These Highlights Do Not Include All The Information Needed To Use Retacrit Safely And Effectively. See Full Prescribing Information For Retacrit.

Chronic Kidney Disease:

• •
  In controlled trials, patients with chronic kidney disease (CKD) experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL [see Warnings and Precautions (5.1)].
• •
  No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Dosage and Administration (2.2)].
• •
  Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions (5.1)].

Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. When exposed to freezing temperatures, the green area of the freeze strip indicator in the carton of the multiple-dose vials will show signs of cloudy or white discoloration.

Do not shake. Do not use RETACRIT that has been shaken or frozen or if the green area of the freeze strip indicator is cloudy or white.

Store RETACRIT vials in the original carton until use to protect from light.

The vial stopper used for RETACRIT is not made with natural rubber latex.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse of RETACRIT may be seen in athletes for the effects on erythropoiesis. Abuse of drugs that increase erythropoiesis, such as RETACRIT, by healthy persons may lead to life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism) [see Warnings and Precautions (5.1)].

In animal studies, epoetin alfa did not distribute to the CNS nor produce behavioral effects that are consistent with CNS activity.

Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, 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.

RETACRIT overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of RETACRIT dosage and/or with phlebotomy, as clinically indicated [see Clinical Pharmacology (12.2)]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.3)].

Epoetin alfa-epbx is an erythropoiesis-stimulating agent. Epoetin alfa-epbx is a 165-amino acid glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced in Chinese Hamster Ovary (CHO) cell line. The product contains the identical amino acid sequence of isolated natural erythropoietin.

RETACRIT (epoetin alfa-epbx) injection for intravenous or subcutaneous administration is a sterile, clear, colorless solution in vials in multiple formulations.

Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx contains calcium chloride dihydrate (0.01 mg), glycine (7.5 mg), isoleucine (1 mg), leucine (1 mg), L-glutamic acid (0.25 mg), phenylalanine (0.5 mg), polysorbate 20 (0.1 mg), sodium chloride (2.4 mg), sodium phosphate dibasic anhydrous (4.9 mg), sodium phosphate monobasic monohydrate (1.3 mg), and threonine (0.25 mg), in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 7.0 – 7.5).

Each 1 mL multiple-dose vial of 20,000 Units of epoetin alfa-epbx contains benzyl alcohol (8.5 mg), L-methionine (0.45 mg), polysorbate 20 (0.04 mg), sodium phosphate dibasic anhydrous (0.09 mg), sodium phosphate monobasic monohydrate (2.67 mg), and sucrose (60 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6).

Each 2 mL multiple-dose vial of 20,000 Units (10,000 Units/mL) of epoetin alfa-epbx contains benzyl alcohol (17 mg), L-methionine (0.9 mg), polysorbate 20 (0.08 mg), sodium phosphate dibasic anhydrous (0.18 mg), sodium phosphate monobasic monohydrate (5.34 mg), and sucrose (120 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6).

RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, 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 epoetin alfa.

Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].

The multiple-dose vials are formulated with benzyl alcohol and are contraindicated for use in neonates and infants [see Contraindications (4), Warnings and Precautions (5.9)]. When therapy with RETACRIT is needed in neonates and infants, use the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix the single-dose vials with bacteriostatic saline when administering RETACRIT to neonates or infants because it contains benzyl alcohol [see Dosage and Administration (2.6)].

Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.9)].

Of the 4553 patients who received epoetin alfa 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 epoetin alfa 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 [see Dosage and Administration (2)].

Among 778 patients enrolled in the 3 clinical studies of epoetin alfa for the treatment of anemia due to concomitant chemotherapy, 419 received epoetin alfa and 359 received placebo. Of the 419 who received epoetin alfa, 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 epoetin alfa in geriatric and younger patients within the 3 studies were similar.

Among 1731 patients enrolled in the 6 clinical studies of epoetin alfa for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received epoetin alfa and 646 received placebo or standard of care treatment. Of the 1085 patients who received epoetin alfa, 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 epoetin alfa 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 epoetin alfa for the treatment of patients treated with zidovudine for HIV infection to determine whether they respond differently from younger patients.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of epoetin alfa or of other epoetin alfa products.

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)].

• •
  Uncontrolled hypertension (4).
• •
  Pure red cell aplasia (PRCA) that begins after treatment with RETACRIT or other erythropoietin protein drugs (4).
• •
  Serious allergic reactions to RETACRIT or other epoetin alfa products (4).
• •
  Use of the multiple-dose vials containing benzyl alcohol in neonates, infants, pregnant women, and lactating women (4).

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)]

The recommended RETACRIT 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 RETACRIT therapy [see Warnings and Precautions (5.1)].

