alto, Calif., and Takeda Pharmaceuticals Company Limited, of Deerfiel"...
Risk in Premature Infants
The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal.
Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke
Patients with chronic renal failure experienced greater risks for death, serious cardiovascular events, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target hemoglobin levels of 13 g/dL and above in clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® (epoetin alfa) and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.
In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).40
In a randomized, double-blind, placebo-controlled study of 4038 patients, there was an increased risk of stroke when darbepoetin alfa was administered to patients with anemia, type 2 diabetes, and CRF who were not on dialysis. Patients were randomized to darbepoetin alfa treatment targeted to a hemoglobin level of 13 g/dL or to placebo. Placebo patients received darbepoetin alfa only if their hemoglobin levels were less than 9 g/dL. A total of 101 patients receiving darbepoetin alfa experienced stroke compared to 53 patients receiving placebo (5% vs. 2.6%; HR 1.92, 95% CI: 1.38, 2.68; p < 0.001).
Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® (epoetin alfa) treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%.37 Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents.
In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST' study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).43
A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST' and ‘ENHANCE' studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.41
An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events). In a randomized controlled study (referred to as the ‘SPINE' study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION).
Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® (epoetin alfa) in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® (epoetin alfa) versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events.42 ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence
Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).
Table 1: Randomized, Controlled Trials with Decreased Survival
and/or Decreased Locoregional Control
|Study/Tumor/(n)||Hemoglobin Target||Achieved Hemoglobin (Median Q1,Q3)||Primary Endpoint||Adverse Outcome for ESA-containing Arm|
|Cancer Study 1 Metastatic breast cancer (n=939)||12-14 g/dL||12.9 g/dL 12.2, 13.3 g/dL||12-month overall survival||Decreased 12-month survival|
|Cancer Study 2 Lymphoid malignancy (n=344)|| 13-15 g/dL (M)
13-14 g/dL (F)
|11.0 g/dL 9.8, 12.1 g/dL||Proportion ofpatients achieving a hemoglobin response||Decreased overall survival|
|Cancer Study 3 Early breast cancer (n=733)||12.5-13 g/dL||13.1 g/dL 12.5, 13.7 g/dL||Relapse-free and overall survival||Decreased 3 yr. relapse-free and overall survival|
|Cancer Study 4 Cervical Cancer (n=114)||12-14 g/dL||12.7 g/dL 12.1, 13.3 g/dL||Progression-freeand overall survivaland locoregionalcontrol||Decreased 3 yr. progression-free and overall survival and locoregional control|
|Cancer Study 5 Head and neck cancer (n=351)|| ≥ 15 g/dL (M)
≥ 14 g/dL (F)
|Not available||Locoregional progression-free survival||Decreased 5-year locoregional progression-free survival Decreased overall survival|
|Cancer Study 6 Head and neckcancer(n=522)||14-15.5 g/dL||Not available||Locoregional disease control||Decreased locoregional disease control|
|No Chemotherapy or Radiotherapy|
|Cancer Study 7 Non-small cell lung cancer (n=70)||12-14 g/dL||Not available||Quality of life||Decreased overall survival|
|Cancer Study 8 Non-myeloid malignancy (n=989)||12-13 g/dL||10.6 g/dL 9.4, 11.8 g/dL||RBC transfusions||Decreased overall survival|
Decreased overall survival
Cancer Study 1 (the ‘BEST' study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).43
Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.
Decreased progression-free survival and overall survival
Cancer Study 3 (the ‘PREPARE' study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfa-treated arm compared to the control arm.
Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).
Cancer Study 5 (the ‘ENHANCE' study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).38
Decreased locoregional control
Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
ESA APPRISE Oncology Program
Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense PROCRIT® (epoetin alfa) to patients with cancer. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prescribers and patients must provide written acknowledgement of a discussion of the risks associated with PROCRIT® (epoetin alfa) .
Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT® (epoetin alfa) . This has been reported predominantly in patients with CRF receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon and ribavirin. Any patient who develops a sudden loss of response to PROCRIT® (epoetin alfa) , accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® (epoetin alfa) and other ESAs. Contact CENTOCOR ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies. PROCRIT® (epoetin alfa) should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other ESAs as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).
PROCRIT® (epoetin alfa) contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Chronic Renal Failure Patients
Hypertension: Patients with uncontrolled hypertension should not be treated with PROCRIT® (epoetin alfa) ; blood pressure should be controlled adequately before initiation of therapy. Although there do not appear to be any direct pressor effects of PROCRIT® (epoetin alfa) , blood pressure may rise during PROCRIT® (epoetin alfa) therapy. During the early phase of treatment when the hematocrit is increasing, approximately 25% of patients on dialysis may require initiation of, or increases in, antihypertensive therapy. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with PROCRIT® (epoetin alfa) .
Special care should be taken to closely monitor and aggressively control blood pressure in patients treated with PROCRIT® (epoetin alfa) . Patients should be advised as to the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control by initiation of appropriate measures, the hemoglobin may be reduced by decreasing or withholding the dose of PROCRIT® (epoetin alfa) . A clinically significant decrease in hemoglobin may not be observed for several weeks.
It is recommended that the dose of PROCRIT® (epoetin alfa) be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period, because of the possible association of excessive rate of rise of hemoglobin with an exacerbation of hypertension. In CRF patients on hemodialysis with clinically evident ischemic heart disease or congestive heart failure, the dose of PROCRIT® (epoetin alfa) should be carefully adjusted to achieve and maintain hemoglobin levels between 10-12 g/dL (see WARNINGS: Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke, and DOSAGE AND ADMINISTRATION: Chronic Renal Failure Patients).
Seizures: Seizures have occurred in patients with CRF participating in PROCRIT® (epoetin alfa) clinical trials.
In adult patients on dialysis, there was a higher incidence of seizures during the first 90 days of therapy (occurring in approximately 2.5% of patients) as compared with later timepoints.
Given the potential for an increased risk of seizures during the first 90 days of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Patients should be cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery during this period.
While the relationship between seizures and the rate of rise of hemoglobin is uncertain, it is recommended that the dose of PROCRIT® (epoetin alfa) be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period.
Thrombotic Events: During hemodialysis, patients treated with PROCRIT® (epoetin alfa) may require increased anticoagulation with heparin to prevent clotting of the artificial kidney (see ADVERSE REACTIONS for more information about thrombotic events).
Other thrombotic events (eg, myocardial infarction, cerebrovascular accident, transient ischemic attack) have occurred in clinical trials at an annualized rate of less than 0.04 events per patient year of PROCRIT® (epoetin alfa) therapy. These trials were conducted in adult patients with CRF (whether on dialysis or not) in whom the target hematocrit was 32% to 40%. However, the risk of thrombotic events, including vascular access thrombosis, was significantly increased in adult patients with ischemic heart disease or congestive heart failure receiving PROCRIT® (epoetin alfa) therapy with the goal of reaching a normal hematocrit (42%) as compared to a target hematocrit of 30%. Patients with pre-existing cardiovascular disease should be monitored closely.
Zidovudine-treated HIV-infected Patients
In contrast to CRF patients, PROCRIT® (epoetin alfa) therapy has not been linked to exacerbation of hypertension, seizures, and thrombotic events in HIV-infected patients. However, the clinical data do not rule out an increased risk for serious cardiovascular events.
The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® (epoetin alfa) therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information regarding allergic reactions).
The safety and efficacy of PROCRIT® (epoetin alfa) therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).
In some female patients, menses have resumed following PROCRIT® (epoetin alfa) therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.
Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT® (epoetin alfa) . However, PROCRIT® (epoetin alfa) has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® (epoetin alfa) should be used with caution in patients with known porphyria.
In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® (epoetin alfa) therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® (epoetin alfa) for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT® (epoetin alfa) .
Hemoglobin in CRF patients should be measured twice a week; zidovudine-treated HIV-infected and cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.
