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Active ingredient: Erythropoietin

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Erythropoietin uses


WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

Chronic Kidney Disease:


Cancer:


Perisurgery:


WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

See full prescribing information for complete boxed warning.

Chronic Kidney Disease:


Cancer:


Perisurgery:

Indications and Usage, Limitations of Use (1.5) 04/2017
Warnings and Precautions, Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer (5.2) 04/2017
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1 INDICATIONS AND USAGE

Erythropoietin is an erythropoiesis-stimulating agent indicated for:


Limitations of Use

Erythropoietin has not been shown to improve quality of life, fatigue, or patient well-being (1.5).

Erythropoietin is not indicated for use:

1.1 Anemia Due to Chronic Kidney Disease

Erythropoietin is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusion.

1.2 Anemia Due to Zidovudine in HIV-infected Patients

Erythropoietin is indicated for the treatment of anemia due to zidovudine administered at ≤ 4200 mg/week in HIV-infected patients with endogenous serum Erythropoietin levels of ≤ 500 mUnits/mL.

1.3 Anemia Due to Chemotherapy in Patients With Cancer

Erythropoietin is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

1.4 Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery

Erythropoietin is indicated to reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin > 10 to ≤ 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery. Erythropoietin is not indicated for patients who are willing to donate autologous blood pre-operatively.

1.5 Limitations of Use

Erythropoietin has not been shown to improve quality of life, fatigue, or patient well-being.

Erythropoietin is not indicated for use:

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2 DOSAGE AND ADMINISTRATION

2.1 Evaluation of Iron Stores and Nutritional Factors

Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Erythropoietin .

2.2 Patients with Chronic Kidney Disease

In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Erythropoietin sufficient to reduce the need for RBC transfusions . Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.

For all patients with CKD:

When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.


For patients with CKD on dialysis:


For patients with CKD not on dialysis:


When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.2) .

Refer patients who self-administer Erythropoietin to the Instructions for Use .

2.3 Zidovudine-treated HIV-infected Patients

Starting Dose

The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.

Dose Adjustment


Discontinue Erythropoietin if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.

2.4 Patients on Cancer Chemotherapy

Initiate Erythropoietin in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.

Use the lowest dose of Erythropoietin necessary to avoid RBC transfusions.

Recommended Starting Dose

Adults:


Pediatric Patients :


Dose Reduction

Reduce dose by 25% if:


Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.

Dose Increase

After the initial 4 weeks of Erythropoietin therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:


After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Erythropoietin.

2.5 Surgery Patients

The recommended Erythropoietin regimens are:


Deep venous thrombosis prophylaxis is recommended during Erythropoietin therapy .

2.6 Preparation and Administration

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3 DOSAGE FORMS AND STRENGTHS

Single-dose vials: 2000, 3000, 4000, 10,000, and 40,000 Units Erythropoietin /1 mL

Multiple-dose vials (contains benzyl alcohol): 20,000 Units Erythropoietin /2 mL and 20,000 Units Erythropoietin /1 mL

4 CONTRAINDICATIONS

Erythropoietin is contraindicated in patients with:


Erythropoietin from multiple-dose vials contains benzyl alcohol and is contraindicated in:

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5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism


The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.

Normal Hematocrit Study (NHS)

(N=1265)

 CHOIR

(N=1432)

 TREAT

(N=4038)
Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009
Population CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL
Hemoglobin Target;

Higher vs. Lower (g/dL)

14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0
Median (Q1, Q3)

Achieved Hemoglobin level (g/dL)

12.6 (11.6, 13.3) vs.

10.3 (10.0, 10.7)

 13.0 (12.2, 13.4) vs.

11.4 (11.1, 11.6)

 12.5 (12.0, 12.8) vs.

10.6 (9.9, 11.3)
Primary Endpoint All-cause mortality or non-fatal MI All-cause mortality, MI, hospitalization for CHF, or stroke All-cause mortality, MI, myocardial ischemia, heart failure, and stroke
Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17)
Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke
Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68)

Patients with Chronic Kidney Disease

Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.

CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p=0.03].

TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment, but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.

Patients with Cancer

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.

In a randomized, placebo-controlled study (Study 2 in Table 2 ) of 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 epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study 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).

Patients Having Surgery

An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated . In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n=340) or to SOC treatment alone (n=340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n=680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients .

Increased mortality was observed in a randomized, placebo-controlled study of Erythropoietin in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to Erythropoietin versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.

5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer

ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (OS). Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7); and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

Study/Tumor/(n) Hemoglobin Target Achieved Hemoglobin

(Median; Q1, Q3Q1=25th percentile

Q3=75th percentile)

 Primary Efficacy Outcome Adverse Outcome for ESA-containing Arm
Chemotherapy
Study 1

Metastatic breast cancer

(n=2098)

≤12 g/dLThis study did not include a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL. 11.6 g/dL

10.7, 12.1 g/dL

 Progression-free survival (PFS) Decreased progression-free and overall survival
Study 2

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
Study 3

Lymphoid malignancy

(n=344)

 13–15 g/dL (M)

13–14 g/dL (F)

 11 g/dL;

9.8, 12.1 g/dL

 Proportion of patients achieving a hemoglobin response Decreased overall survival
Study 4

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-year relapse-free and overall survival
Study 5

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 control Decreased 3-year progression-free and overall survival and locoregional control
Radiotherapy Alone
Study 6

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 and overall survival
Study 7

Head and neck cancer

(n=522)

 14–15.5 g/dL Not available Locoregional disease control Decreased locoregional disease control
No Chemotherapy or Radiotherapy
Study 8

Non-small cell lung cancer

(n=70)

 12–14 g/dL Not available Quality of life Decreased overall survival
Study 9

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

Study 2 was described in the previous section . 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 2 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).