RETACRIT^® (Ret-uh-krit)

(epoetin alfa-epbx)

Use these Instructions for Use if you or your caregiver has been trained to give RETACRIT 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 RETACRIT for the most important information you need to know.

When you receive your RETACRIT vial make sure that:

• •
  The name RETACRIT appears on the carton and vial label.
• •
  The expiration date on the vial label has not passed. Do not use a vial of RETACRIT after the expiration date on the label.
• •
  The dose strength of the RETACRIT vial (number of Units per mL on the vial label) is the same as your healthcare provider prescribed.
• •
  You understand what the dose strength of RETACRIT means. RETACRIT vials come in several dose strengths. For example, the dose strength may be described as 10,000 Units/mL on the vial label. This strength means that 10,000 Units of medicine are contained in each 1 mL (milliliter) of liquid. Your healthcare provider may also refer to a mL as a "cc." One mL is the same as one "cc."
• •
  The RETACRIT liquid in the vial is clear and colorless. Do not use RETACRIT if the liquid in the vial looks discolored or cloudy, or if the liquid has lumps, flakes, or particles.
• •
  The RETACRIT vial has a color cap on the top of the vial. Do not use a vial of RETACRIT if the color cap on the top of the vial has been removed or is missing.
• •
  Use only the type of disposable syringe and needle that your healthcare provider has prescribed.
• •
  Do not shake RETACRIT. Shaking could cause RETACRIT not to work. If you shake RETACRIT, the solution in the vial may look foamy and should not be used.
• •
  Do not freeze RETACRIT. Do not use a vial of RETACRIT that has been frozen.
• •
  Do not use the carton of RETACRIT multiple-dose vials if it has been frozen or if the green area on the freeze strip indicator inside the RETACRIT carton looks white or cloudy.
• •
  Store RETACRIT in the refrigerator between 36°F to 46°F (2°C to 8°C).
• •
  Keep RETACRIT away from light.
• •
  Single-dose vials of RETACRIT should be used only one time. Throw the vial away after use even if there is medicine left in the vial.
• •
  After removing a dose from the multiple-dose vial, store the vial in the refrigerator (but not the freezer). Do not store the vial for more than 21 days.
• •
  Throw away the multiple-dose vials as directed by your healthcare provider:
  • o
    if there is not enough medicine left in the multiple-dose vial for another dose, or
  • o
    if it has been more than 21 days since you first put a needle into the multiple-dose vial

How should I prepare for an injection of RETACRIT?

• •
  Always keep an extra syringe and needle on hand.
• •
  Follow your healthcare provider's instructions on how to measure your dose of RETACRIT. This dose will be measured in Units per mL or cc (1 mL is the same as 1 cc). Use a syringe that is marked in tenths of mL (for example, 0.2 mL or 0.2 cc). Using the wrong syringe can lead to a mistake in your dose and you could inject too much or too little RETACRIT.

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 RETACRIT vials?

RETACRIT comes in two different types of vials:

• •
  Single-dose vials
• •
  Multiple-dose vials

The multiple-dose vial of RETACRIT 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. RETACRIT that comes in single-dose vials does not contain benzyl alcohol.

Important: Follow these instructions exactly to help avoid infections.

Preparing the dose:

• 1.
  Remove the vial of RETACRIT from the refrigerator. During this time, protect the solution from light.
• 2.
  Do not use a single-dose vial of RETACRIT more than one time.
• 3.
  Do not shake RETACRIT.
• 4.
  Gather the other supplies you will need for your injection (vial, syringe, alcohol wipes, cotton ball, and a puncture-proof container for throwing away the syringe and needle). See Figure 1.
  
  

Figure 1

• 5.
  Check the date on the RETACRIT vial to be sure that the drug has not expired.
• 6.
  Wash your hands well with soap and water before preparing the medicine. See Figure 2.
  
  

Figure 2

• 7.
  Flip off the protective color cap on the top of the vial. Do not remove the grey rubber stopper. Wipe the top of the grey rubber stopper with an alcohol wipe. See Figures 3 and 4.

• 8.
  Check the package containing the syringe. If the package has been opened or damaged, do not use that syringe. Throw away the syringe in the puncture-proof disposable container. If the syringe package is undamaged, open the package and remove the syringe.
• 9.
  Using a syringe and needle that has been recommended by your healthcare provider, carefully remove the needle cover. See Figure 5. Then draw air into the syringe by pulling back on the plunger. The amount of air drawn into the syringe should be equal to the amount (mL or cc) of the RETACRIT dose prescribed by your healthcare provider. See Figure 6.

