Epoetin (Systemic)


VA CLASSIFICATION
Primary: BL400

Commonly used brand name(s): Epogen; Eprex; Procrit.

Other commonly used names are
human erythropoietin, recombinant {01}; EPO {13} {19}; and r-HuEPO {03} {10} {11} {18} {20}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antianemic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anemia associated with chronic renal failure (treatment)—Epoetin is indicated for the treatment of anemia associated with chronic renal failure in adults and children{01} {02} {03} {04} {05} {09} {10} {11} {18} {19} {20} {21} {40} {44}. It is used for adults and children who do not require dialysis {01} {18} {29} {40} as well as adults and children receiving dialysis (continuous peritoneal dialysis {19} {21}, high-flux short-time hemodialysis {20}, or conventional hemodialysis). However, in patients not receiving dialysis, use of epoetin should be limited to individuals having hematocrit values below 30% {01} {40}.

Anemia, severe, associated with zidovudine therapy in human immunodeficiency virus (HIV) –infected patients (treatment)—Epoetin is indicated for the treatment of severe anemia associated with zidovudine therapy in HIV-infected adults and children {01} {24} {32} {40} {44}. Epoetin is not indicated for the treatment of anemia in HIV-infected patients due to other factors {01} {44}.

Anemia associated with chemotherapy in cancer patients (treatment) —Epoetin is indicated for the treatment of anemia in adults and children with nonmyeloid malignancies in which the anemia is due to the effect of concomitantly administered chemotherapy {01} {40} {44}.

Blood transfusions, allogeneic, in anemic surgery patients, reduction of—Epoetin is indicated for use in anemic patients (hemoglobin > 10 to £ 13 grams per dL) who are scheduled to undergo elective, noncardiac, nonvascular surgery, to reduce the need for allogeneic blood transfusions. It is indicated for patients who are at high risk for perioperative transfusions with significant, anticipated blood loss. {01} {40} {44}

[Anemia associated with frequent blood donation (prophylaxis) ] {32} {40}— Epoetin is indicated to prevent anemia in patients who donate blood and to increase the capacity for donation (for future autologous transfusion) prior to elective surgery. The medication has been found to be effective in females, patients with low packed-cell volumes due to anemia or small body size, and patients requiring donation of 4 units or more of blood {33}.

[Anemia associated with malignancy (treatment)]—Epoetin is indicated for treatment of chronic anemia associated with neoplastic diseases {40} {41} {42} {43}.

[Anemia associated with myelodysplastic syndromes (treatment)1]—Epoetin is indicated for treatment of anemia associated with myelodysplastic syndromes in selected patients {45} {46} {47} {48}. (Evidence rating: IIID)

Note: Epoetin is not a substitute for blood transfusions, which may be required for the emergency treatment of severe anemia {01}. However, with chronic use, epoetin reduces the need for repeated maintenance blood transfusions {01} {02} {04} {05} {11} {21} {25}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Epoetin alfa: 30,400 daltons {01}

Mechanism of action/Effect:

Epoetin alfa is a glycoprotein, produced by recombinant DNA technology, that contains 165 amino acids {01} {25} in a sequence identical to that of endogenous human erythropoietin {01}. Recombinant epoetin has the same biological activity as the endogenous hormone, which induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells {01} {25}, including burst-forming units–erythroid, colony-forming units–erythroid, erythroblasts, and reticulocytes {25}, in bone marrow {01} {25}. Erythropoietin also induces the release of reticulocytes from the bone marrow into the blood stream, where they mature into erythrocytes {25}.

Endogenous erythropoietin is produced primarily in the kidney {01} {02} {11} {25}. The anemia associated with chronic renal failure is caused primarily by inadequate production of the hormone {01} {02} {03} {07} {09} {10} {11} {20} {25}. Administration of epoetin corrects the erythropoietin deficiency in patients with chronic renal failure {01} {02} {03} {07} {09} {10} {11} {20} {25}. Epoetin also stimulates red blood cell production in patients who do not have a documented erythropoietin deficiency, i.e., patients with normal or slightly elevated concentrations of endogenous erythropoietin. However, it may not be effective in patients who are anemic despite having significantly elevated concentrations of erythropoietin {34} {42}.


Other actions/effects:

The increase in hematocrit induced by epoetin may increase blood viscosity and peripheral vascular resistance {05} {07} {08}, leading to a rise in blood pressure {01} {04} {07} {08}. The medication does not appear to have a direct pressor effect {01}.

Epoetin may correct the bleeding tendency associated with chronic renal failure, which may be caused partially by red blood cell deficiency {06} {12}. However, the medication may also increase the thrombotic tendency in some patients {01} {07} {08}.

