Epoetin Alfa

Class: Hematopoietic Agents
VA Class: BL400
Chemical Name: 1-165-Erythropoietin (human clone λHEPOFL13 protein moiety)
Molecular Formula: C₈₀₉H₁₃₀₁N₂₂₉O₂₄₀S₅
CAS Number: 113427-24-0
Brands: Epogen, Procrit

Special Alerts:

[Posted 06/24/2011] ISSUE: FDA notified healthcare professionals that new, modified recommendations for more conservative dosing of Erythropoiesis-Stimulating Agents (ESAs) in patients with chronic kidney disease (CKD) have been approved to improve the safe use of these drugs. FDA has made these recommendations because of data showing increased risks of cardiovascular events with ESAs in this patient population. The new dosing recommendations are based on clinical trials showing that using ESAs to target a hemoglobin level of greater than 11 g/dL in patients with CKD provides no additional benefit than lower target levels, and increases the risk of experiencing serious adverse cardiovascular events, such as heart attack or stroke.

BACKGROUND: ESAs treat certain types of anemia by stimulating the bone marrow to produce red blood cells and by decreasing the need for blood transfusions. The manufacturer has revised the Boxed Warning, Warnings and Precautions, and Dosage and Administration sections of the labels for the ESAs to include this new information.

RECOMMENDATION: Healthcare professionals should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions in CKD patients against the increased risks for serious cardiovascular events, and should inform their patients of the current understanding of potential risks and benefits. Therapy should be individualized to the patient and the lowest possible ESA dose given to reduce the need for transfusions. See the Drug Safety Communication for additional information including a table of key trials and other supporting references. Treatment with ESAs in CKD was discussed at the Drug Safety and Risk Management Advisory Committee, held October 18, 2010. For summary minutes of that Advisory Committee, see the following link: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for epoetin alfa to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of epoetin alfa and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, Stroke, and Increased Risk of Tumor Progression or Recurrence


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  Increased risk of death, serious cardiovascular events, and stroke reported in patients with chronic renal failure (CRF) receiving therapy with epoetin alfa or other erythropoiesis-stimulating agents (ESAs) targeted to hemoglobin concentrations ≥13 g/dL in clinical studies.^{1 400 585 586 587 588 589 590 594 597 602 603 604 615 620 622} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions.)

  
  


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  Individualize dosing of ESAs in CRF patients to achieve and maintain hemoglobin concentrations within 10–12 g/dL.^{1 400 597}

  
  


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  ESA therapy shortened overall survival and increased risk of tumor progression or recurrence in some studies in patients with breast, non-small cell lung, head and neck, lymphoid, or cervical cancers.^{1 400 589 590 597 599 600 602 603 604 605 606} (See Increased Mortality and/or Tumor Progression under Cautions.)

  
  


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  To decrease these risks and risk of serious cardiovascular and thromboembolic events in anemic patients with cancer, titrate ESA dosage to lowest hemoglobin concentration sufficient to avoid RBC transfusion.^{1 400 585 586 587 588 589 590 597}

  
  


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  Epoetin alfa may be prescribed and/or dispensed to cancer patients only by clinicians and institutions enrolled in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program.^{1 619 621} (See Risk Management Plan under Dosage and Administration.)

  
  


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  Use ESAs in cancer patients only for treatment of anemia caused by concomitant myelosuppressive chemotherapy.^{1 400 589 590 597 602 603 604 605}

  
  


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  ESAs not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.^{1 400 597 608}

  
  


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  Discontinue ESAs following completion of a course of chemotherapy.^{1 400 597}

  
  


• 
  

  Consider DVT prophylaxis in surgical patients receiving epoetin alfa to reduce the need for allogeneic blood transfusions.^{1 400 589 590 602 604}

  
  

Introduction

Biosynthetic (recombinant DNA origin) form of the glycoprotein hormone erythropoietin, a hematopoietic agent that principally affects erythropoiesis.^{1 2 3 4 5 7 8 10 11 13 14 18 19 21 23 25 32 33 34 37 43 51 52 53 54 55 58 70 71 72 120 121 122 159 164 166 169 174 187 206 222 236 246 255 305 336 346 366 399 400 405 408 414 418 453 464}

