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Warning & Precautions

WARNINGS

Pediatrics

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.

Adults

Increased Mortality, Serious Cardiovascular and Thromboembolic Events

Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two 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. EPOETIN® 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 Erythropoietin (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

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 EPOETIN® 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 Erythropoietin 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 Erythropoietin. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Erythropoietin 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 3 - 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 Erythropoietin 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 Erythropoietin (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 Erythropoietin group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Erythropoietin 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 EPOETIN® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to EPOETIN® 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 Tumor Progression

Erythropoiesis-stimulating agents, when administered to target a hemoglobin of > 12 g/dL, shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy [Cancer Studies 3 and 4 (DAHANCA 10) in Table 1]. ESAs also shortened survival in patients with metastatic breast cancer (Cancer Study 1) and in patients with lymphoid malignancy (Cancer Study 2) receiving chemotherapy when administered to target a hemoglobin of ≥ 12 g/dL. In addition, ESAs shortened survival in patients with non-small cell lung cancer and in a study enrolling patients with various malignancies who were not receiving chemotherapy or radiotherapy; in these two studies, ESAs were administered to target a hemoglobin of ≥ 12 g/dL (Cancer Studies 5 and 6 in Table 1). Although studies evaluated hemoglobin targets of ≥ 12 g/dL in these tumor types, the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of < 12 g/dL.

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

Chemotherapy

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 of
patients achieving
a hemoglobin response

Decreased overall survival

Radiotherapy Alone

Cancer Study 3
Head and neck cancer (n=351)

> 15 g/dL (M)
> 14 g/dL (F)

Not available

Locoregiona
progression-free
survival

Decreased 5-year locoregional
progression-free survival Decreased overall survival

Cancer Study 4
Head and neck cancer (n=522)

14-15.5 g/dL

Not available

Locoregional
disease control

Decreased locoregional disease control

No Chemotherapy or Radiotherapy

Cancer Study 5
Non-small cell lung cancer(n=70)

12-14 g/dL

Not available

Quality of life

Decreased overall survival

Cancer Study 6
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 and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Erythropoietin arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Erythropoietin 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 Erythropoietin 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 (darbErythropoietin 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 darbErythropoietin as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 5 was a Phase 3, multicenter, randomized (Erythropoietin 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 Erythropoietin 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 6 was a Phase 3, double-blind, randomized (darbErythropoietin 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 darbErythropoietin treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased locoregional progression-free survival and overall survival

Cancer Study 3 (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 4 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbErythropoietin with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbErythropoietin (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbErythropoietin (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

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 EPOETIN®. This has been reported predominantly in patients with CRF receiving EPOETIN® by subcutaneous administration. Any patient who develops a sudden loss of response to EPOETIN®, 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 EPOETIN® and other erythropoietic proteins. Contact Amgen (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies. EPOETIN® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

Albumin (Human)

EPOETIN® 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 EPOETIN®; blood pressure should be controlled adequately before initiation of therapy. Although there do not appear to be any direct pressor effects of EPOETIN®, blood pressure may rise during EPOETIN® 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 EPOETIN®.

Special care should be taken to closely monitor and aggressively control blood pressure in patients treated with EPOETIN®. 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 EPOETIN®. A clinically significant decrease in hemoglobin may not be observed for several weeks.

It is recommended that the dose of EPOETIN® 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 EPOETIN® should be carefully adjusted to achieve and maintain hemoglobin levels between 10-12 g/dL (see WARNINGS: Mortality, Serious Cardiovascular and Thromboembolic Events and DOSAGE AND ADMINISTRATION: Chronic Renal Failure Patients).

Seizures: Seizures have occurred in patients with CRF participating in EPOETIN® 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 EPOETIN® be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period.

Thrombotic Events: During hemodialysis, patients treated with EPOETIN® 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 EPOETIN® 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 EPOETIN® 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, EPOETIN® 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.

 

PRECAUTIONS

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 EPOETIN® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information regarding allergic reactions).

The safety and efficacy of EPOETIN® 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 EPOETIN® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

Hematology

Exacerbation of porphyria has been observed rarely in patients with CRF treated with EPOETIN®. However, EPOETIN® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, EPOETIN® should be used with caution in patients with known porphyria.

In preclinical studies in dogs and rats, but not in monkeys, EPOETIN® 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 EPOETIN® 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 EPOETIN®.

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.

Hemolysis.

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 EPOETIN® therapy.

Iron Evaluation

During EPOETIN® 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 EPOETIN® 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 EPOETIN®. All surgery patients being treated with EPOETIN® 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 EPOETIN® has not been evaluated. EPOETIN® 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 EPOETIN®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C

EPOETIN® 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. EPOETIN® 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

 
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