Study 3 was a randomized, double-blind study (darbepoetin alfa vs. placebo) 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).

Study 8 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) 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 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04).

Study 9 was a randomized, double-blind study (darbepoetin alfa vs. placebo) 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 than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).

Decreased Progression-free Survival and Overall Survival

Study 1 was a randomized, open label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non-inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. The median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. At the time of clinical data cutoff, 1337 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.2 months compared with 17.4 months in the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%).

Study 4 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.

Study 5 was a randomized, open-label, 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 RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions 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).

Study 6 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 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 medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p=0.02).

Decreased Locoregional Control

Study 7 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed 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).

5.3 Hypertension

Erythropoietin is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of Erythropoietin, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Erythropoietin.

Appropriately control hypertension prior to initiation of and during treatment with Erythropoietin. Reduce or withhold Erythropoietin if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions .

5.4 Seizures

Erythropoietin increases the risk of seizures in patients with CKD. During the first several months following initiation of Erythropoietin, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.

5.5 Lack or Loss of Hemoglobin Response to Erythropoietin

For lack or loss of hemoglobin response to Erythropoietin, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA . In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Erythropoietin therapy .

5.6 Pure Red Cell Aplasia

Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to Erythropoietin have been reported in patients treated with Erythropoietin. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Erythropoietin is not approved).

If severe anemia and low reticulocyte count develop during treatment with Erythropoietin, withhold Erythropoietin and evaluate patients for neutralizing antibodies to Erythropoietin. Contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) to perform assays for binding and neutralizing antibodies. Permanently discontinue Erythropoietin in patients who develop PRCA following treatment with Erythropoietin or other Erythropoietin protein drugs. Do not switch patients to other ESAs.

5.7 Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Erythropoietin. Immediately and permanently discontinue Erythropoietin and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

5.8 Albumin

Erythropoietin 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.

5.9 Dialysis Management

Patients may require adjustments in their dialysis prescriptions after initiation of Erythropoietin. Patients receiving Erythropoietin may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

5.10 Laboratory Monitoring

Evaluate transferrin saturation and serum ferritin prior to and during Erythropoietin treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% . The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:


To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidney Disease

Adult Patients

Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Erythropoietin. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.

Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to Erythropoietin. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.

The adverse reactions with a reported incidence of ≥ 5% in PROCRIT-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Adverse Reaction PROCRIT-treated Patients

(n=148)

 Placebo-treated Patients

(n=96)
Hypertension 27.7% 12.5%
Arthralgia 16.2% 3.1%
Muscle spasm 7.4% 6.3%
Pyrexia 10.1% 8.3%
Dizziness 9.5% 8.3%
Medical Device Malfunction (artificial kidney clotting during dialysis) 8.1% 4.2%
Vascular Occlusion (vascular access thrombosis) 8.1% 2.1%
Upper respiratory tract infection 6.8% 5.2%

An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% Erythropoietin and 1% placebo) .

The adverse reactions with a reported incidence of ≥ 5% in PROCRIT-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Adverse Reactions PROCRIT-treated Patients

(n=131)

 Placebo-treated Patients

(n=79)
Hypertension 13.7% 10.1%
Arthralgia 12.2% 7.6%

Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% Erythropoietin and 0% placebo) and myocardial infarction (0.8% Erythropoietin and 0% placebo) .

Pediatric Patients

In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.

Zidovudine-treated HIV-infected Patients

A total of 297 zidovudine-treated HIV-infected patients were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Erythropoietin and 153 (52%) patients were randomly assigned to receive placebo. Erythropoietin was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.

For the combined Erythropoietin treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined Erythropoietin treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.

In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Erythropoietin were:

Adverse Reaction Erythropoietin

(n=144)

 Placebo

(n=153)
Pyrexia 42% 34%
Cough 26% 14%
Rash 19% 7%
Injection site irritation 7% 4%
Urticaria 3% 1%
Respiratory tract congestion 1% Not reported
Pulmonary embolism 1% Not reported

Cancer Patients on Chemotherapy

The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to Erythropoietin received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly PROCRIT-treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the PROCRIT-treatment group was 158 white (94%) and 10 black (6%). Erythropoietin was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).

The adverse reactions with a reported incidence of ≥ 5% in PROCRIT-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Adverse Reaction Erythropoietin

(n=168)

 Placebo

(n=165)
Nausea 35% 30%
Vomiting 20% 16%
Myalgia 10% 5%
Arthralgia 10% 6%
Stomatitis 10% 8%
Cough 9% 7%
Weight decrease 9% 5%
Leukopenia 8% 7%
Bone pain 7% 4%
Rash 7% 5%
Hyperglycemia 6% 4%
Insomnia 6% 2%
Headache 5% 4%
Depression 5% 4%
Dysphagia 5% 2%
Hypokalemia 5% 3%
Thrombosis 5% 3%

Surgery Patients

Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive Erythropoietin and 103 (22%) patients were randomly assigned to receive placebo. Erythropoietin was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.

For the combined Erythropoietin treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Erythropoietin treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.