Uses for Epoetin Alfa

Anemia of Chronic Renal Failure

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment of anemia associated with CRF; designated an orphan drug by FDA for this use.^{1 3 4 5 11 22 23 32 50 51 52 53 59 65 66 68 70 76 77 119 122 159 165 173 283 312 322 324 336 366 371 400 410 414 519}

First-line therapy for appropriately selected patients with anemia of CRF.^{2 51 453 510 565 601}

Used to increase and/or maintain hemoglobin concentrations and hematocrit and decrease the need for transfusions.^{1 3 4 5 11 22 23 32 66 70 119 173 303 324 366 400 410}

Used in patients who currently are undergoing dialysis therapy, as well as predialysis patients with severe symptoms of anemia who do not yet require maintenance dialysis.^{1 3 4 5 11 22 23 32 50 51 52 53 59 65 66 68 70 76 77 119 122 159 165 173 283 312 322 324 336 366 371 400 410 414} Manufacturers and some authorities recommend use in patients with end-stage renal disease who currently are undergoing hemodialysis or peritoneal dialysis therapy and also in predialysis patients with CRF who have a hematocrit <30% or hemoglobin concentration <10 g/dL.^{1 6 11 34 66 112 119 173 247 278 298 312 322 324 400 410 601}

Some evidence suggests once-weekly darbepoetin alfa has similar safety and efficacy as equivalent doses of epoetin alfa given 2 or 3 times weekly in patients with CRF undergoing hemodialysis or peritoneal dialysis.^{573 574 575 576 577 578 579 580}

ESAs, including epoetin alfa, may increase risk for death and serious cardiovascular events when targeted to hemoglobin concentrations ≥13 g/dL.^{1 114 166 187 261 336 400 518 584 585 586 587 588 589 590 594 597 602 603 604 615 620 622} (See Boxed Warning.) FDA has issued public health advisories regarding risks with ESAs;^{584 585 586 587 588 589 590 602 603 604} FDA cautions that dosage of these drugs in patients with CRF should be individualized to achieve and maintain hemoglobin concentrations of 10–12 g/dL.^{1 400 597 602 603 604} Renal Physicians Association (RPA) states that the clinical standard of care in patients with chronic kidney disease or end-stage renal failure now advocated by the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) is use of lowest ESA dosage that will gradually increase target hemoglobin concentration to 11–12 g/dL and not exceed 13 g/dL.^{510 565 596 601 613} RPA advises consideration of individual patient risks and benefits and use of evidence-based guidelines in changing anemia management regimens to avoid unacceptably low hemoglobin concentrations in CRF patients.⁵⁹⁶

Not intended for patients with CRF who require acute correction of severe anemia; should not be used as a substitute for emergency transfusion.^{1 366 400}

Zidovudine-induced Anemia in HIV-infected Patients

Treatment of anemia associated with zidovudine therapy in patients with HIV infection (designated an orphan drug by FDA for this use).^{1 2 122 124 187 199 286 293 294 335 400 429 444 452 478 519 554 1 2 122 124 187 199 286 293 294 335 400 429 444 452 554}

Used to increase and/or maintain hemoglobin concentrations and hematocrit and decrease the need for transfusions.^{1 2 122 124 187 199 286 293 294 335 400 429 444 452 554} Response demonstrated in patients with endogenous serum erythropoietin concentrations of ≤500 milliunits/mL receiving zidovudine ≤4.2 g per week.^{1 335 400 429 444 478 523}

Correction of hemoglobin to concentrations >12 g/dL not recommended because of the risk of adverse effects, including death and serious and/or life-threatening cardiovascular events.^{1 114 166 187 261 336 400 518 584 585 586 587 588 589 590 594} (See Boxed Warning.)

Has been used to treat anemia associated with HIV infection in patients not receiving zidovudine†.^{452 523}

Not indicated for the treatment of anemia due to folate or iron deficiency, hemolysis, or GI bleeding; manage using other measures.^{1 400 478}

Chemotherapy-induced Anemia in Patients with Nonmyeloid Malignancies

Treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies; used to decrease the need for blood transfusions in patients who will be receiving therapy with antineoplastic agents for ≥2 months.^{1 187 247 288 296 344 348 358 359 400 524 525 527 528 530 534 535 536 537 538 572 583}

Not indicated for the treatment of anemia due to folate or iron deficiency, hemolysis, or GI bleeding; manage using other measures.^{1 400}