• 10.
  With the vial on a flat work surface, insert the needle straight down through the grey rubber stopper of the RETACRIT vial. See Figure 7.
• 11.
  Push the plunger of the syringe down to inject the air from the syringe into the vial of RETACRIT. The air injected into the vial will allow RETACRIT to be easily withdrawn into the syringe. See Figure 7.
  
  

Figure 7

• 12.
  Keep the needle inside the vial. Turn the vial and syringe upside down. Be sure the tip of the needle is in the RETACRIT liquid. Keep the vial upside down. Slowly pull back on the plunger to fill the syringe with RETACRIT liquid to the number (mL or cc) that matches the dose your healthcare provider prescribed. See Figure 8.
  
  

Figure 8

• 13.
  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 RETACRIT 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 RETACRIT 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.

• 14.
  Double-check that you have the correct dose in the syringe. Lay the vial down on its side with the needle still in it until after you have selected and prepared your site for injection.

Selecting and preparing the injection site:

RETACRIT can be injected into your body using two different ways (routes) as described below. Follow your healthcare provider's instructions about how you should inject RETACRIT. In patients on hemodialysis, the intravenous (IV) route is recommended.

• 1.
  Subcutaneous Route:
  • •
    RETACRIT can be injected directly into a layer of fat under your skin. This is called a subcutaneous injection. When giving subcutaneous injections, follow your healthcare provider's instructions about changing the site for each injection. You may wish to write down the site where you have injected.
  • •
    Do not inject RETACRIT into an area that is tender, red, bruised, hard, or has scars or stretch marks. Recommended sites for injection are shown in Figure 11 below, including:
    • o
      The outer area of the upper arms
    • o
      The abdomen (except for the 2-inch area around the navel)
    • o
      The front of the middle thighs
    • o
      The upper outer area of the buttocks
      
      

Figure 11

•  
  • •
    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.
    
    

Figure 12

•  
  • •
    Double-check that the correct amount of RETACRIT is in the syringe.
  • •
    Remove the prepared syringe and needle from the vial of RETACRIT 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.

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.

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.
• 2.
  Intravenous Route:
  • •
    RETACRIT can be injected in your vein through a special access port placed by your healthcare provider. This type of RETACRIT 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.
    
    

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 RETACRIT. See Figure 16.

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 RETACRIT 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 Hospira, Inc., a Pfizer Company, Lake Forest, IL 60045 USA

US License No. 1974

Distributed by Vifor (International) Inc., Rechenstrasse 37, 9014 St. Gallen, Switzerland

LAB-1282-5.0

Revised: 6/2024

Epoetin alfa products increase 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 epoetin alfa products administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.

In adult and pediatric patients with CKD, the elimination half-life (t_1/2) of plasma erythropoietin after intravenous administration of epoetin alfa ranged from 4 to 13 hours. After subcutaneous administration, C_max was achieved within 5 to 24 hours. The t_1/2 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 epoetin alfa t_1/2 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 C_max (3- to 7-fold), longer T_max (2- to 3-fold), higher AUC_{0–168 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 t_1/2 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 T_max 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 T_max (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 epoetin alfa in pediatric patients appeared similar to that of adults.

The pharmacokinetics of epoetin alfa products has not been studied in patients with HIV infection.

The safety and efficacy of epoetin alfa 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 epoetin alfa, 100 Units/kg epoetin alfa, 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 epoetin alfa 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 epoetin alfa 300 Units/kg, 6/26 (23%) of patients treated with epoetin alfa 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 epoetin alfa (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 epoetin alfa is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per epoetin alfa-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 epoetin alfa.

Epoetin alfa 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 epoetin alfa (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.

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

RETACRIT 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.

RETACRIT is an erythropoiesis-stimulating agent (ESA) indicated for:

• •
  Treatment of anemia due to
  • o
    Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis (1.1).
  • o
    Zidovudine in patients with Human Immunodeficiency Virus (HIV) infection (1.2).
  • o
    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

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

RETACRIT 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).

Epoetin alfa products stimulate erythropoiesis by the same mechanism as endogenous erythropoietin.

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

RETACRIT contains epoetin alfa-epbx, which is not a controlled substance.

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 epoetin alfa. 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 RETACRIT is not approved).

If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer Company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.

• •
  Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1).
• •
  Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2).
• •
  Hypertension: Control hypertension prior to initiating and during treatment with RETACRIT (5.3).
• •
  Seizures: Epoetin alfa products increase the risk for seizures in patients with CKD (5.4). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.4).
• •
  PRCA: If severe anemia and low reticulocyte count develop during RETACRIT treatment, withhold RETACRIT and evaluate for PRCA (5.6).
• •
  Serious Allergic Reactions: Discontinue RETACRIT and manage reactions (5.7).
• •
  Severe Cutaneous Reactions: Discontinue RETACRIT (5.8).
• •
  Phenylketonurics: Contains phenylalanine (5.10).

