epoetin alfa (Epogen, Procrit, Eprex, erythropoietin)

Dosing and uses of Epogen, Procrit (epoetin alfa)

• Adult
• Pediatric

 

Adult dosage forms and strengths

injectable solution

• 2000 units/mL
• 3000 units/mL
• 4000 units/mL
• 10,000 units/mL
• 20,000 units/mL
• 40,000 units/mL

 

Chronic Kidney Disease-Associated Anemia

Reduction of need for red blood cell (RBC) transfusion in patients with chronic kidney disease (CKD)

Patient not on dialysis: 50-100 units/kg IV/SC 3 times weekly initially

Initiate only when (1) hemoglobin level <10 g/dL, (2) rate of hemoglobin decline indicates likely necessity of RBC transfusion, and (3) reducing risk of alloimmunization or other risks related to RBC transfusion is goal; if hemoglobin level >10 g/dL, reduce or interrupt dose and use lowest dose sufficient to reduce need for RBC transfusion

Patient on dialysis: 50-100 units/kg IV 3 times weekly initially

Initiate when hemoglobin level <10 g/dL; if hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt dose

Dosing considerations

• Evaluate iron status before and during treatment, and maintain iron repletion
• When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until they are stable, then monitor at least monthly
• When adjusting therapy, consider rate of hemoglobin rise or decline, responsiveness to erythropoiesis-stimulating agents (ESAs), and hemoglobin variability
• A single hemoglobin excursion may not necessitate dosing change
• Do not increase the dose more frequently than every 4 weeks
• Decreases in dose can occur more frequently; avoid frequent dose adjustment
• If the hemoglobin rises rapidly (eg, >1 g/dL in any 2-week period), reduce dose by 25% or more as needed to reduce rapid responses; may reduce dose more frequently than once every 4 weeks; avoid frequent dose adjustments
• Inadequate response: If hemoglobin has not increased by >1 g/dL after 4 weeks of therapy, increase dose by 25%; if patient does not respond adequately over 12-week escalation period, further dose increase is unlikely to improve response and may increase risks
• Individualize dosing, and use lowest dose that will maintain hemoglobin level sufficient to reduce need for RBC transfusions
• Evaluate other causes of anemia
• Discontinue if responsiveness does not improve
• Correct or exclude other causes of anemia (eg, vitamin deficiency, metabolic/chronic inflammatory conditions, bleeding) before initiating therapy

 

Zidovudine-Related Anemia

Treatment of anemia due to zidovudine administered at <4200 mg/week in HIV-infected patients with endogenous serum erythropoietin levels of <500 milliunits/mL

100 units/kg IV/SC 3 times weekly initially

Dosing considerations

• If response is inadequate after 8 weeks, increase dose by 50-100 units/kg every 4-8 weeks until hemoglobin reaches level sufficient to avoid RBC transfusions; alternatively, administer 300 units/kg
• If increase in hemoglobin is not achieved with administration of 300 units/kg for 8 weeks, discontinue
• If hemoglobin >12 g/dL, withhold therapy; when hemoglobin is <11 g/dL, resume therapy at dose 25% below previous dose

 

Chemotherapy-Related Anemia

Treatment of anemia in patients with nonmyeloid malignancies where anemia is due to effect of concomitant myelosuppressive chemotherapy for >2 months

150 units/kg IV/SC 3 times weekly initially; alternatively, 40,000 units SC once weekly until completion of chemotherapy course

Dosing considerations

• If response is inadequate after 4 weeks and hemoglobin increases by <1 g/dL and remains <10 g/dL, increase to 300 units/kg 3 times weekly or 60,000 units once weekly
• If response is inadequate after 8 weeks and hemoglobin levels have not responded measurably or if RBC transfusions are still required, discontinue therapy
• If hemoglobin increases by >1 g/dL in any 2-week period or reaches level sufficient to avoid RBC transfusion, reduce dose by 25%
• If hemoglobin reaches level sufficient to avoid RBC transfusion, withhold dose; when hemoglobin approaches level where RBC transfusions may be required, reinitiate at dose 25% below previous dose
• Initiate therapy only if hemoglobin is <10g/dL and if ≥2 additional months of chemotherapy is planned

 

Preparation for Surgery With High Risk of Blood Loss

Reduction of need for allogeneic RBC transfusions in patients with perioperative hemoglobin >10 g/dL but ≤13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery

300 units/kg SC once daily for 15 consecutive days (10 days preceding surgery, day of surgery, 4 days following surgery); alternatively, 600 units/kg SC in 4 doses administered 21, 14, and 7 days before surgery and on day of surgery