Lack or Loss of Response
If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated:
- Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see Iron Evaluation).
- Underlying infectious, inflammatory, or malignant processes.
- Occult blood loss.
- Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders).
- Vitamin deficiencies: Folic acid or vitamin B12.
- Aluminum intoxication.
- Osteitis fibrosa cystica.
- Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia).
See DOSAGE AND ADMINISTRATION: Chronic Renal Failure Patients for management of patients with an insufficient hemoglobin response to PROCRIT® (epoetin alfa) therapy.
During PROCRIT® (epoetin alfa) therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL.
Prior to and during PROCRIT® (epoetin alfa) therapy, the patient's iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT® (epoetin alfa) . All surgery patients being treated with PROCRIT® (epoetin alfa) should receive adequate iron supplementation throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenic potential of PROCRIT® (epoetin alfa) has not been evaluated. PROCRIT® (epoetin alfa) does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT® (epoetin alfa) , there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.
Pregnancy Category C
PROCRIT® (epoetin alfa) has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® (epoetin alfa) should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® (epoetin alfa) has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).
Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® (epoetin alfa) during gestation and lactation revealed no effect of PROCRIT® (epoetin alfa) at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT® (epoetin alfa) -related effects on the F2 generation fetuses.
It is not known whether PROCRIT® (epoetin alfa) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® (epoetin alfa) is administered to a nursing woman.
See WARNINGS: Pediatrics.
Pediatric Patients on Dialysis: PROCRIT® (epoetin alfa) is indicated in infants (1 month to 2 years), children (2 years to 12 years), and adolescents (12 years to 16 years) for the treatment of anemia associated with CRF requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established (see Clinical Experience: Chronic Renal Failure, Pediatric Patients On Dialysis). The safety data from these studies show that there is no increased risk to pediatric CRF patients on dialysis when compared to the safety profile of PROCRIT (epoetin alfa) ® in adult CRF patients (see ADVERSE REACTIONS and WARNINGS). Published literature27-30 provides supportive evidence of the safety and effectiveness of PROCRIT® (epoetin alfa) in pediatric CRF patients on dialysis.
Pediatric Patients Not Requiring Dialysis: Published literature30,31 has reported the use of PROCRIT® (epoetin alfa) in 133 pediatric patients with anemia associated with CRF not requiring dialysis, ages 3 months to 20 years‚ treated with 50 to 250 Units/kg SC or IV‚ QW to TIW. Dose-dependent increases in hemoglobin and hematocrit were observed with reductions in transfusion requirements.
Pediatric HIV-infected Patients: Published literature32,33 has reported the use of PROCRIT® (epoetin alfa) in 20 zidovudine-treated anemic HIV-infected pediatric patients ages 8 months to 17 years‚ treated with 50 to 400 Units/kg SC or IV‚ 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts‚ and decreases in or elimination of blood transfusions were observed.
Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® (epoetin alfa) were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see Clinical Experience, Weekly (QW) Dosing, Pediatric Patients).
Among 1051 patients enrolled in the 5 clinical trials of PROCRIT® (epoetin alfa) for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received PROCRIT® (epoetin alfa) and 306 received placebo. Of the 745 patients who received PROCRIT® (epoetin alfa) , 432 (58%) were aged 65 and over, while 175 (23%) were 75 and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for PROCRIT® (epoetin alfa) in geriatric and younger patients within the 4 trials using the TIW schedule were similar. Insufficient numbers of patients were enrolled in the study using the weekly dosing regimen to determine whether the dosing requirements differ for this schedule.
Of the 882 patients enrolled in the 3 studies of chronic renal failure patients on dialysis, 757 received PROCRIT® (epoetin alfa) and 125 received placebo. Of the 757 patients who received PROCRIT® (epoetin alfa) , 361 (47%) were aged 65 and over, while 100 (13%) were 75 and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hematocrit (See DOSAGE AND ADMINISTRATION).
Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® (epoetin alfa) for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.