Correction of anemia by epoetin may result in an improved feeling of well-being {02} {09} {20} {25} {26} {27}; increased appetite {04} {07} {20} {21} {25} {26} {27}; relief of anemia-induced fatigue, tachycardia, headache, weakness, or angina pectoris {25}; increased exercise tolerance {02} {09} {20} {25} {26} {27} and physical activity {21}; and improved sleep {26} {27}, sexual function {26} {27}, and cognitive function {28}.

Administration of epoetin alfa apparently does not induce antibody formation, because antibodies have not been detected in the blood of patients treated with the recombinant hormone for up to 12 months {12} {21}.

Endogenous erythropoietin production may be suppressed by chronic administration of recombinant epoetin {22}.

Half-life:

Elimination—May average 4 to 13 hours following intravenous or subcutaneous administration {01}. The elimination half-life is generally higher after the first few doses (> 7.5 hours) {17} {18} {19} than after 2 or more weeks of treatment (6.2 hours after 7 doses {17}; 4.6 hours after 24 doses {18}).

Note: The pharmacokinetic profile of epoetin alfa in children and adolescents is similar to that of adults.{01}


Onset of action:

Increase in reticulocyte count (initial effect)—Within 7 {03} to 10 {01} days.

Increase in red cell count, hematocrit, hemoglobin—Clinically significant increases generally occur in 2 to 6 weeks {01} {07} {11} {18} {21}. The rate and extent of the response are dependent on dosage {01} {04} {10} {13} {18} {20} {25} and availability of iron stores {01}. Over a 2-week period, administration of 50 Units per kg of body weight 3 times weekly increases the hematocrit by an average of 1.5 points, administration of 100 Units per kg of body weight 3 times weekly increases the hematocrit by an average of 2.5 points, and administration of 150 Units per kg of body weight 3 times weekly increases the hematocrit by an average of 3.5 points {01}.

Time to peak concentration:

Single intravenous dose—15 minutes {19}.

Single subcutaneous dose—5 to 24 hours {01} {17} {19}. Peak concentrations may be maintained for 12 to 16 hours {17}, and detectable quantities are present for at least 24 hours {01}, after administration.

Note: With repeated subcutaneous administration, peak concentrations are achieved and maintained over the same time periods as with single subcutaneous doses, but are substantially lower than those achieved by a single dose {17}. However, the lower epoetin concentrations are sufficient for achieving {17}, and even lower concentrations are sufficient for maintaining {22}, the desired response {22}.


Time to peak effect:

Increase in hematocrit to target area—Dose dependent; usually within 2 months with administration of 100 or 150 Units per kg of body weight 3 times weekly {20}.

Duration of action:

The hematocrit may begin to decrease about 2 weeks after treatment has been discontinued {11}.


Precautions to Consider

Carcinogenicity

The carcinogenic potential of epoetin alfa has not been investigated {01}.

Mutagenicity

Epoetin alfa does not induce bacterial gene mutation (Ames test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus {01}. Also, examination of the bone marrow of patients receiving epoetin for up to 8 weeks has revealed no evidence of karyotypic abnormalities or alteration in the sister chromatid exchange rate {10}.

Pregnancy/Reproduction
Fertility—
Administration of 100 or 500 Units per kg of body weight intravenously to male and female rats showed a trend toward slightly increased fetal wastage.{01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, administration of 500 Units per kg of body weight to female rats caused decreases in weight gain, delays in the appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in first-generation fetuses. Administration of up to 500 Units per kg of body weight to female rabbits from Day 6 to Day 18 of gestation produced no adverse effects. {01}

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether epoetin alfa is excreted in human breast milk. However, in animal studies, administration of up to 500 Units per kg of body weight to female rats during lactation produced no adverse effects in the pups. {01}

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of epoetin alfa in children. Limited data are available in neonates.{01}

Note: The multidose vials contain benzyl alcohol, which is not recommended for use in neonates.



Geriatrics


No published geriatrics-specific information is available {35}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antihypertensive agents    (epoetin may increase blood pressure, possibly to hypertensive levels, especially when the hematocrit is rising rapidly; more intensive antihypertensive therapy [increase in dosage, administration of additional and/or more potent medications] may be required to control blood pressure {01} {02} {07} {09} {11} {20} {29})


Heparin    (an increase in heparin dosage may be required in patients receiving hemodialysis, because epoetin-induced increases in red blood cell volume may lead to blood clotting in the dialyzer and/or vascular access [arteriovenous shunt] {01} {05} {07} {09} {11} {20})


Iron supplements    (iron requirement may be increased as existing iron stores are used for erythropoiesis {01} {02} {04} {07} {09} {20} {21} {25} {29}; some clinicians recommend supplementation for all patients who are not overloaded with iron because of frequent blood transfusions {10} {25}; in some patients, oral iron supplementation may be insufficient and intravenous iron dextran may be required {25})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Bleeding time    (may be decreased; also, the prolonged bleeding time associated with chronic renal failure in some patients may be corrected during epoetin treatment {06})