Dosing considerations

• Concomitant deep vein thrombosis (DVT) prophylaxis is recommended
• Not indicated for patients who are willing to donate autologous blood preoperatively
• Monitor hemoglobin, blood pressure, electrolytes, renal function

 

Pediatric dosage forms and strengths

injectable solution

• 2000 units/mL
• 3000 units/mL
• 4000 units/mL
• 10,000 units/mL
• 20,000 units/mL
• 40,000 units/mL

 

Chronic Kidney Disease-Associated Anemia

<1 month: Safety and efficacy not established

>1 month: 50 units/kg IV/SC 3 times weekly initially; if patient on dialysis, IV route recommended

Initiate when hemoglobin level <10 g/dL; if hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt dose

Dosing considerations

• Do not increase the dose more frequently than every 4 weeks
• Decreases in dose can occur more frequently; avoid frequent dose adjustments
• If hemoglobin rises rapidly (eg, >1 g/dL in any 2-week period), reduce dose by 25% or more as needed to reduce rapid responses
• Inadequate response: If hemoglobin has not increased by >1 g/dL after 4 weeks of therapy, increase dose by 25%; if patient does not respond adequately over 12-week escalation period, further dose increase is unlikely to improve response and may increase risks
• Evaluate iron status before and during treatment, and maintain iron repletion
• When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until they are stable, then monitor at least monthly
• When adjusting therapy, consider rate of hemoglobin rise or decline, responsiveness to ESAs, and hemoglobin variability
• A single hemoglobin excursion may not necessitate dosing change
• Use lowest dose that will maintain hemoglobin level sufficient to reduce need for RBC transfusions
• Evaluate other causes of anemia
• Discontinue if responsiveness does not improve

 

Prematurity-Related Anemia

25-100 units/kg SC 3 times weekly or 200-400 units/kg SC/IV q24-48hr for 2-6 weeks

 

Zidovudine-Related Anemia

<8 months: Safety and efficacy not established

8 months-17 years: 50-400 units/kg SC/IV 2-3 times weekly

 

Chemotherapy-Related Anemia

<5 years: Safety and efficacy not established

5-18 years: 600 units/kg IV once weekly; not to exceed 40,000 units

Dosing considerations

• If response is inadequate after 4 weeks and if hemoglobin increases by <1 g/dL and remains <10 g/dL, increase dose to 900 units/kg 3 times weekly; not to exceed 60,000 units weekly
• If response is inadequate after 8 weeks and hemoglobin levels have not responded measurably or if RBC transfusions are still required, discontinue therapy
• If hemoglobin increases by >1 g/dL in any 2-week period or reaches level sufficient to avoid RBC transfusion, reduce dose by 25%
• If hemoglobin reaches level sufficient to avoid RBC transfusion, withhold dose; when hemoglobin approaches level where RBC transfusions may be required, reinitiate at dose 25% below previous dose
• Monitor hemoglobin, blood pressure, iron, electrolytes, renal function

 

Epogen, Procrit (epoetin alfa) adverse (side) effects

>10%

Pyrexia (10-42%)

Nausea (11-35%)

Hypertension (14-27%)

Cough (4-26%)

Vomiting (12-28%)

Pruritus (12-21%)

Rash (2-19%)

Headache (5-18%)

Arthralgias (10-16%)

 

1-10%

Arthralgia (10%)

Myalgia (10%)

Stomatitis (10%)

Diarrhea (9%)

Dizziness (9%)

Edema (9%)

Fatigue (9%)

Weight decrease (9%)

Medical device malfunction (artificial kidney clotting during dialysis) (8%)

Vascular occlusion (vascular access thrombosis) (8%)

Vomiting (8%)

Asthenia (7%)

Chest pain (7%)

Injection-site irritation (7%)

Muscle spasm (7%)

Upper respiratory tract infection (URTI) (7%)

Urticaria (3%)

Seizures (2.5%)

Pulmonary embolism (1%)

Respiratory tract congestion (1%)

 

Postmarketing Reports

Seizures

Pure red-cell aplasia

Serious allergic reactions

Injection-site reactions (eg, irritation, pain)

Porphyria

 

Warnings

Black box warnings

Chronic kidney disease

• In controlled trials, CKD patients were at greater risk for death, serious adverse cardiovascular reactions, and stroke when receiving ESA therapy to target hemoglobin level of >11 g/dL
• No trial has identified hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks
• Use lowest dose sufficient to reduce need for RBC transfusions