• •
  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).

Injection

• •
  2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, and 10,000 Units/mL in single-dose vials (3).
• •
  20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol (3).

The following adverse reactions have been identified during post-approval use of epoetin alfa.

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)]

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

Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Inform patients:

• •
  Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression [see Warnings and Precautions (5.1, 5.2)].
• •
  To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions.
• •
  To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.
• •
  Of the need to have regular laboratory tests for hemoglobin.
• •
  Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and lactating women [see Use in Specific Populations (8.1, 8.2, 8.4)].

Instruct patients who self-administer RETACRIT of the:

• •
  Importance of following the Instructions for Use.
• •
  Dangers of reusing needles, syringes, or unused portions of single-dose vials.
• •
  Proper disposal of used syringes, needles, and unused vials, and of the full container.

• •
  Do not shake. Do not use RETACRIT 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 RETACRIT in preservative-free vials. Do not re-enter preservative-free vials.
• •
  Store unused portions of RETACRIT in multiple-dose vials at 2°C to 8°C (36°F to 46°F). Discard 21 days after initial entry.
• •
  Do not dilute. Do not mix with other drug solutions.
• •
  The vial stopper used for RETACRIT is not made with natural rubber latex.

Initiate RETACRIT 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 RETACRIT necessary to avoid RBC transfusions.

RETACRIT (epoetin alfa-epbx) injection is a sterile, clear, and colorless solution in single-dose and multiple-dose vials available as:

RETACRIT 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.

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 RETACRIT 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)].

The safety and effectiveness of epoetin alfa was assessed in two multicenter, randomized (1:1), 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.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.

The safety and efficacy of epoetin alfa 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 epoetin alfa and 88/130 placebo) with pre-study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, epoetin alfa 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 epoetin alfa versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Epoetin alfa 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 epoetin alfa (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 epoetin alfa 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, epoetin alfa therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.

For lack or loss of hemoglobin response to RETACRIT, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions (5.6)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see Dosage and Administration (2.2)].

NDC 59353-002-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

2,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-003-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

3,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-004-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

4,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-010-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

10,000 Units/mL

1 mL single-dose vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 2,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-002-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

2,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

NDC 59353-120-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/mL

1 mL Multiple-Dose Vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 3,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-003-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

3,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 4,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-004-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

4,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 10,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-010-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

10,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 20,000 Units/mL multiple-dose vials (containing 1 mL)

NDC 59353-120-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/mL

For Intravenous or Subcutaneous Use Only

Sterile Solution - Preserved

Multiple-Dose Vials

Rx only

RETACRIT 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.

NDC 59353-220-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/2 mL

(10,000 Units/mL)

2 mL Multiple-Dose Vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

NDC 59353-220-10

10 x 20,000 Units/2 mL (10,000 Units/mL) multiple-dose vials (containing 2 mL)

Retacrit^®

Epoetin Alfa-epbx

recombinant

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

For Intravenous or Subcutaneous Use Only

Sterile Solution - Preserved

Multiple-Dose Vials

Rx only

The carcinogenic potential of epoetin alfa products has not been evaluated.

Epoetin alfa was not mutagenic or clastogenic under the conditions tested: epoetin alfa was negative in the in vitro bacterial reverse mutation assay (Ames test), 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.

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 epoetin alfa 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.

RETACRIT is indicated for the treatment of anemia due to zidovudine administered at ≤ 4,200 mg/week in patients with HIV infection with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women [see Contraindications (4)]. In addition, do not mix RETACRIT with bacteriostatic saline (which also contains benzyl alcohol) when administering RETACRIT to these patient populations [see Dosage and Administration (2)].

Serious and fatal reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including RETACRIT multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. RETACRIT multiple-dose vials contain 8.5 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1 , 8.2 , and 8.4)].

• •
  In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 – 11.3 g/dL), epoetin alfa and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
• •
  Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
• •
  In controlled clinical trials of patients with cancer, epoetin alfa and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
• •
  In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.

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

ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).

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).

RETACRIT 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. RETACRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.

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:

• •
  In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1).
• •
  No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (2.2).
• •
  Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).

Cancer:

• •
  ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (5.2).
• •
  Use the lowest dose to avoid RBC transfusions (2.4).
• •
  Use ESAs only for anemia from myelosuppressive chemotherapy (1.3).
• •
  ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.5).
• •
  Discontinue following the completion of a chemotherapy course (2.4).

Perisurgery:

• •
  Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended (5.1).

Chronic Kidney Disease:

• •
  In controlled trials, patients with chronic kidney disease (CKD) experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL [see Warnings and Precautions (5.1)].
• •
  No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Dosage and Administration (2.2)].
• •
  Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions (5.1)].

Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. When exposed to freezing temperatures, the green area of the freeze strip indicator in the carton of the multiple-dose vials will show signs of cloudy or white discoloration.

Do not shake. Do not use RETACRIT that has been shaken or frozen or if the green area of the freeze strip indicator is cloudy or white.

Store RETACRIT vials in the original carton until use to protect from light.

The vial stopper used for RETACRIT is not made with natural rubber latex.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse of RETACRIT may be seen in athletes for the effects on erythropoiesis. Abuse of drugs that increase erythropoiesis, such as RETACRIT, by healthy persons may lead to life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism) [see Warnings and Precautions (5.1)].

In animal studies, epoetin alfa did not distribute to the CNS nor produce behavioral effects that are consistent with CNS activity.

Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, 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.

RETACRIT overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of RETACRIT dosage and/or with phlebotomy, as clinically indicated [see Clinical Pharmacology (12.2)]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.3)].

Epoetin alfa-epbx is an erythropoiesis-stimulating agent. Epoetin alfa-epbx is a 165-amino acid glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced in Chinese Hamster Ovary (CHO) cell line. The product contains the identical amino acid sequence of isolated natural erythropoietin.

RETACRIT (epoetin alfa-epbx) injection for intravenous or subcutaneous administration is a sterile, clear, colorless solution in vials in multiple formulations.

Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx contains calcium chloride dihydrate (0.01 mg), glycine (7.5 mg), isoleucine (1 mg), leucine (1 mg), L-glutamic acid (0.25 mg), phenylalanine (0.5 mg), polysorbate 20 (0.1 mg), sodium chloride (2.4 mg), sodium phosphate dibasic anhydrous (4.9 mg), sodium phosphate monobasic monohydrate (1.3 mg), and threonine (0.25 mg), in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 7.0 – 7.5).

Each 1 mL multiple-dose vial of 20,000 Units of epoetin alfa-epbx contains benzyl alcohol (8.5 mg), L-methionine (0.45 mg), polysorbate 20 (0.04 mg), sodium phosphate dibasic anhydrous (0.09 mg), sodium phosphate monobasic monohydrate (2.67 mg), and sucrose (60 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6).

Each 2 mL multiple-dose vial of 20,000 Units (10,000 Units/mL) of epoetin alfa-epbx contains benzyl alcohol (17 mg), L-methionine (0.9 mg), polysorbate 20 (0.08 mg), sodium phosphate dibasic anhydrous (0.18 mg), sodium phosphate monobasic monohydrate (5.34 mg), and sucrose (120 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6).

RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, 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 epoetin alfa.

Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].

The multiple-dose vials are formulated with benzyl alcohol and are contraindicated for use in neonates and infants [see Contraindications (4), Warnings and Precautions (5.9)]. When therapy with RETACRIT is needed in neonates and infants, use the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix the single-dose vials with bacteriostatic saline when administering RETACRIT to neonates or infants because it contains benzyl alcohol [see Dosage and Administration (2.6)].

Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.9)].

Of the 4553 patients who received epoetin alfa 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 epoetin alfa 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 [see Dosage and Administration (2)].

Among 778 patients enrolled in the 3 clinical studies of epoetin alfa for the treatment of anemia due to concomitant chemotherapy, 419 received epoetin alfa and 359 received placebo. Of the 419 who received epoetin alfa, 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 epoetin alfa in geriatric and younger patients within the 3 studies were similar.

Among 1731 patients enrolled in the 6 clinical studies of epoetin alfa for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received epoetin alfa and 646 received placebo or standard of care treatment. Of the 1085 patients who received epoetin alfa, 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 epoetin alfa 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 epoetin alfa for the treatment of patients treated with zidovudine for HIV infection to determine whether they respond differently from younger patients.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of epoetin alfa or of other epoetin alfa products.

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)].

• •
  Uncontrolled hypertension (4).
• •
  Pure red cell aplasia (PRCA) that begins after treatment with RETACRIT or other erythropoietin protein drugs (4).
• •
  Serious allergic reactions to RETACRIT or other epoetin alfa products (4).
• •
  Use of the multiple-dose vials containing benzyl alcohol in neonates, infants, pregnant women, and lactating women (4).

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)]

The recommended RETACRIT 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 RETACRIT therapy [see Warnings and Precautions (5.1)].

RETACRIT^® (Ret-uh-krit)

(epoetin alfa-epbx)

Use these Instructions for Use if you or your caregiver has been trained to give RETACRIT 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 RETACRIT for the most important information you need to know.