The adverse reactions with a reported incidence of ≥ 1% in PROCRIT-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Adverse Reaction Study S1 Study S2
Erythropoietin

300 U/kg

 Erythropoietin

100 U/kg

 Placebo Erythropoietin

600 U/kg × 4 weeks

 Erythropoietin

300 U/kg × 15 days
(n=112)Study included patients undergoing orthopedic surgery treated with Erythropoietin or placebo for 15 days. (n=101) (n=103) (n=73)Study included patients undergoing orthopedic surgery treated with Erythropoietin 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days. (n=72)
Nausea 47% 43% 45% 45% 56%
Vomiting 21% 12% 14% 19% 28%
Pruritus 16% 16% 14% 12% 21%
Headache 13% 11% 9% 10% 18%
Injection site pain 13% 9% 8% 12% 11%
Chills 7% 4% 1% 1% 0%
Deep vein thrombosis 6% 3% 3% 0%DVTs were determined by clinical symptoms. 0%
Cough 5% 4% 0% 4% 4%
Hypertension 5% 3% 5% 5% 6%
Rash 2% 2% 1% 3% 3%
Edema 1% 2% 2% 1% 3%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Erythropoietin.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to epoetin alfa that cross-react with endogenous Erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.6) ].

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erythropoietin with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted with Erythropoietin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

The multiple-dose vials are formulated with benzyl alcohol. Do not administer Erythropoietin from multiple-dose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with Erythropoietin is needed during pregnancy, use a benzyl alcohol-free formulation .

Pregnancy Category C (single-dose vials only)

There are no adequate and well-controlled studies of Erythropoietin use during pregnancy. There are limited data on Erythropoietin use in pregnant women. In animal reproductive and developmental toxicity studies, adverse fetal effects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses. Single-dose formulations of Erythropoietin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are reports of at least 33 pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received Erythropoietin. Polyhydramnios and intrauterine growth restriction were reported in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum and hypospadias following exposure during the first trimester. Due to the limited number of exposed pregnancies and multiple confounding factors (such as underlying maternal conditions, other maternal medications, and gestational timing of exposure), these published case reports and studies do not reliably estimate the frequency or absence of adverse outcomes.

When healthy rats received Erythropoietin at doses of 100 Units/kg/day during mating and through early pregnancy (dosing stopped prior to organogenesis), there were slight increases in the incidences of pre- and post-implantation loss, and a decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When healthy pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of Erythropoietin only during organogenesis, no teratogenic effects were observed in the offspring.

When healthy pregnant rats received Erythropoietin at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis), offspring had decreased number of caudal vertebrae and growth delays [see Nonclinical Toxicology (13.3) ].

8.3 Nursing Mothers

The multiple-dose vials of Erythropoietin are formulated with benzyl alcohol. Do not administer Erythropoietin from multiple-dose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with Erythropoietin is needed in nursing women, use a benzyl alcohol-free formulation .

It is not known whether Erythropoietin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Erythropoietin from single-dose vials is administered to a nursing woman.

8.4 Pediatric Use

The multiple-dose vials are formulated with benzyl alcohol. Do not administer Erythropoietin from multiple-dose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with Erythropoietin is needed in neonates and infants, use a benzyl alcohol-free formulation .

Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Pediatric Patients on Dialysis

Erythropoietin is indicated in pediatric patients, ages 1 month to 16 years of age, for the treatment of anemia associated with CKD requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established .

The safety data from these studies are similar to those obtained from the studies of Erythropoietin in adult patients with CKD .

Pediatric Cancer Patients on Chemotherapy

Erythropoietin is indicated in patients 5 to 18 years old for the treatment of anemia due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in pediatric patients less than 5 years of age have not been established. The safety data from these studies are similar to those obtained from the studies of Erythropoietin in adult patients with cancer.

Pediatric Patients With HIV Infection Receiving Zidovudine

Published literature has reported the use of Erythropoietin in 20 zidovudine-treated, anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts and decreases in or elimination of RBC transfusions were observed.

Pharmacokinetics in Neonates

Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous Erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.

8.5 Geriatric Use

Of the 4553 patients who received Erythropoietin in the 6 studies for treatment of anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over, while 1418 (31%) were 75 years and over. Of the 757 patients who received Erythropoietin in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and over, while 100 (13%) were 75 years 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 hemoglobin .

Among 778 patients enrolled in the 3 clinical studies of Erythropoietin for the treatment of anemia due to concomitant chemotherapy, 419 received Erythropoietin and 359 received placebo. Of the 419 who received Erythropoietin, 247 (59%) were age 65 years and over, while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Erythropoietin in geriatric and younger patients within the 3 studies were similar.

Among 1731 patients enrolled in the 6 clinical studies of Erythropoietin for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received Erythropoietin and 646 received placebo or standard of care treatment. Of the 1085 patients who received Erythropoietin, 582 (54%) were age 65 years and over, while 245 (23%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Erythropoietin in geriatric and younger patients within the 4 studies using the 3 times weekly schedule and 2 studies using the weekly schedule were similar.

Insufficient numbers of patients age 65 years or older were enrolled in clinical studies of Erythropoietin for the treatment of zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.

10 OVERDOSAGE

Erythropoietin overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Erythropoietin dosage and/or with phlebotomy, as clinically indicated . Cases of severe hypertension have been observed following overdose with ESAs.

11 DESCRIPTION

Erythropoietin (epoetin alfa) is a 165-amino acid erythropoiesis-stimulating glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced by mammalian cells into which the human Erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural Erythropoietin.

Erythropoietin is formulated as a sterile, colorless liquid in vials in multiple formulations. Single-dose vials, formulated with an isotonic sodium chloride/sodium citrate-buffered solution, are supplied in multiple strengths. Each 1 mL vial contains 2000, 3000, 4000, or 10,000 Units of epoetin alfa, Albumin (Human) (2.5 mg), citric acid (0.06 mg), sodium chloride (5.9 mg), and sodium citrate (5.8 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Single-dose 1 mL vials formulated with an isotonic sodium chloride/sodium phosphate buffer contain 40,000 Units of epoetin alfa albumin (human) (2.5 mg),citric acid (0.0068 mg), sodium chloride (5.8 mg), sodium citrate (0.7 mg), sodium phosphate dibasic anhydrate (1.8 mg), and sodium phosphate monobasic monohydrate (1.2 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Multiple-dose, 2 mL vials contain 10,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg) per 1 mL Water for Injection, USP (pH 6.1 ± 0.3). Multiple-dose 1 mL vials contain 20,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg), per 1 mL in Water for Injection, USP (pH 6.1 ± 0.3).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Erythropoietin stimulates erythropoiesis by the same mechanism as endogenous Erythropoietin.

