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Epogen (Epoetin Alfa) - Warnings and Precautions

 
 



WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE

Renal failure: Patients 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. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.

Cancer:

  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).
  • To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.
  • Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
  • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.
  • Discontinue following the completion of a chemotherapy course.

Perisurgery: EPOGEN® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION.)

 

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. EPOGEN® 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

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 EPOGEN® 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 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 EPOGEN® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to EPOGEN® 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 EndpointAdverse 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

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 survivalDecreased 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-free and overall survival and locoregional controlDecreased 3 yr. progression-free and overall survival and locoregional control
Radiotherapy Alone

Cancer Study 5

Head and neck cancer

(n=351)

≥15 g/dL (M)

≥14 g/dL (F)

Not availableLocoregional progression-free survival

Decreased 5-year locoregional progression-free survival

Decreased overall survival

Cancer Study 6

Head and neck cancer

(n=522)

14-15.5 g/dL Not availableLocoregional disease controlDecreased locoregional disease control
No Chemotherapy or Radiotherapy

Cancer Study 7

Non-small cell lung cancer

(n=70)

12-14 g/dLNot availableQuality of lifeDecreased 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 and Thromboembolic Events). 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).

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 EPOGEN®. This has been reported predominantly in patients with CRF receiving EPOGEN® by subcutaneous administration. Any patient who develops a sudden loss of response to EPOGEN®, 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 EPOGEN® and other erythropoietic proteins. Contact Amgen (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies. EPOGEN® 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)

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

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

It is recommended that the dose of EPOGEN® 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 EPOGEN® 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 EPOGEN® 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 EPOGEN® be decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week period.

Thrombotic Events: During hemodialysis, patients treated with EPOGEN® 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 EPOGEN® 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 EPOGEN® 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, EPOGEN® 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 EPOGEN® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information regarding allergic reactions).

The safety and efficacy of EPOGEN® 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 EPOGEN® 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 EPOGEN®. However, EPOGEN® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, EPOGEN® should be used with caution in patients with known porphyria.

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

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:

  1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION).
  2. Underlying infectious, inflammatory, or malignant processes.
  3. Occult blood loss.
  4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders).
  5. Vitamin deficiencies: Folic acid or vitamin B12.
  6. Hemolysis.
  7. Aluminum intoxication.
  8. Osteitis fibrosa cystica.
  9. 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 EPOGEN® therapy.

Iron Evaluation

During EPOGEN® 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 EPOGEN® 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 EPOGEN®. All surgery patients being treated with EPOGEN® should receive adequate iron supplementation throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores.

Drug Interaction

No evidence of interaction of EPOGEN® with other drugs was observed in the course of clinical trials.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenic potential of EPOGEN® has not been evaluated. EPOGEN® 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 EPOGEN®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C

EPOGEN® 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. EPOGEN® 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. EPOGEN® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers

Postnatal observations of the live offspring (F1 generation) of female rats treated with EPOGEN® during gestation and lactation revealed no effect of EPOGEN® 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 EPOGEN®-related effects on the F2 generation fetuses.

It is not known whether EPOGEN® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when EPOGEN® is administered to a nursing woman.

Pediatric Use

See WARNINGS: Pediatrics.

Pediatric Patients on Dialysis: EPOGEN® 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 EPOGEN® in adult CRF patients (see ADVERSE REACTIONS and WARNINGS). Published literature27-30 provides supportive evidence of the safety and effectiveness of EPOGEN® in pediatric CRF patients on dialysis.

Pediatric Patients Not Requiring Dialysis: Published literature30,31 has reported the use of EPOGEN® 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 literature 32,33 has reported the use of EPOGEN® 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 EPOGEN® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients).

Geriatric Use

Among 1051 patients enrolled in the 5 clinical trials of EPOGEN® for reduction of allogeneic blood transfusions in patients undergoing elective surgery 745 received EPOGEN® and 306 received placebo. Of the 745 patients who received EPOGEN®, 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 EPOGEN® 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 EPOGEN® and 125 received placebo. Of the 757 patients who received EPOGEN®, 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 EPOGEN®  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.

Information for Patients

Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer EPOGEN® at home, instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the EPOGEN® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of EPOGEN® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container.

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.

Hematology

Sufficient time should be allowed to determine a patient’s responsiveness to a dosage of EPOGEN® 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 EPOGEN® with a rapid increase in hemoglobin (eg, more than 1 g/dL in any 2-week period), the dose of EPOGEN® 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 EPOGEN®. Reduction of bleeding time also occurs after correction of anemia by transfusion.

Laboratory Monitoring

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 EPOGEN®, 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.

Diet

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 EPOGEN® therapy, often in association with poor compliance to medication, diet, and/or dialysis.

Dialysis Management

Therapy with EPOGEN® 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 EPOGEN® 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 EPOGEN® should be monitored regularly to assure the adequacy of the dialysis prescription.

Renal Function

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 EPOGEN® 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 EPOGEN® therapy.

Zidovudine-treated HIV-infected Patients

Hypertension

Exacerbation of hypertension has not been observed in zidovudine-treated HIV-infected patients treated with EPOGEN®. However, EPOGEN® 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 EPOGEN®.23

Cancer Patients on Chemotherapy

Hypertension

Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with EPOGEN®. Nevertheless, blood pressure in patients treated with EPOGEN® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.

Seizures

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with EPOGEN® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with EPOGEN® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with EPOGEN® also had underlying CNS pathology which may have been related to seizure activity.

In a placebo-controlled, double-blind trial utilizing weekly dosing with EPOGEN®, 1.2% (n = 2/168) of safety-evaluable patients treated with EPOGEN® and 1% (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly EPOGEN® 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.

Thrombotic Events

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with EPOGEN® 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 and Thromboembolic Events).

In a placebo-controlled, double-blind trial utilizing weekly dosing with EPOGEN®, 6.0% (n = 10/168) of safety-evaluable patients treated with EPOGEN® 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 EPOGEN ® 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 EPOGEN ® on the incidence of thrombotic events could not be performed. In the EPOGEN ® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.

Surgery Patients

Hypertension

Blood pressure may rise in the perioperative period in patients being treated with EPOGEN®. Therefore, blood pressure should be monitored carefully.

Page last updated: 2009-02-20

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