Epoetin Alfa (Erythropoietin; EPO)

( Erythropoietin ; EPO ) Pronunciation: (e-POE-e-tin AL-fa)Class: Recombinant human erythropoietin

Trade Names:Epogen- Injection, solution 2,000 units/mL- Injection, solution 3,000 units/mL- Injection, solution 4,000 units/mL- Injection, solution 10,000 units/mL- Injection, solution 20,000 units/mL- Injection, solution 40,000 units/mL

Trade Names:Procrit- Injection, solution 2,000 units/mL- Injection, solution 3,000 units/mL- Injection, solution 4,000 units/mL- Injection, solution 10,000 units/mL- Injection, solution 20,000 units/mL- Injection, solution 40,000 units/mL

Eprex (Canada)

Pharmacology

Stimulates RBC production.

Pharmacokinetics

Absorption

T max is 5 to 24 h (subcutaneous).

Elimination

Elimination half-life is approximately 4 to 13 h (IV).

Special Populations

Elderly

Pharmacokinetic data indicate no apparent difference in half-life among adult patients older or younger than 65 yr of age.

Children

Pharmacokinetic profile in children and adolescents is similar to that of adults. Limited data are available for neonates.

Indications and Usage

Treatment of anemia related to chronic renal failure (CRF), anemia related to zidovudine therapy in HIV-infected patients, and anemia due to chemotherapy in patients with metastatic nonmyeloid malignancies; reduction of allogeneic blood transfusions in surgery patients.

Unlabeled Uses

Anemia associated with critically ill patients, CHF, chronic disease (eg, rheumatoid arthritis), postpartum anemia, sickle cell disease, thalassemia, multiple myeloma, Jehovah's witnesses, radiation treatment, epidermolysis bullosa, porphyria, for athletic enhancement, sexual dysfunction, transfusional iron overload, uremic pruritus.

Contraindications

Hypersensitivity to mammalian cell–derived products or human albumin; uncontrolled hypertension.

Dosage and Administration

Cancer PatientsAdults

Subcutaneous 3 times/wk dosing: 150 units/kg 3 times/wk. Reduce the dose by 25% when Hgb reaches a level needed to avoid transfusion or increases more than 1 g/dL in any 2-wk period. Withhold the dose when Hgb exceeds a level needed to avoid transfusion and restart at 25% below the previous dose when the Hgb approaches a level where transfusions may be required. Increase the dosage to 300 units/kg 3 times/wk if the response is not satisfactory after 4 wk to achieve and maintain the lowest Hgb levels sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of 12 g/dL. Discontinue if after 8 wk there is no response as measured by Hgb levels or if transfusions are still required. Weekly dosing: 40,000 units/wk. Reduce the dose by 25% when the Hgb reaches a level needed to avoid transfusion or increases more than 1 g/dL in any 2-wk period. Withhold the dose if the Hgb exceeds a level needed to avoid transfusion and restart at 25% below the previous dose when the Hgb approaches a level where transfusion may be required. Increase the dosage to 60,000 units/wk if the response is not satisfactory (no increase in Hgb by at least 1 g/dL after 4 wk of therapy, in the absence of an RBC transfusion) to achieve and maintain the lowest Hgb levels sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of 12 g/dL. Discontinue if after 8 wk there is no response as measured by Hgb levels or if transfusions are still required.

Children

IV Weekly dosing: 600 units/kg/wk (max, 40,000 units/wk). Reduce the dose by 25% when the Hgb reaches a level needed to avoid transfusion or increases more than 1 g/dL in any 2-wk period. Withhold the dose if the Hgb exceeds a level needed to avoid transfusion and restart at 25% below the previous dose when the Hgb approaches a level where transfusion may be required. Increase the dosage to 900 units/kg/wk (max, 60,000 units/wk) if the response is not satisfactory (no increase in Hgb by at least 1 g/dL after 4 wk of therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest Hgb levels sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of 12 g/dL. Discontinue if after 8 wk there is no response as measured by Hgb levels or if transfusions are still required.

CRFAdults

IV / Subcutaneous Individually titrate to achieve and maintain Hgb levels between 10 and 12 g/dL. Increases in dose should not be made more often than once monthly. Start with 50 to 100 units/kg 3 times/wk. Increase the dose by 25% if the Hgb is less than 10 g/dL and has not increased by 1 g/dL after 4 wk of therapy or if the Hgb decreases below 10 g/dL. Reduce the dose by 25% when the Hgb approaches 12 g/dL or the Hgb increases by more then 1 g/dL in any 2-wk period. If the Hgb continues to increase, temporarily withhold the dose until the Hgb begins to decrease, then reinitiate treatment at a dose approximately 25% below the previous dose.