12.2 Pharmacodynamics

Erythropoietin increases the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. The rate of hemoglobin increase varies among patients and is dependent upon the dose of Erythropoietin administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.

12.3 Pharmacokinetics

In adult and pediatric patients with CKD, the elimination half-life (t1/2) of plasma Erythropoietin after intravenous administration of Erythropoietin ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t1/2 in adult patients with serum creatinine greater than 3 mg/dL was similar between those not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in Erythropoietin t1/2 among adult patients above or below 65 years of age.

A pharmacokinetic study comparing 150 Units/kg subcutaneous 3 times weekly to 40,000 Units subcutaneous weekly dosing regimen was conducted for 4 weeks in healthy subjects (n=12) and for 6 weeks in anemic cancer patients (n=32) receiving cyclic chemotherapy. There was no accumulation of serum Erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3- to 7-fold), longer Tmax (2- to 3-fold), higher AUC0–168 h (2- to 3-fold) of Erythropoietin and lower clearance (CL) (50%) than the 150 Units/kg 3 times weekly regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg 3 times weekly dosing, the values of Tmax and CL were similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/hr/kg) between week 1 when patients were receiving chemotherapy (n=14) and week 3 when patients were not receiving chemotherapy (n=4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower CL (9.2 ± 4.7 mL/hr/kg) during week 1 when patients were receiving chemotherapy (n=18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/hr/kg, respectively) during week 3 when patients were not receiving chemotherapy (n=7).

The pharmacokinetic profile of Erythropoietin in children and adolescents appeared similar to that of adults.

The pharmacokinetics of Erythropoietin has not been studied in patients with HIV infection.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The carcinogenic potential of Erythropoietin has not been evaluated.

Mutagenicity

Erythropoietin was not mutagenic or clastogenic under the conditions tested: Erythropoietin was negative in the in vitro bacterial reverse mutation assay, in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus), in an in vitro chromosomal aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.

Impairment of Fertility

When administered intravenously to male and female rats prior to and during mating, and to females through the beginning of implantation (up to gestational day 7; dosing stopped prior to the beginning of organogenesis), doses of 100 and 500 Units/kg/day of Erythropoietin caused slight increases in pre-implantation loss, post-implantation loss and decreases in the incidence of live fetuses. It is not clear whether these effects reflect a drug effect on the uterine environment or on the conceptus. This animal dose level of 100 Units/kg/day approximates the clinical recommended starting dose, depending on the patient's treatment indication, but may be lower than the clinical dose in patients whose doses have been adjusted.

13.3 Reproductive and Developmental Toxicology

When pregnant rats were administered intravenous Erythropoietin, 500 Units/kg/day, after the period of organogenesis (from day 17 of gestation through day 21 of lactation), their pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification. This animal dose level of 500 Units/kg/day is approximately 5-fold higher than the clinical recommended starting dose, depending on the patient's treatment indication.

When Erythropoietin was administered intravenously during the period of organogenesis to pregnant rats (gestational days 7 to 17) and pregnant rabbits (gestational days 6 to 18), no evidence of teratogenic outcome was observed at the doses tested, up to 500 Units/kg/day. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no PROCRIT-related effects were apparent for their offspring (F2 generation fetuses).

14 CLINICAL STUDIES

14.1 Patients With Chronic Kidney Disease

Adult Patients on Dialysis

Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion

In clinical studies of CKD patients on dialysis, Erythropoietin increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving Erythropoietin for 3 months. In clinical studies at starting doses of 50 to 150 Units/kg 3 times weekly, adult patients responded with an average rate of hemoglobin rise as presented in Table 8.

Starting Dose

 Hemoglobin Increase in 2 Weeks
50 Units/kg 0.5 g/dL
100 Units/kg 0.8 g/dL
150 Units/kg 1.2 g/dL

The safety and efficacy of Erythropoietin were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 anemic patients on dialysis. Overall, more than 90% of the patients treated with Erythropoietin experienced improvement in hemoglobin concentrations. In the 3 largest of these clinical studies, the median maintenance dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 Units/kg 3 times weekly. More than 95% of patients were able to avoid RBC transfusions. In the largest US multicenter study, approximately 65% of the patients received doses of 100 Units/kg 3 times weekly or less to maintain their hemoglobin at approximately 11.7 g/dL. Almost 10% of patients received a dose of 25 Units/kg or less, and approximately 10% received a dose of more than 200 Units/kg 3 times weekly to maintain their hemoglobin at this level.

In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).

Other ESA trials

In a 26-week, double-blind, placebo-controlled study, 118 patients on dialysis with an average hemoglobin of approximately 7 g/dL were randomized to either Erythropoietin or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the PROCRIT-treated patients and remained unchanged in patients receiving placebo. PROCRIT-treated patients experienced improvements in exercise tolerance and patient-reported physical functioning at month 2 that were maintained throughout the study.

A multicenter, unit-dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered Erythropoietin subcutaneously. Patients responded to Erythropoietin administered subcutaneously in a manner similar to patients receiving intravenous administration.