ESAs not indicated in patients with chemotherapy-induced anemia when the anticipated outcome is cure of the underlying malignancy.^{1 400 608} ESAs do not improve outcomes of cancer chemotherapy (e.g., in terms of greater tumor shrinkage, delayed tumor progression, increased survival).^{1 400 589 590 597 599 600 602 603 604 607 608 609 614} Not established that ESAs improve health-related quality of life, including effects on fatigue, energy, or strength, in patients with chemotherapy-induced anemia.^{589 590}

Chronic Anemia Associated with Malignancy

Epoetin alfa and other ESAs not indicated for use in anemic patients with active malignant disease who are not receiving cancer chemotherapy†.^{1 400 597}

Has been used for the treatment and prevention of the normocytic, normochromic anemia associated with malignancy†;^{4 10 122 187 247 296 348 349 404 405 411 412 413 461 464 510 518 524 525 529 530 601} however, ESAs shorten the time to death and/or tumor progression in such patients when therapy is targeted to hemoglobin concentrations >12 g/dL.^{1 400 589 590 611}

Reduction of Allogeneic Blood Transfusions in Anemic Surgical Patients

Treatment of anemic patients (hemoglobin >10 to ≤13 g/dL) scheduled to undergo elective, noncardiac, nonvascular surgery; used preoperatively to reduce the need for allogeneic blood transfusions.^{1 161 173 174 187 199 211 239 247 344 377 400 406 419 453 464 510}

Indicated for such patients who are at high risk for perioperative transfusion and substantial, anticipated blood loss. ^{1 400}

Not indicated to increase volume of blood available for donation in patients who are able and willing to donate autologous blood prior to elective surgery.^{1 400}

Not indicated for reduction of allogeneic RBC transfusions in patients scheduled for cardiac surgery†.^{1 400 597 601} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions.)

Anemia Associated with Rheumatoid Arthritis and Rheumatic Disease

Has been used for treatment of anemia associated with rheumatoid arthritis and/or rheumatic disease.^{2 4 5 7 10 122 154 174 187 247 336 344 373 420 437 462 464 510}

Anemia of Prematurity

May be beneficial in the treatment of anemia of prematurity†.^{2 18 36 37 187 331 336 338 350 453 465 519 562 563 564} Optimal patient selection criteria not established.^{338 562 563 564}

Myelodysplastic Syndrome

Has been used in patients with myelodysplastic syndromes (designated an orphan drug by FDA for this use).^{460 464 519 531 532 533} Relatively limited response rates reported; effects of the hormone on nonerythroid cell lines and potential risks of leukemic transformation require elucidation.^{460 464 531 532 533}

Misuse and Abuse

Potential exists for abuse of the drug by athletes, especially those participating in high-aerobic demand, endurance-type events.^{4 21 247 385 386 453 468 469 501} Effects of epoetin alfa would be expected to be similar to those of homologous or autologous RBC cell transfusions (“blood doping”), which have been used by athletes to increase cardiac output, maximal oxygen uptake capacity of blood, and aerobic exercise endurance by increasing arterial blood oxygen content; effects may be particularly evident in individuals with greater initial aerobic fitness.^{21 340 341 342 343 385 386 501}

Abuse by athletes is difficult to detect; no reliable way to distinguish epoetin alfa from the endogenous hormone using readily available drug-screening methods (e.g., immunoradiometric assay).^{4 385 386}

Medical and sports experts, including the US and International Olympic Committees and the National Collegiate Athletic Association, consider the use of epoetin alfa to enhance athletic ergogenic potential inappropriate and unacceptable; use by athletes is contrary to the rules and ethical principles of athletic competition.^{469 504 508 510 518}

Epoetin Alfa Dosage and Administration

General

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  Administer under the supervision of a health-care professional.^{1 400 510 518} (See Advice to Patients.)