Children

IV / Subcutaneous Individually titrate to achieve and maintain Hgb levels between 10 and 12 g/dL. Increases in dose should not be made more often than once monthly. Start with 50 units/kg 3 times/wk. Increase the dose by 25% if the Hgb is less than 10 g/dL and has not increased by 1 g/dL after 4 wk of therapy or if the Hgb decreases below 10 g/dL. Reduce the dose by 25% if Hgb approaches 12 g/dL or the Hgb increases by more then 1 g/dL in any 2-wk period. If the Hgb continues to increase, temporarily withhold the dose until the Hgb begins to decrease, then reinitiate treatment at a dose approximately 25% below the previous dose.

SurgeryAdults

Subcutaneous Prior to starting treatment, obtain Hgb to establish that it is more than 10 to less than 13 g/dL.

Usual dosage

300 units/kg/day for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

Alternative dose schedule

Subcutaneous 600 units/kg in once-weekly doses (21, 14, and 7 days before surgery), plus a fourth dose on the day of surgery.

Zidovudine-Treated, HIV-Infected PatientsAdults

IV / Subcutaneous Prior to starting therapy, determine the endogenous serum erythropoietin level. Evidence suggests that patients receiving zidovudine with endogenous serum erythropoietin levels more than 500 milliunits/mL are unlikely to respond to epoetin alfa therapy. Titrate the epoetin alfa dosage to achieve and maintain the lowest Hgb level sufficient to avoid the need for blood transfusion and not to exceed the upper safety limit of 12 g/dL. For patients with serum erythropoietin levels of 500 milliunits/mL or less who are receiving zidovudine 4,200 mg/wk or less, the recommended starting dosage is epoetin alfa 100 units/kg 3 times/wk for 8 wk. Monitor the Hgb weekly. If the response is not satisfactory in terms of reducing transfusion requirement or increasing Hgb after 8 wk of therapy, the dosage of epoetin alfa can be increased by 50 to 100 units/kg 3 times/wk. Thereafter, evaluate the response every 4 to 8 wk and adjust the dose accordingly, in 50 to 100 units/kg increments 3 times/wk, to a dosage of epoetin alfa 300 units/kg 3 times/wk. After attaining the desired response, titrate the epoetin alfa dose to maintain the response. If the Hgb exceeds the upper safety limit of 12 g/dL, stop until the Hgb drops below 11 g/dL. Reduce by 25% when treatment is resumed and titrated to maintain the desired Hgb.

General Advice

  • For subcutaneous or IV bolus administration only. Not for intradermal, IM, or intra-arterial administration. IV route recommended for patients on hemodialysis.
  • Do not shake or vigorously agitate vial. Prolonged vigorous shaking may denature the glycoprotein, rendering it biologically inactive.
  • Do not administer if particulate matter, cloudiness, or discoloration is noted.
  • If transferrin saturation is less than 20%, give supplemental iron.
  • IV dose may be administered into venous line at end of dialysis procedure to obviate need for additional venous access.
  • Rotate subcutaneous injection sites.
  • Single-dose vials contain no preservative. Use only 1 dose/vial. Do not reenter vial. Discard any unused portion. Do not combine unused portions or save unused portions for later use.
  • Do not administer in conjunction with other drug solutions. However, at time of subcutaneous administration, single-use vials may be admixed in a syringe with bacteriostatic sodium chloride 0.9% with benzyl alcohol 0.9% at a 1:1 ratio. Multidose vials contain benzyl alcohol and admixing is not necessary.
  • Adjust dose to achieve and maintain lowest Hgb level sufficient to avoid the need for RBC transfusion and not to exceed 12 g/dL.

Storage/Stability

Store vials in refrigerator (36° to 46°F). Do not freeze or shake. Protect from light. Multidose vials may be stored in refrigerator at 36° to 46°F for up to 21 days after initial entry.

Drug Interactions

None well documented.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (24%); deep venous thrombosis (DVT) (10%).

CNS

Fatigue (25%); dizziness, insomnia (21%); headache (19%); asthenia (13%); anxiety, paresthesia (11%); seizure.

Dermatologic

Pruritus (22%); skin pain (18%); rash (16%).

GI

Nausea (58%); constipation (53%); vomiting (29%); diarrhea (21%); dyspepsia (11%).

Genitourinary

UTI (12%).

Local

Skin reaction at injection site (29%).

Musculoskeletal

Arthralgia (11%); trunk pain (3%).

Respiratory

Cough (18%); congestion (15%); shortness of breath (14%); upper respiratory tract infection (11%).

Miscellaneous

Pyrexia (51%); edema (17%); chest pain, clotted access (7%).