Pediatric Patients on Dialysis

The safety and efficacy of Erythropoietin were studied in a placebo-controlled, randomized study of 113 children with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of Erythropoietin was 50 Units/kg intravenously or subcutaneously 3 times weekly. The dose of study drug was titrated to achieve either a hemoglobin of 10 to 12 g/dL or an absolute increase in hemoglobin of 2 g/dL over baseline.

At the end of the initial 12 weeks, a statistically significant rise in mean hemoglobin (3.1 g/dL vs. 0.3 g/dL) was observed only in the Erythropoietin arm. The proportion of children achieving a hemoglobin of 10 g/dL, or an increase in hemoglobin of 2 g/dL over baseline, at any time during the first 12 weeks was higher in the Erythropoietin arm (96% vs. 58%). Within 12 weeks of initiating Erythropoietin therapy, 92.3% of the pediatric patients were RBC transfusion independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of Erythropoietin, hemodialysis patients received a higher median maintenance dose [167 Units/kg/week (n=28) vs. 76 Units/kg/week (n=36)] and took longer to achieve a hemoglobin of 10 to 12 g/dL (median time to response 69 days vs. 32 days) than patients undergoing peritoneal dialysis.

Adult Patients With CKD Not Requiring Dialysis

Four clinical studies were conducted in patients with CKD not on dialysis involving 181 patients treated with Erythropoietin. These patients responded to Erythropoietin therapy in a manner similar to that observed in patients on dialysis. Patients with CKD not on dialysis demonstrated a dose-dependent and sustained increase in hemoglobin when Erythropoietin was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when Erythropoietin was administered by either route.

Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion

In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions (5.1)].

ESA Effects on rates of death and other serious cardiac adverse events

Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile .

14.2 Zidovudine-treated Patients With HIV Infection

The safety and efficacy of Erythropoietin were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV infection receiving concomitant therapy with zidovudine. In the subgroup of patients (89/125 Erythropoietin and 88/130 placebo) with pre-study endogenous serum Erythropoietin levels ≤ 500 mUnits/mL, Erythropoietin reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with Erythropoietin versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Erythropoietin therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with Erythropoietin (n=51) compared to placebo-treated patients (n=54) whose mean weekly zidovudine dose was ≤ 4200 mg/week.

Approximately 17% of the patients with endogenous serum Erythropoietin levels ≤ 500 mUnits/mL receiving Erythropoietin in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose pre-study endogenous serum Erythropoietin levels were > 500 mUnits/mL, Erythropoietin therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.

14.3 Cancer Patients on Chemotherapy

The safety and effectiveness of Erythropoietin was assessed in two multicenter, randomized, placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.

Study C1

Study C1 was conducted in anemic patients (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin (< 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n=174) or placebo (n=170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.

Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.

Week 5 Through Week 16 or End of StudyLast-known RBC transfusion status carried forward for patients who discontinued treatment.
Chemotherapy Regimen Erythropoietin

(n=174)

 Placebo

(n=170)
All Regimens 14% (25/174)Two-sided p < 0.001, logistic regression analysis adjusting for accrual rate and stratification variables. 28% (48/170)
Regimens without cisplatin 14% (21/148) 26% (35/137)
Regimens containing cisplatin 15% (4/26) 39% (13/33)

Study C2

Study C2 was conducted in 222 anemic patients, ages 5 to 18, receiving chemotherapy for the treatment of various childhood malignancies. Randomization was stratified by cancer type (solid tumors, Hodgkin's disease, acute lymphocytic leukemia, vs. non-Hodgkin's lymphoma); patients were randomized to receive epoetin alfa at 600 Units/kg maximum 40,000 Units (n=111) or placebo (n=111) as a weekly intravenous injection.

Sixty-nine percent of patients were white, 55% were male, and the median age of patients was 12 years (range: 5 to 18 years). Two (2%) of placebo-treated patients and 3 (3%) of epoetin alfa-treated patients dropped out of the study prior to week 5. There were fewer RBC transfusions from week 5 through the end-of-study in epoetin-alfa treated patients [51% (57/111)] compared to placebo-treated patients [69% (77/111)]. There was no evidence of an improvement in health-related quality of life, including no evidence of an effect on fatigue, energy, or strength in patients receiving Erythropoietin as compared to those receiving placebo.

Pooled Analysis (Three Times Per Week Dosing)

The results of 6 studies of similar design and that randomized 131 patients to epoetin alfa or placebo were pooled to assess the safety and effectiveness of epoetin alfa. Patients were randomized to receive epoetin alfa at 150 Units/kg (n=63) or placebo (n=68), subcutaneously three times per week for 12 weeks in each study. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Twelve patients (19%) in the epoetin alfa arm and 10 patients (15%) in the placebo-arm dropped out prior to week 6 and are excluded from efficacy analyses.

Week 5 Through Week 12 or End of StudyLimited to patients remaining on study beyond week 6 and includes only RBC transfusions during weeks 5–12.
Chemotherapy Regimen Erythropoietin Placebo
All Regimens 22% (11/51)Two-sided p < 0.05, unadjusted. 43% (25/58)
Regimens without cisplatin 21% (6/29) 33% (11/33)
Regimens containing cisplatin 23% (5/22) 56% (14/25)

14.4 Surgery Patients

The safety and efficacy of Erythropoietin were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin [≤ 10 g/dL (n=2), > 10 to ≤ 13 g/dL (n=96), and > 13 to ≤ 15 g/dL (n=218)] and then randomly assigned to receive 300 Units/kg Erythropoietin, 100 Units/kg Erythropoietin, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.