Chronic Renal Failure Patients
Patients with CRF Not Requiring Dialysis
Blood pressure and hemoglobin should be monitored no less frequently than for patients maintained on dialysis. Renal function and fluid and electrolyte balance should be closely monitored.
Sufficient time should be allowed to determine a patient's responsiveness to a dosage of PROCRIT® (epoetin alfa) before adjusting the dose. Because of the time required for erythropoiesis and the red cell half-life, an interval of 2 to 6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontinuation) and a significant change in hemoglobin.
For patients who respond to PROCRIT® (epoetin alfa) with a rapid increase in hemoglobin (eg, more than 1 g/dL in any 2-week period), the dose of PROCRIT® (epoetin alfa) should be reduced because of the possible association of excessive rate of rise of hemoglobin with an exacerbation of hypertension.
The elevated bleeding time characteristic of CRF decreases toward normal after correction of anemia in adult patients treated with PROCRIT® (epoetin alfa) . Reduction of bleeding time also occurs after correction of anemia by transfusion.
The hemoglobin should be determined twice a week until it has stabilized in the suggested hemoglobin range and the maintenance dose has been established. After any dose adjustment, the hemoglobin should also be determined twice weekly for at least 2 to 6 weeks until it has been determined that the hemoglobin has stabilized in response to the dose change. The hemoglobin should then be monitored at regular intervals.
A complete blood count with differential and platelet count should be performed regularly. During clinical trials, modest increases were seen in platelets and white blood cell counts. While these changes were statistically significant, they were not clinically significant and the values remained within normal ranges.
In patients with CRF, serum chemistry values (including blood urea nitrogen [BUN], uric acid, creatinine, phosphorus, and potassium) should be monitored regularly. During clinical trials in adult patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. In some adult patients with CRF not on dialysis treated with PROCRIT® (epoetin alfa) , modest increases in serum uric acid and phosphorus were observed. While changes were statistically significant, the values remained within the ranges normally seen in patients with CRF.
The importance of compliance with dietary and dialysis prescriptions should be reinforced. In particular, hyperkalemia is not uncommon in patients with CRF. In US studies in patients on dialysis, hyperkalemia has occurred at an annualized rate of approximately 0.11 episodes per patient-year of PROCRIT® (epoetin alfa) therapy, often in association with poor compliance to medication, diet, and/or dialysis.
Therapy with PROCRIT® (epoetin alfa) results in an increase in hematocrit and a decrease in plasma volume which could affect dialysis efficiency. In studies to date, the resulting increase in hematocrit did not appear to adversely affect dialyzer function8,9 or the efficiency of high flux hemodialysis.10 During hemodialysis, patients treated with PROCRIT® (epoetin alfa) may require increased anticoagulation with heparin to prevent clotting of the artificial kidney.
Patients who are marginally dialyzed may require adjustments in their dialysis prescription. As with all patients on dialysis, the serum chemistry values (including BUN, creatinine, phosphorus, and potassium) in patients treated with PROCRIT® (epoetin alfa) should be monitored regularly to assure the adequacy of the dialysis prescription.
In adult patients with CRF not on dialysis, renal function and fluid and electrolyte balance should be closely monitored. In patients with CRF not on dialysis, placebo-controlled studies of progression of renal dysfunction over periods of greater than 1 year have not been completed. In shorter term trials in adult patients with CRF not on dialysis, changes in creatinine and creatinine clearance were not significantly different in patients treated with PROCRIT® (epoetin alfa) compared with placebo-treated patients. Analysis of the slope of 1/serum creatinine versus time plots in these patients indicates no significant change in the slope after the initiation of PROCRIT® (epoetin alfa) therapy.
Zidovudine-treated HIV-infected Patients
Exacerbation of hypertension has not been observed in zidovudine-treated HIV-infected patients treated with PROCRIT® (epoetin alfa) . However, PROCRIT® (epoetin alfa) should be withheld in these patients if pre-existing hypertension is uncontrolled, and should not be started until blood pressure is controlled. In double-blind studies, a single seizure has been experienced by a patient treated with PROCRIT® (epoetin alfa) .23
Cancer Patients on Chemotherapy
Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT® (epoetin alfa) . Nevertheless, blood pressure in patients treated with PROCRIT® (epoetin alfa) should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.