Precautions

Warnings

Cancer

Erythropoiesis-stimulating agents (ESAs) shortened overall survival and/or time to tumor progression in clinical studies in patients with breast, non–small cell lung, head and neck, lymphoid, and cervical cancer when dosed to a target Hgb of 12 g/dL or more. The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a Hgb of less than 12 g/dL. To minimize these risks and the risk of serious CV and thrombovascular events, use the lowest dose needed to avoid RBC transfusions. Use only for treatment of anemia due to concurrent myelosuppressive chemotherapy. Discontinue following completion of a chemotherapy course.

Perisurgery

Epoetin alfa increased the rate of DVT in patients not receiving prophylactic anticoagulants. Consider DVT prophylaxis.

Renal failure

Patients experienced greater risks for death and serious CV events when administered ESAs to target higher versus lower Hgb levels. Individualize dosing to achieve and maintain Hgb levels within the 10 to 12 g/dL range.

Monitor

Determine Hgb twice a week in CRF patients and once weekly in zidovudine-treated HIV patients until Hgb has stabilized and the maintenance dose has been established. Then, determine Hgb weekly for at least 4 wk, until it has been determined that Hgb has stabilized in response to the dose change. Then, monitor at regular intervals. Closely monitor BP during therapy. Monitor iron stores, including transferrin saturation and serum ferritin, renal function, fluid and electrolyte balance, CBC with differential and platelet count, and serum chemistry regularly. In CRF patients, after any dose adjustment, determine the Hgb twice weekly for at least 2 to 6 wk until it is determined that the Hgb has stabilized. Then monitor at regular intervals.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 1 mo of age.

Hypersensitivity

Mild and transient skin rashes and urticaria may occur.

Albumin

Epoetin alfa contains albumin, which is derived from human blood and carries an extremely remote risk for transmission of viral diseases.

Anemia

Because epoetin alfa may obviate the need for maintenance transfusion, it is not intended for CRF patients who require correction of severe anemia or for anemia in HIV-infected or cancer patients caused by other factors (eg, GI bleeding, hemolysis, iron or folate deficiencies).

Benzyl alcohol

Benzyl alcohol preservative present in some of these products has been associated with a fatal “gasping syndrome” in premature infants.

Dialysis management

Increased anticoagulation with heparin may be required to prevent clotting of the artificial kidney.

Dose reduction

It is recommended that the epoetin alfa dose be reduced if the Hgb increase exceeds 1 g/dL in any 2-wk period.

Hematologic response

An interval of 2 to 6 wk may occur between time of dose adjustment and a change in Hgb.

Hematology

Elevated bleeding time decreases toward normal after correction of anemia.

Hypertension

Not for use in patients with uncontrolled hypertension; control BP adequately before initiation of therapy.

Porphyria

May be exacerbated.

Pure red cell aplasia (PRCA)

PRCA and severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported, especially in patients with CRF. Evaluate any patient developing a loss of response to epoetin alfa accompanied by severe anemia and low reticulocyte count for the etiology of the loss of effect. Withhold epoetin if anti-erythropoietin antibody-associated anemia is suspected. Permanently discontinue epoetin in patients with antibody-mediated anemia.

Seizures

May occur; relationship to drug uncertain.

Thrombotic events

During hemodialysis, patients may need increased anticoagulation to prevent clotting of vascular access. Epoetin alfa also appears to increase the risk of thrombotic events and mortality in patients at risk.

Surgery patients

BP may rise in perioperative period; therefore, carefully monitor BP. Administer adequate iron supplementation throughout therapy.

Overdosage

Symptoms

Polycythemia.

Patient Information

  • If patient or caregiver will be administering at home, review patient information leaflet with the patient or caregiver. Ensure patient or caregiver understands how to store, prepare, and administer the dose, and how to dispose of used equipment and supplies.
  • Advise patient that dose will be adjusted based upon measured Hgb levels.
  • Advise CRF patient to continue to follow dietary and dialysis prescriptions while taking this medication.
  • Advise patient that iron supplementation will probably be needed and to take iron supplement as prescribed.
  • Advise hypertensive patient to continue to take antihypertensive medications as prescribed and to follow dietary guidelines. Advise patient to continue to monitor and record BP and pulse at home and to inform health care provider if abnormal measurements are noted. Also advise patient to take record of BP and pulse to each follow-up visit.
  • Advise patient to notify health care provider immediately of the following: hives; intolerable GI effects (eg, diarrhea, nausea, vomiting); intolerable injection-site reaction; palpitations; rash; severe headache; shortness of breath; swelling of the eyes, mouth, or throat; or swelling of feet or ankles.
  • Inform patient that drug may be associated with risk of seizures during first 90 days of treatment and to avoid driving or performing other hazardous tasks during this period.
  • Caution women of childbearing potential that menses may resume following epoetin therapy. Advise patient that if this occurs, to discuss risk of pregnancy and need for contraception with health care provider.

Copyright © 2009 Wolters Kluwer Health.