Treatment with Erythropoietin 300 Units/kg significantly (p=0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with Erythropoietin 300 Units/kg, 6/26 (23%) of patients treated with Erythropoietin 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between Erythropoietin (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if Erythropoietin is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per PROCRIT-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p=0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with Erythropoietin.

Erythropoietin was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of Erythropoietin (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.

From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 × 106/mm3) compared to the daily group (0.17 × 106/mm3). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group]. The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING

Store at 36°F to 46°F (2°C to 8°C). Do not freeze.

Do not shake. Protect from light; store Erythropoietin in the carton until use.

Do not use Erythropoietin that has been shaken or frozen.

Single-dose, Preservative-free Vial: Each 1 mL of solution contains 2000 (NDC 59676-302-01), 3000 (NDC 59676-303-01), 4000 (NDC 59676-304-01), or 10,000 Units (NDC 59676-310-01) of epoetin alfa. Each strength is supplied in cartons, each carton containing 6 single-dose vials.

Single-dose, Preservative-free Vial (Tray): Each 1 mL of solution contains 10,000 Units (NDC 59676-310-02) of epoetin alfa and is supplied in dispensing packs containing 25 single-dose vials.

Single-dose, Preservative-free Vial (in phosphate-buffered formulation): Each 1 mL of solution contains 40,000 Units (NDC 59676-340-01) of epoetin alfa and is supplied in dispensing packs containing 4 single-dose vials.

Multiple-dose, Preserved Vial: 2 mL (20,000 Units total; 10,000 Units/mL). Each 1 mL of solution contains 10,000 Units (NDC 59676-312-04) of epoetin alfa and is supplied in dispensing packs containing 4 multiple-dose vials.

Multiple-dose, Preserved Vial: 1 mL (20,000 Units/mL). Each 1 mL of solution contains 20,000 Units (NDC 59676-320-04) of epoetin alfa and is supplied in dispensing packs containing 4 multiple-dose vials.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Prior to treatment, inform patients of the risks and benefits of Erythropoietin.

Inform patients:


Instruct patients who self-administer Erythropoietin of the:


Erythropoietin® (epoetin alfa)

Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, CA 91320-1799 U.S.A.

U.S. License Number 1080

Manufactured for:

Janssen Products, LP

Horsham, Pennsylvania 19044

©Janssen Products, LP 2000

Printed in U. S. A.

Patent: www.procrit.com/patents/

MEDICATION GUIDE

Erythropoietin® (PRO'–KRIT)

(epoetin alfa)

Read this Medication Guide:


This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Talk with your healthcare provider regularly about the use of Erythropoietin and ask if there is new information about Erythropoietin.

What is the most important information I should know about Erythropoietin?

Erythropoietin may cause serious side effects that can lead to death, including:

For people with cancer:


For all people who take Erythropoietin, including people with cancer or chronic kidney disease:


See "What are the possible side effects of Erythropoietin?" below for more information.

If you decide to take Erythropoietin, your healthcare provider should prescribe the smallest dose of Erythropoietin that is necessary to reduce your chance of needing RBC transfusions.

What is Erythropoietin?

Erythropoietin is a prescription medicine used to treat anemia. People with anemia have a lower-than-normal number of RBCs. Erythropoietin works like the human protein called Erythropoietin to help your body make more RBCs. Erythropoietin is used to reduce or avoid the need for RBC transfusions.

Erythropoietin may be used to treat anemia if it is caused by:


Erythropoietin may also be used to reduce the chance you will need RBC transfusions if you are scheduled for certain surgeries where a lot of blood loss is expected.

If your hemoglobin level stays too high or if your hemoglobin goes up too quickly, this may lead to serious health problems which may result in death. These serious health problems may happen if you take Erythropoietin, even if you do not have an increase in your hemoglobin level.

Erythropoietin should not be used for treatment of anemia:


Erythropoietin has not been proven to improve quality of life, fatigue, or well-being.

Erythropoietin should not be used to reduce the chance of RBC transfusions if:

Who should not take Erythropoietin?

Do not take Erythropoietin if you:


Do not give Erythropoietin from multiple-dose vials to:


What should I tell my healthcare provider before taking Erythropoietin?

Erythropoietin may not be right for you. Tell your healthcare provider about all your health conditions, including if you:


Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider when you get a new medicine.

How should I take Erythropoietin?

What are the possible side effects of Erythropoietin?

Erythropoietin may cause serious side effects.


Common side effects of Erythropoietin include:


These are not all of the possible side effects of Erythropoietin. Your healthcare provider can give you a more complete list. Tell your healthcare provider about any side effects that bother you or that do not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Erythropoietin?


Keep Erythropoietin and all medicines out of the reach of children.

General information about Erythropoietin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use Erythropoietin only for the condition for which it has been prescribed. Do not give Erythropoietin to other patients even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Erythropoietin. If you would like more information about Erythropoietin, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Erythropoietin that is written for healthcare professionals. For more information, go to the following website: www. PROCRIT.com or call 1-800-JANSSEN (1-800-526-7736).

What are the ingredients in Erythropoietin?

Active Ingredient: epoetin alfa

Inactive Ingredients:


This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, CA 91320-1799 U.S.A.

Manufactured for:

Janssen Products, LP

Horsham, Pennsylvania 19044

© Janssen Products, LP 2000

Printed in U. S. A.

Revised: 04/2017

Instructions for Use

Erythropoietin® (PRO'–KRIT)

(epoetin alfa)

Use these Instructions for Use if you or your caregiver has been trained to give Erythropoietin injections at home. Do not give yourself the injection unless you have received training from your healthcare provider. If you are not sure about giving the injection or you have questions, ask your healthcare provider for help.

Before reading these Instructions for Use, read the Medication Guide that comes with Erythropoietin for the most important information you need to know.