When you receive your RETACRIT vial make sure that:

• •
  The name RETACRIT appears on the carton and vial label.
• •
  The expiration date on the vial label has not passed. Do not use a vial of RETACRIT after the expiration date on the label.
• •
  The dose strength of the RETACRIT vial (number of Units per mL on the vial label) is the same as your healthcare provider prescribed.
• •
  You understand what the dose strength of RETACRIT means. RETACRIT vials come in several dose strengths. For example, the dose strength may be described as 10,000 Units/mL on the vial label. This strength means that 10,000 Units of medicine are contained in each 1 mL (milliliter) of liquid. Your healthcare provider may also refer to a mL as a "cc." One mL is the same as one "cc."
• •
  The RETACRIT liquid in the vial is clear and colorless. Do not use RETACRIT if the liquid in the vial looks discolored or cloudy, or if the liquid has lumps, flakes, or particles.
• •
  The RETACRIT vial has a color cap on the top of the vial. Do not use a vial of RETACRIT if the color cap on the top of the vial has been removed or is missing.
• •
  Use only the type of disposable syringe and needle that your healthcare provider has prescribed.
• •
  Do not shake RETACRIT. Shaking could cause RETACRIT not to work. If you shake RETACRIT, the solution in the vial may look foamy and should not be used.
• •
  Do not freeze RETACRIT. Do not use a vial of RETACRIT that has been frozen.
• •
  Do not use the carton of RETACRIT multiple-dose vials if it has been frozen or if the green area on the freeze strip indicator inside the RETACRIT carton looks white or cloudy.
• •
  Store RETACRIT in the refrigerator between 36°F to 46°F (2°C to 8°C).
• •
  Keep RETACRIT away from light.
• •
  Single-dose vials of RETACRIT should be used only one time. Throw the vial away after use even if there is medicine left in the vial.
• •
  After removing a dose from the multiple-dose vial, store the vial in the refrigerator (but not the freezer). Do not store the vial for more than 21 days.
• •
  Throw away the multiple-dose vials as directed by your healthcare provider:
  • o
    if there is not enough medicine left in the multiple-dose vial for another dose, or
  • o
    if it has been more than 21 days since you first put a needle into the multiple-dose vial

How should I prepare for an injection of RETACRIT?

• •
  Always keep an extra syringe and needle on hand.
• •
  Follow your healthcare provider's instructions on how to measure your dose of RETACRIT. This dose will be measured in Units per mL or cc (1 mL is the same as 1 cc). Use a syringe that is marked in tenths of mL (for example, 0.2 mL or 0.2 cc). Using the wrong syringe can lead to a mistake in your dose and you could inject too much or too little RETACRIT.

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 RETACRIT vials?

RETACRIT comes in two different types of vials:

• •
  Single-dose vials
• •
  Multiple-dose vials

The multiple-dose vial of RETACRIT 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. RETACRIT that comes in single-dose vials does not contain benzyl alcohol.

Important: Follow these instructions exactly to help avoid infections.

Preparing the dose:

• 1.
  Remove the vial of RETACRIT from the refrigerator. During this time, protect the solution from light.
• 2.
  Do not use a single-dose vial of RETACRIT more than one time.
• 3.
  Do not shake RETACRIT.
• 4.
  Gather the other supplies you will need for your injection (vial, syringe, alcohol wipes, cotton ball, and a puncture-proof container for throwing away the syringe and needle). See Figure 1.
  
  

Figure 1

• 5.
  Check the date on the RETACRIT vial to be sure that the drug has not expired.
• 6.
  Wash your hands well with soap and water before preparing the medicine. See Figure 2.
  
  

Figure 2

• 7.
  Flip off the protective color cap on the top of the vial. Do not remove the grey rubber stopper. Wipe the top of the grey rubber stopper with an alcohol wipe. See Figures 3 and 4.

• 8.
  Check the package containing the syringe. If the package has been opened or damaged, do not use that syringe. Throw away the syringe in the puncture-proof disposable container. If the syringe package is undamaged, open the package and remove the syringe.
• 9.
  Using a syringe and needle that has been recommended by your healthcare provider, carefully remove the needle cover. See Figure 5. Then draw air into the syringe by pulling back on the plunger. The amount of air drawn into the syringe should be equal to the amount (mL or cc) of the RETACRIT dose prescribed by your healthcare provider. See Figure 6.

• 10.
  With the vial on a flat work surface, insert the needle straight down through the grey rubber stopper of the RETACRIT vial. See Figure 7.
• 11.
  Push the plunger of the syringe down to inject the air from the syringe into the vial of RETACRIT. The air injected into the vial will allow RETACRIT to be easily withdrawn into the syringe. See Figure 7.
  