  
  


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  Titrate to the lowest dosage that will gradually increase hemoglobin to the lowest concentration sufficient to avoid RBC transfusion.^{1 400 589 590} Do not exceed a hemoglobin concentration of 12 g/dL or a rate of increase in hemoglobin concentrations of 1 g/dL in any 2-week period.^{1 400 589 590}

  
  

Risk Management Plan

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  A required risk management plan (Risk Evaluation and Mitigation Strategy, REMS) has been developed for all ESAs.^{1 619}

  
  


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  A medication guide explaining the risks and benefits of ESA therapy must be distributed to and discussed with all patients receiving these drugs.^{615 619 621}

  
  


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  In addition, the APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program has been created to minimize risk of decreased survival and poor tumor response in cancer patients receiving ESAs.^{1 619} Clinicians and institutions must enroll in and comply with all requirements of the program (e.g., training module, signed acknowledgment of patient counseling) before they can prescribe and/or dispense ESAs to patients with cancer; participants must re-enroll every 3 years.^{1 619} For additional information or to enroll in the ESA APPRISE Oncology program, contact 866-284-8089 or visit www.esa-apprise.com.¹

  
  

Administration

Administer by IV or sub-Q injection.¹ IV injection recommended in patients with CRF undergoing hemodialysis.^{1 400 581 582}

Do not dilute or shake prior to use; vigorous shaking may physically denature the glycoprotein structure and inactivate the molecule.^{1 400}

IV Administration

Administer by direct IV injection.^{1 400}

Commercially available epoetin alfa injection generally⁵¹⁸ should not be diluted further prior to administration nor transferred to other containers and/or admixed with other drugs or IV solutions.^{187 251 366 467 518}

Epoetin alfa injections should not be administered through the same IV tubing as other drugs.^{1 366 400}

In patients undergoing hemodialysis, injection into the venous return line of the dialysis tubing following dialysis eliminates the need for additional venous access.^{1 50 51 59 65 66 68 70 112 115 122 138 173 187 233 247 256 306 400}

Sub-Q Administration

At the time of administration, preservative-free epoetin alfa (single-use vial) can be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection (preserved with benzyl alcohol) in a 1:1 ratio; presence of benzyl alcohol may ameliorate injection site discomfort.^{1 400}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Potency of epoetin alfa has been expressed in units of activity per mg of protein^{268 509} as tested against the WHO Second International Reference Preparation of human urinary erythropoietin.^{268 355}

Pediatric Patients

Anemia of Chronic Renal Failure

IV or Sub-Q

Children and infants ≥1 month of age on dialysis: Initially, 50 units/kg 3 times weekly; IV administration recommended in patients undergoing hemodialysis.^{1 400}

Children ≥3 months of age who do not require dialysis†: 50–250 units/kg 1–3 times weekly has been used.^{1 400}

Maintenance dosage: Median of 167 units/kg (range 49–447 units/kg) or 76 units/kg (range 24–323 units/kg) per week in 2 or 3 divided doses weekly used in pediatric hemodialysis or peritoneal dialysis patients, respectively, in clinical studies.^{1 400}

Dosage Modifications

If the hemoglobin has not increased by ≥1 g/dL within 4 weeks and iron stores are adequate, increase dosage by approximately 25%.^{1 400} Thereafter, dosage may be increased at 4-week intervals to achieve and maintain a hemoglobin of 10–12 g/dL.^{1 400 589 590}

Monitor hemoglobin concentration twice weekly until stabilized during initiation of therapy and at regular intervals thereafter.^{1 400} Following dosage adjustment, monitor hemoglobin concentrations weekly for at least 2–6 weeks until stabilized, then at regular intervals thereafter.^{1 400} Dosage adjustments should not be made more frequently than once a month; 2–6 weeks are required to elicit a clinically important change in hemoglobin following dosage adjustment.^{1 400 590}

If the hemoglobin approaches 12 g/dL or increases by >1 g/dL in any 2-week period, reduce dosage by approximately 25%.^{1 400} If the hemoglobin continues to increase, withhold therapy temporarily until the hemoglobin begins to fall, then resume at a dosage approximately 25% less than the previous dosage.^{1 400}

Maintenance dosages subject to interindividual variation;³³⁶ titrate according to patient response.^{1 29 32 70 112 122 186 187 247 303 366 400 601}

Zidovudine-associated Anemia in HIV-infected Patients

IV or Sub-Q

Children 8 months to 17 years of age have received dosages of 50–400 units/kg 2 or 3 times weekly.^{1 400}

Chemotherapy-induced Anemia in Patients with Nonmyeloid Malignancies

IV

Do not initiate epoetin alfa therapy if hemoglobin concentration ≥10 g/dL.^{1 400}

Initially, 600 units/kg (maximum 40,000 units) once weekly.^{1 400 583 601}

Discontinue epoetin alfa therapy following completion of a course of chemotherapy.^{1 400 589 590} (See Boxed Warning.)