When you receive your Erythropoietin vial and syringes make sure that:


How should I prepare for an injection of Erythropoietin?


Only use disposable syringes and needles. Use the syringes and needles only one time and then throw them away as instructed by your healthcare provider .

What do I need to know about the different types of Erythropoietin vials?

Erythropoietin comes in two different types of vials.


The multidose vial of Erythropoietin contains the preservative benzyl alcohol. Benzyl alcohol has been shown to cause brain damage, other serious side effects, and death in newborn and premature babies. Erythropoietin that comes in single-dose vials does not contain benzyl alcohol.

Important: Follow these instructions exactly to help avoid infections.

Preparing the dose:

  • Keep the needle inside the vial. Turn the vial and syringe upside down. Be sure the tip of the needle is in the Erythropoietin liquid. Keep the vial upside down. Slowly pull back on the plunger to fill the syringe with Erythropoietin liquid to the number (mL or cc) that matches the dose your healthcare provider prescribed. See Figure 8.
  • Keep the needle in the vial. Check for air bubbles in the syringe. A small amount of air is harmless. Too large an air bubble will give you the wrong Erythropoietin dose. To remove air bubbles, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. Slowly push the plunger up to force the air bubbles out of the syringe. Keep the tip of the needle in the Erythropoietin liquid. Pull the plunger back to the number on the syringe that matches your dose. Check again for air bubbles. If there are still air bubbles, repeat the steps above to remove them. See Figures 9 and 10.
  • Clean the skin with an alcohol wipe where the injection is to be made. Be careful not to touch the skin that has been wiped clean. See Figure 12.

  • Double-check that the correct amount of Erythropoietin is in the syringe.
  • Remove the prepared syringe and needle from the vial of Erythropoietin and hold it in the hand that you will use to inject the medicine.
  • Use the other hand to pinch a fold of skin at the cleaned injection site. Do not touch the cleaned area of skin. See Figure 13.

  • Hold the syringe like you would hold a pencil. Use a quick "dart-like" motion to insert the needle either straight up and down (90-degree angle) or at a slight angle (45 degrees) into the skin. Inject the prescribed dose subcutaneously as directed by your doctor, nurse or pharmacist. See Figure 14.

  • Pull the needle out of the skin and press a cotton ball or gauze over the injection site and hold it there for several seconds. Do not recap the needle.
  • Dispose of the used syringe and needle as described below. Do not reuse syringes and needles.
  • Intravenous Route:
    • Erythropoietin can be injected in your vein through a special access port placed by your healthcare provider. This type of Erythropoietin injection is called an intravenous (IV) injection. This route is usually for hemodialysis patients.
    • If you have a dialysis vascular access, make sure it is working by checking it as your healthcare provider has shown you. Be sure to let your healthcare provider know right away if you are having any problems, or if you have any questions.
    • Wipe off the venous port of the hemodialysis tubing with an alcohol wipe. See Figure 15.

    • Insert the needle of the syringe into the cleaned venous port and push the plunger all the way down to inject all the Erythropoietin. See Figure 16.

    • Remove the syringe from the venous port. Do not recap the needle.
    • Dispose of the used syringe and needle as described below.

    • How should I dispose of the vials, syringes, and needles?

    Do not reuse the single-dose vials, syringes, or needles. Throw away the vials, syringes, and needles as instructed by your healthcare provider or by following these steps:

    • Do not throw the vials, syringes, or needles in the household trash or recycle.
    • Do not put the needle cover back on the needle.
    • Place all used needles and syringes in a puncture-proof disposable container with a lid. Do not use glass or clear plastic containers, or any container that will be recycled or returned to a store.
    • Keep the puncture-proof disposable container out of the reach of children.
    • When the puncture-proof disposable container is full, tape around the cap or lid to make sure the cap or lid does not come off. Throw away the puncture-proof disposable container as instructed by your healthcare provider. There may be special state and local laws for disposing of used needles and syringes. Do not throw the puncture-proof disposable container in the household trash. Do not recycle.

    Keep Erythropoietin and all medicines out of reach of children.

    These Instructions for Use have been approved by the U.S. Food and Drug Administration.

    Manufactured by:

    Amgen Inc.

    One Amgen Center Drive

    Thousand Oaks, CA 91320-1799 U.S.A.

    Manufactured for:

    Janssen Products, LP

    Horsham, Pennsylvania 19044

    © Janssen Products, LP 2000

    Printed in U. S. A.

    Revised: 05/2012

    Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16

    PRINCIPAL DISPLAY PANEL - 2,000 Unit Vial Carton

    2,000 Units/mL

    NDC 59676-302-01

    6-1 mL Vials

    Erythropoietin®

    EPOETIN ALFA

    2,000 Units/mL

    Single Use Vial

    Attention: A medication

    guide is required for each patient.

    For more copies see Erythropoietin.com

    or call 1-800-JANSSEN (1-800-526-7736)

    Each 1 mL vial contains: 2,000 units of recombinant epoetin alfa and

    2.5 mg Albumin (Human) in a sterile, buffered solution (pH 6.9 ± 0.3)

    of sodium citrate (5.8 mg), sodium chloride (5.9 mg) and citric acid

    (0.06 mg) in Water for Injection, USP. No U.S. standard of potency.

    Patent: www.procrit.com/patents/

    Principal Display Panel - 2,000 Unit Vial Carton

    PRINCIPAL DISPLAY PANEL - 3,000 Unit Vial Carton

    3,000 Units/mL

    NDC 59676-303-01

    6-1 mL Vials

    Erythropoietin®

    EPOETIN ALFA

    3,000 Units/mL

    Single Use Vial

    Attention: A medication

    guide is required for each patient.