  

Figure 7

• 12.
  Keep the needle inside the vial. Turn the vial and syringe upside down. Be sure the tip of the needle is in the RETACRIT liquid. Keep the vial upside down. Slowly pull back on the plunger to fill the syringe with RETACRIT liquid to the number (mL or cc) that matches the dose your healthcare provider prescribed. See Figure 8.
  
  

Figure 8

• 13.
  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 RETACRIT 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 RETACRIT 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.

• 14.
  Double-check that you have the correct dose in the syringe. Lay the vial down on its side with the needle still in it until after you have selected and prepared your site for injection.

Selecting and preparing the injection site:

RETACRIT can be injected into your body using two different ways (routes) as described below. Follow your healthcare provider's instructions about how you should inject RETACRIT. In patients on hemodialysis, the intravenous (IV) route is recommended.

• 1.
  Subcutaneous Route:
  • •
    RETACRIT can be injected directly into a layer of fat under your skin. This is called a subcutaneous injection. When giving subcutaneous injections, follow your healthcare provider's instructions about changing the site for each injection. You may wish to write down the site where you have injected.
  • •
    Do not inject RETACRIT into an area that is tender, red, bruised, hard, or has scars or stretch marks. Recommended sites for injection are shown in Figure 11 below, including:
    • o
      The outer area of the upper arms
    • o
      The abdomen (except for the 2-inch area around the navel)
    • o
      The front of the middle thighs
    • o
      The upper outer area of the buttocks
      
      

Figure 11

•  
  • •
    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.
    
    

Figure 12

•  
  • •
    Double-check that the correct amount of RETACRIT is in the syringe.
  • •
    Remove the prepared syringe and needle from the vial of RETACRIT 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.

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.

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.
• 2.
  Intravenous Route:
  • •
    RETACRIT can be injected in your vein through a special access port placed by your healthcare provider. This type of RETACRIT 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.
    
    

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 RETACRIT. See Figure 16.

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 RETACRIT 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 Hospira, Inc., a Pfizer Company, Lake Forest, IL 60045 USA

US License No. 1974

Distributed by Vifor (International) Inc., Rechenstrasse 37, 9014 St. Gallen, Switzerland

LAB-1282-5.0

Revised: 6/2024

Epoetin alfa products increase 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 epoetin alfa products administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.

In adult and pediatric patients with CKD, the elimination half-life (t_1/2) of plasma erythropoietin after intravenous administration of epoetin alfa ranged from 4 to 13 hours. After subcutaneous administration, C_max was achieved within 5 to 24 hours. The t_1/2 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 epoetin alfa t_1/2 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 C_max (3- to 7-fold), longer T_max (2- to 3-fold), higher AUC_{0–168 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 t_1/2 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 T_max 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 T_max (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 epoetin alfa in pediatric patients appeared similar to that of adults.

The pharmacokinetics of epoetin alfa products has not been studied in patients with HIV infection.

The safety and efficacy of epoetin alfa 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 epoetin alfa, 100 Units/kg epoetin alfa, 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 epoetin alfa 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 epoetin alfa 300 Units/kg, 6/26 (23%) of patients treated with epoetin alfa 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 epoetin alfa (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 epoetin alfa is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per epoetin alfa-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 epoetin alfa.

Epoetin alfa 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 epoetin alfa (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.

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

RETACRIT 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.

RETACRIT is an erythropoiesis-stimulating agent (ESA) indicated for:

• •
  Treatment of anemia due to
  • o
    Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis (1.1).
  • o
    Zidovudine in patients with Human Immunodeficiency Virus (HIV) infection (1.2).
  • o
    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

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

RETACRIT 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).

Epoetin alfa products stimulate erythropoiesis by the same mechanism as endogenous erythropoietin.

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

RETACRIT contains epoetin alfa-epbx, which is not a controlled substance.

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 epoetin alfa. 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 RETACRIT is not approved).

If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer Company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.

• •
  Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1).
• •
  Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (5.2).
• •
  Hypertension: Control hypertension prior to initiating and during treatment with RETACRIT (5.3).
• •
  Seizures: Epoetin alfa products increase the risk for seizures in patients with CKD (5.4). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.4).
• •
  PRCA: If severe anemia and low reticulocyte count develop during RETACRIT treatment, withhold RETACRIT and evaluate for PRCA (5.6).
• •
  Serious Allergic Reactions: Discontinue RETACRIT and manage reactions (5.7).
• •
  Severe Cutaneous Reactions: Discontinue RETACRIT (5.8).
• •
  Phenylketonurics: Contains phenylalanine (5.10).

• •
  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).

Injection

• •
  2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, and 10,000 Units/mL in single-dose vials (3).
• •
  20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol (3).

The following adverse reactions have been identified during post-approval use of epoetin alfa.