Dosage Modifications

If the hemoglobin has not increased by ≥1 g/dL within 4 weeks (in the absence of RBC transfusion), increase weekly dosage to 900 units/kg (maximum 60,000 units weekly).^{1 400}

Titrate dosage to achieve and maintain the lowest hemoglobin concentration sufficient to avoid RBC transfusions.^{1 400 584 585 586 587 588 589 590}

If epoetin alfa therapy produces a very rapid hemoglobin response (e.g., an increase of >1 g/dL in any 2-week period) or if hemoglobin reaches a concentration sufficient to avoid the need for RBC transfusion, reduce dosage by 25%.^{1 400} If hemoglobin exceeds a level needed to avoid RBC transfusion, withhold therapy until the hemoglobin falls to a level where RBC transfusion may be required, then resume at a dosage 25% less than the previous dosage.^{1 400 601}

Discontinue epoetin alfa therapy after 8 weeks if no response based on hemoglobin concentrations or if RBC transfusions are still required.^{1 400}

Adults

Anemia of Chronic Renal Failure

IV or Sub-Q

Initially, 50–100 units/kg 3 times weekly; IV administration recommended in patients undergoing hemodialysis.^{1 400}

Median maintenance dosage of 75 units/kg (range: 12.5–525 units/kg) 3 times weekly in clinical studies in patients on hemodialysis.^{1 400}

Dosages of 75–150 units/kg per week shown to maintain hematocrit of 36–38% for up to 6 months in patients not on dialysis.^{1 400}

Individually titrate dosage to achieve and maintain hemoglobin concentration in the range of 10–12 g/dL.^{1 400} (See Boxed Warning.)

Dosage Modifications

Increase dosage by approximately 25% if the hemoglobin is <10 g/dL and has not increased by ≥1 g/dL within 4 weeks (in the presence of adequate iron stores) or if hemoglobin drops below 10 g/dL.^{1 400} Thereafter, increase dosage at 4-week intervals until the specified hemoglobin is obtained.^{1 400}

Monitor hemoglobin concentration twice weekly until stabilized during initiation of therapy and at regular intervals thereafter.^{1 400} Following dosage adjustment, monitor hemoglobin concentrations weekly for at least 2–6 weeks until stabilized, then at regular intervals thereafter.^{1 400} Dosage adjustments should not be made more frequently than once a month; 2–6 weeks are required to elicit a clinically important change in hemoglobin following dosage adjustment.^{1 400 590}

If hemoglobin of 10–12 g/dL not obtained despite appropriate dosage titration of epoetin alfa over a 12-week period, do not increase dosage; continue therapy at the lowest dosage that will gradually increase hemoglobin to the lowest concentration sufficient to avoid recurrent RBC transfusion.^{1 400} In addition, evaluate and treat patient for other causes of anemia.^{1 400} Discontinue epoetin alfa therapy if responsiveness does not improve and patient requires recurrent RBC transfusions.^{1 400}

If the hemoglobin approaches 12 g/dL or increases by >1 g/dL in any 2-week period, reduce dosage by approximately 25%.^{1 400} If the hemoglobin continues to increase, withhold therapy temporarily until the hemoglobin begins to fall, then resume at a dosage approximately 25% less than the previous dosage.^{1 400}

Maintenance dosages: subject to interindividual variation; ³³⁶ titrate according to patient response.^{1 29 32 70 112 122 186 187 247 303 366 400}

Zidovudine-associated Anemia in HIV-infected Patients

IV or Sub-Q

Initially, 100 units/kg 3 times weekly for 8 weeks in patients with endogenous serum erythropoietin concentrations ≤500 milliunits/mL receiving ≤4.2 g/week of zidovudine.^{1 400 601}

Titrate dosage to achieve and maintain the lowest hemoglobin concentration sufficient to avoid the need for RBC transfusion, not to exceed a hemoglobin of 12 g/dL.^{1 400}

If the response is not satisfactory (transfusion requirements not reduced or hemoglobin not increased) after 8 weeks, increase the 3-times-weekly dose by 50–100 units/kg.^{1 400 478} Thereafter, increase the 3-times-weekly dose every 4–8 weeks in increments of 50–100 units/kg as necessary.^{1 400}

If the hemoglobin is >12 g/dL, withhold drug until the hemoglobin de