    For more copies see Erythropoietin.com

    or call 1-800-JANSSEN (1-800-526-7736)

    Each 1 mL vial contains: 3,000 units of recombinant epoetin alfa and

    2.5 mg Albumin (Human) in a sterile, buffered solution (pH 6.9 ± 0.3)

    of sodium citrate (5.8 mg), sodium chloride (5.9 mg) and citric acid

    (0.06 mg) in Water for Injection, USP. No U.S. standard of potency.

    Patent: www.procrit.com/patents/

    Principal Display Panel - 3,000 Unit Vial Carton

    PRINCIPAL DISPLAY PANEL - 4,000 Unit Vial Carton

    4,000 Units/mL

    NDC 59676-304-01

    6-1 mL Vials

    Erythropoietin®

    EPOETIN ALFA

    4,000 Units/mL

    Single Use Vial

    Attention: A medication

    guide is required for each patient.

    For more copies see Erythropoietin.com

    or call 1-800-JANSSEN (1-800-526-7736)

    Each 1 mL vial contains: 4,000 units of recombinant epoetin alfa and

    2.5 mg Albumin (Human) in a sterile, buffered solution (pH 6.9 ± 0.3)

    of sodium citrate (5.8 mg), sodium chloride (5.9 mg) and citric acid

    (0.06 mg) in Water for Injection, USP. No U.S. standard of potency.

    Patent: www.procrit.com/patents/

    Principal Display Panel - 4,000 Unit Vial Carton

    PRINCIPAL DISPLAY PANEL - 10,000 Unit Vial Carton

    10,000 Units/mL

    NDC 59676-310-01

    6-1 mL Vials

    Erythropoietin®

    EPOETIN ALFA

    10,000 Units/mL

    Single Use Vial

    Attention: A medication

    guide is required for each patient.

    For more copies see Erythropoietin.com

    or call 1-800-JANSSEN (1-800-526-7736)

    Each 1 mL vial contains: 10,000 units of recombinant epoetin alfa and

    2.5 mg Albumin (Human) in a sterile, buffered solution (pH 6.9 ± 0.3)

    of sodium citrate (5.8 mg), sodium chloride (5.9 mg) and citric acid

    (0.06 mg) in Water for Injection, USP. No U.S. standard of potency.

    Patent: www.procrit.com/patents/

    Principal Display Panel - 10,000 Unit Vial Carton

    PRINCIPAL DISPLAY PANEL - 40,000 Unit Vial Carton

    40,000 Units/mL

    NDC 59676-340-01

    4-1 mL Vials

    Erythropoietin®

    EPOETIN ALFA

    40,000 Units/mL

    Single Use Vial

    Attention: A medication

    guide is required for each patient.

    For more copies see Erythropoietin.com

    or call 1-800-JANSSEN

    (1-800-526-7736)

    Each 1 mL vial contains: 40,000 units of recombinant

    epoetin alfa and 2.5 mg Albumin (Human) in a sterile,

    buffered solution (pH 6.9 ± 0.3) of sodium phosphate

    monobasic monohydrate (1.2 mg), sodium phosphate

    dibasic anhydrate (1.8 mg), sodium citrate (0.7 mg),

    sodium chloride (5.8 mg), and citric acid (6.8 mcg) in

    Water for Injection, USP. No U.S. standard of potency.

    Patent: www.procrit.com/patents/

    Principal Display Panel - 40,000 Unit Vial Carton

    PRINCIPAL DISPLAY PANEL - 20,000 Units/2 mL Vial Carton

    20,000 Units/2 mL

    (10,000 Units/mL)

    NDC 59676-312-04

    4-2 mL Multidose Vials

    Erythropoietin®

    EPOETIN ALFA

    20,000 Units/2 mL (10,000 Units/mL)

    Multidose Vials

    Sterile solution - Preserved. 10,000 Units/mL

    For Intravenous or Subcutaneous Use Only.

    Attention:

    A medication guide is

    required for each

    patient. For more

    copies see Erythropoietin.com

    or call 1-800-JANSSEN

    (1-800-526-7736)

    2 mL

    Rx only

    Principal Display Panel - 20,000 Units/2 mL Vial Carton

    PRINCIPAL DISPLAY PANEL - 20,000 Unit Vial Carton

    20,000 Units/mL

    NDC 59676-320-04

    4-1 mL Multidose Vials

    Erythropoietin®

    EPOETIN ALFA

    20,000 Units/mL

    Multidose Vials

    Sterile solution - Preserved. 20,000 Units/mL

    For Intravenous or Subcutaneous Use Only

    Attention:

    A medication guide is required

    for each patient. For more copies

    see Erythropoietin.com or call

    1-800-JANSSEN (1-800-526-7736)

    1 mL

    Rx only

    Principal Display Panel - 20,000 Unit Vial Carton

    Erythropoietin available forms, composition, doses:

    • N/A

    Indications and Usages:

    ATC codes:


    ICD-10 codes:

    • N/A

    Erythropoietin destination | category:

    • N/A

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    Drugs with same active ingredients (Pharmaceutical companies):


    References

    1. Dailymed."PROCRIT (ERYTHROPOIETIN) INJECTION, SOLUTION [JANSSEN PRODUCTS, LP]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

    Frequently asked Questions

    Can i drive or operate heavy machine after consuming Erythropoietin?

    Depending on the reaction of the Erythropoietin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Erythropoietin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

    Is Erythropoietin addictive or habit forming?

    Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

    Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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    Review

    sdrugs.com conducted a study on Erythropoietin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Erythropoietin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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    The information was verified by Dr. Rachana Salvi, MD Pharmacology


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