In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® (epoetin alfa) TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® (epoetin alfa) TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® (epoetin alfa) also had underlying CNS pathology which may have been related to seizure activity.
In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT® (epoetin alfa) , 1.2% (n = 2/168) of safety-evaluable patients treated with PROCRIT® (epoetin alfa) and 1% (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly PROCRIT® (epoetin alfa) occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology.
In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® (epoetin alfa) TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, and Stroke).
In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT® (epoetin alfa) , 6.0% (n = 10/168) of safety-evaluable patients treated with PROCRIT® (epoetin alfa) and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study.
The safety and efficacy of PROCRIT® (epoetin alfa) were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® (epoetin alfa) on the incidence of thrombotic events could not be performed. In the PROCRIT® (epoetin alfa) arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.
Blood pressure may rise in the perioperative period in patients being treated with PROCRIT® (epoetin alfa) . Therefore, blood pressure should be monitored carefully.
8. Paganini E, Garcia J, Ellis P, et al. Clinical Sequelae of Correction of Anemia with Recombinant Human Erythropoietin (r-HuEPO); Urea Kinetics, Dialyzer Function and Reuse. Am J Kid Dis. 1988;11:16.
9. Delano BG, Lundin AP, Golansky R, et al. Dialyzer Urea and Creatinine Clearances Not Significantly Changed in r-HuEPO Treated Maintenance Hemodialysis (MD) Patients. Kidney Intl. 1988;33:219.
10. Stivelman J, Van Wyck D, Ogden D. Use of Recombinant Erythropoietin (r-HuEPO) with High Flux Dialysis (HFD) Does Not Worsen Azotemia or Shorten Access Survival. Kidney Intl. 1988;33:239.
23. Ortho Biologics, Inc., data on file.
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28. Montini G, Zacchello G, Baraldi E, et al. Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodialysis. J Pediatr. 1990;117:556-560.
29. Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J, Scigalla P. One year's experience with recombinant erythropoietin in children undergoing continuous ambulatory or cycling peritoneal dialysis. Pediatr Nephrol. 1990;4:498-500.
30. Muller-Wiefel DE, Scigalla P. Specific problems of renal anemia in childhood. Contrib Nephrol. 1988;66:71-84.
31. Scharer K, Klare B, Dressel P, Gretz N. Treatment of renal anemia by subcutaneous erythropoietin in children with preterminal chronic renal failure. Acta Paediatr. 1993;82:953-958.
32. Mueller BU, Jacobsen RN, Jarosinski P, et al. Erythropoietin for zidovudine-associated anemia in children with HIV infection. Pediatr AIDS and HIV Infect: Fetus to Adolesc. 1994;5:169-173.
33. Zuccotti GV, Plebani A, Biasucci G, et al. Granulocyte-colony stimulating factor and erythropoietin therapy in children with human immunodeficiency virus infection. J Int Med Res. 1996;24:115-121.
37. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. NEJM. 1998;339:584-90.
38. Henke, M, Laszig, R, Rübe, C., et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. The Lancet. 2003;362:1255-1260.
40. Singh AK, Szczech L, Tang KL, et al. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease, N Engl j Med. 2006; 355:2085-98.
41. Bohlius J, Wilson J, Seidenfeld J, et at. Recombinant Human Erythropoietins and Cancer Patients: Updated Meta-Analysis of 57 Studies Including 9353 Patients. J Natl Cancer Inst. 2006; 98:708-14.
42. D'Ambra MN, Gray RJ, Hillman R, et al. Effect of Recombinant Human Erythropoietin on Transfusion Risk in Coronary Bypass Patients. Ann Thorac Surg. 1997; 64: 1686-93.
43. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study. JCO. 2005; 23(25): 1-13.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/20/2012
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