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)]

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

Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Inform patients:

• •
  Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression [see Warnings and Precautions (5.1, 5.2)].
• •
  To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions.
• •
  To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.
• •
  Of the need to have regular laboratory tests for hemoglobin.
• •
  Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and lactating women [see Use in Specific Populations (8.1, 8.2, 8.4)].

Instruct patients who self-administer RETACRIT of the:

• •
  Importance of following the Instructions for Use.
• •
  Dangers of reusing needles, syringes, or unused portions of single-dose vials.
• •
  Proper disposal of used syringes, needles, and unused vials, and of the full container.

• •
  Do not shake. Do not use RETACRIT 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 RETACRIT in preservative-free vials. Do not re-enter preservative-free vials.
• •
  Store unused portions of RETACRIT in multiple-dose vials at 2°C to 8°C (36°F to 46°F). Discard 21 days after initial entry.
• •
  Do not dilute. Do not mix with other drug solutions.
• •
  The vial stopper used for RETACRIT is not made with natural rubber latex.

Initiate RETACRIT 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 RETACRIT necessary to avoid RBC transfusions.

RETACRIT (epoetin alfa-epbx) injection is a sterile, clear, and colorless solution in single-dose and multiple-dose vials available as:

RETACRIT 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.

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 RETACRIT 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)].

The safety and effectiveness of epoetin alfa was assessed in two multicenter, randomized (1:1), 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.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.

The safety and efficacy of epoetin alfa 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 epoetin alfa and 88/130 placebo) with pre-study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, epoetin alfa 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 epoetin alfa versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Epoetin alfa 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 epoetin alfa (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 epoetin alfa 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, epoetin alfa therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.

For lack or loss of hemoglobin response to RETACRIT, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions (5.6)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see Dosage and Administration (2.2)].

NDC 59353-002-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

2,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-003-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

3,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-004-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

4,000 Units/mL

1 mL single-dose vial

CSL Vifor

NDC 59353-010-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

10,000 Units/mL

1 mL single-dose vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 2,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-002-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

2,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

NDC 59353-120-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/mL

1 mL Multiple-Dose Vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 3,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-003-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

3,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 4,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-004-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

4,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 10,000 Units/mL single-dose vials (containing 1 mL)

NDC 59353-010-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

10,000 Units/mL

Phenylketonurics: Contains Phenylalanine, 0.5 mg per mL

For Intravenous or Subcutaneous Use Only

Single-dose vial

Discard unused portion

Rx Only

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

10 x 20,000 Units/mL multiple-dose vials (containing 1 mL)

NDC 59353-120-10

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/mL

For Intravenous or Subcutaneous Use Only

Sterile Solution - Preserved

Multiple-Dose Vials

Rx only

RETACRIT 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.

NDC 59353-220-01

Rx only

Retacrit^®

Epoetin Alfa-epbx

recombinant

20,000 Units/2 mL

(10,000 Units/mL)

2 mL Multiple-Dose Vial

CSL Vifor

ALWAYS DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT

NDC 59353-220-10

10 x 20,000 Units/2 mL (10,000 Units/mL) multiple-dose vials (containing 2 mL)

Retacrit^®

Epoetin Alfa-epbx

recombinant

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

For Intravenous or Subcutaneous Use Only

Sterile Solution - Preserved

Multiple-Dose Vials

Rx only

The carcinogenic potential of epoetin alfa products has not been evaluated.

Epoetin alfa was not mutagenic or clastogenic under the conditions tested: epoetin alfa was negative in the in vitro bacterial reverse mutation assay (Ames test), 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.

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 epoetin alfa 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.

RETACRIT is indicated for the treatment of anemia due to zidovudine administered at ≤ 4,200 mg/week in patients with HIV infection with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women [see Contraindications (4)]. In addition, do not mix RETACRIT with bacteriostatic saline (which also contains benzyl alcohol) when administering RETACRIT to these patient populations [see Dosage and Administration (2)].

Serious and fatal reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including RETACRIT multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. RETACRIT multiple-dose vials contain 8.5 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1 , 8.2 , and 8.4)].

• •
  In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 – 11.3 g/dL), epoetin alfa and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
• •
  Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
• •
  In controlled clinical trials of patients with cancer, epoetin alfa and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
• •
  In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.

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

ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).

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).

RETACRIT 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. RETACRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.

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:

• •
  In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1).
• •
  No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (2.2).
• •
  Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).

Cancer:

• •
  ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (5.2).
• •
  Use the lowest dose to avoid RBC transfusions (2.4).
• •
  Use ESAs only for anemia from myelosuppressive chemotherapy (1.3).
• •
  ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.5).
• •
  Discontinue following the completion of a chemotherapy course (2.4).

Perisurgery:

• •
  Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended (5.1).