EPOGEN

1 INDICATIONS AND USAGE Epogen is an erythropoiesis-stimulating agent (ESA) indicated for: Treatment of anemia due to: - Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis ( 1.1 ). - Zidovudine in patients with Human Immunodeficiency Virus (HIV) infection ( 1.2 ). - The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy ( 1.3 ). Reduction of allogeneic red blood cell (RBC) transfusions in patients undergoing elective, noncardiac, nonvascular surgery ( 1.4 ). Limitations of Use Epogen has not been shown to improve quality of life, fatigue, or patient well-being ( 1.5 ). Epogen is not indicated for use: In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy ( 1.5 ). In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure ( 1.5 ). In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion ( 1.5 ). In patients scheduled for surgery who are willing to donate autologous blood ( 1.5 ). In patients undergoing cardiac or vascular surgery ( 1.5 ). As a substitute for RBC transfusions in patients who require immediate correction of anemia ( 1.5 ). 1.1 Anemia Due to Chronic Kidney Disease Epogen 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 Patients with HIV Infection Epogen is indicated for the treatment of anemia due to zidovudine administered at ≤ 4200 mg/week in patients with HIV infection with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL. 1.3 Anemia Due to Chemotherapy in Patients with Cancer Epogen 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 Epogen 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. Epogen is not indicated for patients who are willing to donate autologous blood pre-operatively. 1.5 Limitations of Use Epogen has not been shown to improve quality of life, fatigue, or patient well-being. Epogen is not indicated for use: In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion. In patients scheduled for surgery who are willing to donate autologous blood. In patients undergoing cardiac or vascular surgery. As a substitute for RBC transfusions in patients who require immediate correction of anemia.

2 DOSAGE AND ADMINISTRATION Evaluate iron status before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia before initiating treatment ( 2.1 ). In pregnant women, lactating women, neonates, infants: Use only single-dose vials ( 2.1 ). Patients with CKD: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (pediatric patients). Individualize maintenance dose. Intravenous route recommended for patients on hemodialysis ( 2.2 ). Patients on Zidovudine due to HIV infection: 100 Units/kg 3 times weekly ( 2.3 ). Patients with Cancer on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (pediatric patients ≥ 5 years) ( 2.4 ). Surgery Patients: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly ( 2.5 ). 2.1 Important Dosing Information Evaluation of Iron Stores and Nutritional Factors Evaluate the iron status in all patients before and during 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. Monitoring of Response to Therapy Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen. 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. Selection of Formulation In pregnant women, lactating women, neonates, and infants use only single-dose vials (the benzyl alcohol-free formulation) [see Contraindication s ( 4 ) and Use in Specific Populations ( 8.1 , 8.2 , and 8.4 )] . 2.2 Patients with Chronic Kidney Disease In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs 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 Epogen sufficient to reduce the need for RBC transfusions [see Warnings and Precautions ( 5.1 )] . Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse reactions [see Boxed Warning and Clinical Studies ( 14 ) ] . 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. Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments. If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses. For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%. For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve. For adult patients with CKD on dialysis: Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen. The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. The intravenous route is recommended for patients on hemodialysis. For adult patients with CKD not on dialysis: Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and , Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients with CKD: • Initiate Epogen treatment only when the hemoglobin level is less than 10 g/dL. • If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of Epogen. • The recommended starting dose for pediatric patients (ages 1 month or older) is 50 Units/kg 3 times weekly intravenously or subcutaneously. When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions ( 5.1 and 5.2 ) . 2.3 Zidovudine-treated Patients with HIV Infection Starting Dose The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week. Dose Adjustment If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately 50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg. Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL. Discontinue Epogen 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 Epogen 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 Epogen necessary to avoid RBC transfusions. Recommended Starting Dose Adults: 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or 40,000 Units subcutaneously weekly until completion of a chemotherapy course. Pediatric Patients (5 to 18 years): 600 Units/kg intravenously weekly until completion of a chemotherapy course. Dose Reduction Reduce dose by 25% if: Hemoglobin increases greater than 1 g/dL in any 2-week period or Hemoglobin reaches a level needed to avoid RBC transfusion. 