Cancer

• In some clinical studies, ESAs shortened overall survival or increased risk of tumor progression in patients with breast, head, and neck cancers; lymphoid; non-small cell lung cancers; and cervical cancers
• To prescribe or dispense ESAs to cancer patients, prescribers and hospitals must enroll in and comply with ESA APPRISE Oncology Program
• Use lowest dose sufficient to avoid RBC transfusions
• Use ESAs only for anemia from myelosuppressive chemotherapy; ESAs are not indicated for patients receiving myelosuppressive chemotherapy when anticipated outcome is cure
• Discontinue after completion of chemotherapy course

Cardiovascular events

• Increased risk of serious cardivascular events, including stroke and thromboembolic events

 

Contraindications

Hypersensitivity to epoetin alfa or albumin or mammalian cell-derived products

Cancer patients whose anemia is caused by factors other than chemotherapy

Uncontrolled hypertension

Pure red-cell aplasia that begins after treatment with any erythropoietin protein drugs

Use of multidose vials containing benzyl alcohol in neonates, infants, or pregnant or nursing women, because of increased risk of serious adverse events and death; single-dose vials should be used instead and must not be admixed with bacteriostatic saline containing benzyl alcohoL

 

Cautions

Has not been shown to improve patient well-being, enhance quality of life, or alleviate fatigue

Not indicated for use in (1) patients with cancer who are receiving biologic products, hormonal agents, or radiotherapy, unless they are also receiving concomitant myelosuppressive chemotherapy; (2) patients with cancer who are receiving myelosuppressive chemotherapy when the anticipated outcome is cure; (3) patients scheduled for surgery who are willing to donate autologous blood; (4) patients who are undergoing cardiac or vascular surgery

Not indicated as substitute for RBC transfusions in patients who require immediate correction of anemia

Increased incidence of death, myocardial infarction (MI), stroke, and thromboembolism: Using ESAs to target hemoglobin level of >11 g/dL increases risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (see Black box warnings)

Use caution in hypertension, iron deficiency, folate or B12 deficiency, congestive heart failure (CHF), coronary artery disease (CAD), seizure disorder, sickle-cell disease, hemolytic anemia, porphyria, hematologic disorders

Cancer patients: Increased tumor progression rate when dosed to achieve hemoglobin level of >12 mg/dL

Chronic renal failure: At initiation of therapy, transferrin saturation should be ≥20% and ferritin ≥100 ng/mL

Patients undergoing surgery are at increased risk for DVT; concomitant DVT prophylaxis is strongly recommended

Epogen multidose formulations contain benzyl alcohol, which is associated with potentially fatal "gasping syndrome" in premature neonates

Zidovudine-treated patients may show response only when zidovudine dosage <4200 mg/wk and endogenous epoetin <500 U/mL

To prescribe or dispense to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with ESA APPRISE Oncology Program

Increased risk of seizures during first 90 days of therapy in CKD; monitor closely

Dialysis patients: IV administration recommended to reduce red-cell aplasia risk; increased anticoagulation with heparin may be required to prevent clotting of extracorporeal circuit during hemodialysis

Do not increase dose more frequently than once monthly

Contains albumin; may carry extremely remote risk for transmission or viral diseases or Creutzfeldt-Jakob disease

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown whether drug is excreted in breast milk; use with caution; avoid administering multidose vials

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Epogen, Procrit (epoetin alfa)

Mechanism of action

Recombinant human erythropoietin; stimulates erythropoiesis via division and differentiation of progenitor cells in bone marrow

 

Absorption

Vd: 9L

Bioavailability: 21-31% (SC); 3% (intraperitoneal)

 

Distribution

Onset: Several days

Peak effects: 2-6 weeks

Peak serum time: 5-24 hr (SC)

 

Elimination

Half-life: CKD, 4-13 hr (IV); 16-67 hr (cancer)

Clearance: 14 mL/min

Excretion: Feces (majority); urine (small amounts)

 

Administration

Do not administer multidose vials or single-dose vials admixed with bacteriostatic saline containing benzyl alcohol to neonates or infants

 

IV Incompatibilities

Solution: D10W

 

IV Preparation

For minimal dilution, mix with bacteriostatic NS containing 20 mL NS and benzyl alcohol as bacteriostatic agent in 1:1 ratio

 

IV Administration

Single-dose vial: pH 6.6-7.2

Multidose vial: pH 5.8-6.4

Administer by direct injection without dilution

Do not mix with other drugs

Do not shake

Drug may be given via venous return line of dialysis tubing after dialysis to eliminate need for additional IV access

 

Storage

Vials should be stored at 2-8°C (36-46°F)

Do not freeze or shake

Protect vials from light

Vials are stable for 2 weeks at room temperature