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 Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to: 300 Units/kg three times per week in adults or 60,000 Units weekly in adults 900 Units/kg (maximum 60,000 Units) weekly in pediatric patients After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen. 2.5 Surgery Patients The recommended Epogen regimens are: 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery. 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery. Deep venous thrombosis prophylaxis is recommended during Epogen therapy [see Warning s and Precautions ( 5.1 ) ] . 2.6 Preparation and Administration Do not shake. Do not use Epogen that has been shaken or frozen. Protect vials from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration. Discard unused portions of Epogen in preservative-free vials. Do not re-enter preservative-free vials. Store unused portions of Epogen in multiple-dose vials at 36°F to 46°F (2°C to 8°C). Discard 21 days after initial entry. Do not dilute. Do not mix with other drug solutions except for admixing as described below: Preservative-free Epogen from single-dose vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Do not mix Epogen with bacteriostatic saline when administering to pregnant women, lactating women, neonates, and infants [see Use in Specific Populations ( 8.1 , 8.2 , 8.4 )].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions ( 5.1 )] Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Seizures [see Warnings and Precautions ( 5.4 )] PRCA [see Warnings and Precautions ( 5.6 )] Serious Allergic Reactions [see Warnings and Precautions ( 5.7 )] Severe Cutaneous Reactions [see Warnings and Precautions ( 5.8 )] Patients with CKD: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection ( 6.1 ). Patients on Zidovudine due to HIV infection: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were pyrexia, cough, rash, and injection site irritation ( 6.1 ). Patients with Cancer on Chemotherapy: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis ( 6.1 ). Surgery Patients: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) 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 Epogen. 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 Epogen. 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 Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below: Table 3. Adverse Reactions in Patients with CKD on Dialysis Adverse Reaction Epogen -treated Patients (n = 148 ) Placebo- t reated 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% Epogen and 1% placebo) [see Warnings and Precautions ( 5.1 )] . The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below: Table 4. Adverse Reactions in Patients with CKD Not on Dialysis Adverse Reaction Epogen-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% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen and 0% placebo) [see Warnings and Precautions ( 5.1 )] . Pediatric Patients In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults. Zidovudine-treated Patients with HIV Infect ion A total of 297 zidovudine-treated patients with HIV infection were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Epogen and 153 (52%) patients were randomly assigned to receive placebo. Epogen was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks. For the combined Epogen 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 Epogen 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 patients with HIV infection, adverse reactions with an incidence of ≥ 1% in patients treated with Epogen were: Table 5. Adverse Reactions in Zidovudine-treated Patients with HIV infection Adverse Reaction Epogen (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 Patients with Cancer 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 Epogen 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 Epogen-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 Epogen-treatment group was 158 white (94%) and 10 black (6%). Epogen 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 Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below: Table 6. Adverse Reactions in Patients with Cancer Adverse Reaction Epogen (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 Epogen and 103 (22%) patients were randomly assigned to receive placebo. Epogen 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 Epogen treatment groups, a total of 90 (25%) men and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Epogen 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 Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below: Table 7. Adverse Reactions in Surgery Patients Study S1 Study S2 Adverse Reaction Epogen 300 U/kg (n = 112) Study included patients undergoing orthopedic surgery treated with Epogen or placebo for 15 days. Epogen 100 U/kg (n = 101) Placebo (n = 103) Epogen 600 U/kg × 4 weeks (n = 73) Study included patients undergoing orthopedic surgery treated with Epogen 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days. Epogen 300 U/kg × 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 Epogen. 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. Seizures [see Warnings and Precautions ( 5.4 )] PRCA [see Warnings and Precautions ( 5.6 )] Serious Allergic Reactions [see Warnings and Precautions ( 5.7 )] Injection Site Reactions, including irritation and pain Porphyria Severe Cutaneous Reactions [see Warnings and Precautions ( 5.8 )] 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection 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 epoetin alfa with the incidence of antibodies to other products may be misleading. 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 ) ] .