Blood pressure    (may be increased, possibly to hypertensive levels {01} {02} {07} {09} {11} {20} {29})


Blood urea nitrogen (BUN) and {01} {04}
Serum creatinine concentrations and {01} {04} {05}
Serum phosphorus concentrations and {01} {20}
Serum potassium concentrations and {01} {04} {20}
Serum sodium concentrations and {20}
Serum uric acid concentrations {01} {05} {20}    (may be increased; however, whether the increases reported in patients with chronic renal failure are caused by a direct effect of epoetin on the renal clearance of these substances or the efficacy of dialysis and/or by noncompliance with required dietary restrictions, which may occur when improvement of anemia increases the patient"s appetite and feeling of well-being, has not been established {01} {04} {05} {16} {20})


Iron concentration and
Serum ferritin    (usually are decreased, unless the patient is receiving adequate iron supplementation; as iron stores are utilized for hemoglobin synthesis {04} {09} {10} {11} {21} {25}, functional iron deficiency may occur {04} {21} and lead to a decrease or loss of epoetin efficacy {01} {02} {04} {20} {25})


Platelet counts and
White blood cell counts    (may be increased, but usually remain within expected range{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to human albumin or to mammalian cell–derived products    (risk of a serious allergic reaction to the albumin present in the commercial formulation or to the recombinant product itself)


» Hypertension, uncontrolled {01}    (may be exacerbated {01} {02} {04} {07} {08} {09} {11} {20} {21}, especially during the early phase of treatment {01} or when the hematocrit is rising too rapidly {01} {08} [> 4 points within 2 weeks {01}]; a few cases of hypertensive encephalopathy have occurred in patients with poorly controlled blood pressure during epoetin therapy {01} {02} {04} {05} {25}; initiation of therapy should be delayed until blood pressure is adequately controlled {01})


Risk-benefit should be considered when the following medical problems exist
Any condition that may decrease or delay the response to epoetin alfa, such as:
Aluminum intoxication {01} {05} {07} {12}
Folic acid deficiency {01}
Hemolysis {01}
Infection {01}
Inflammation {01}
Iron deficiency    (virtually all patients will eventually require supplemental iron therapy )

{01}
Malignancy {01}    (the possibility that epoetin can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded)

{01}
Osteitis fibrosa cystica {01}
Occult blood loss{01}
Vitamin B 12 deficiency {01}
Cardiovascular system abnormalities caused by hypertension {12} or
» Hypertension, previous, controlled {04} {08}    (increased risk of hypertension, which may lead to hypertensive encephalopathy )


Hematologic disorders, such as: {01}
Hypercoagulable disorders
Myelodysplastic syndromes
Sickle cell anemia
Vascular disease    (caution and close monitoring are recommended because of an increased thrombotic tendency {01} {07} or other potential complications associated with increases in blood viscosity and peripheral vascular resistance {05} {07} {08} that may occur as a result of epoetin-induced increases in hematocrit {01} {08})

    (the safety and efficacy of epoetin therapy in patients with hematologic disorders have not been determined; also, the presence of myelodysplastic disorders may slow or decrease the bone marrow response to the medication {01})


Porphyria    (may be exacerbated by epoetin therapy{01})


Seizure disorders, history of    (seizures not associated with hypertensive encephalopathy have been reported during epoetin therapy; although a causal association has not been established [in clinical studies, seizures occurred at the same rate in both epoetin-treated and placebo-treated patients with chronic renal failure], caution is recommended {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure determinations    (recommended at frequent intervals because epoetin may increase blood pressure, possibly to hypertensive levels {01} {02} {07} {09} {11} {20} {29}; although the risk may be greatest in patients with pre-existing hypertension [even if optimally controlled at the time epoetin therapy is initiated] {04} {08}, epoetin may also increase blood pressure in previously normotensive patients {01} {02} {07} {08} {09} {11} {20} {21}; control of blood pressure is essential because a few cases of hypertensive encephalopathy have occurred during epoetin therapy in patients with poorly controlled hypertension {01} {02} {04} {05} {25} and because hypertension may be especially hazardous to patients with chronic renal failure, who are predisposed to cardiovascular complications including myocardial ischemia, myocardial infarction, heart failure, and/or stroke {08}; initiation of or increase in antihypertensive therapy {01} {02} {07} {08} {09} {11} {20} {21}, reduction in dosage or temporary withdrawal of epoetin alfa {01} {07} {09} {11}, or even phlebotomy {04} {08} may be required to control hypertension)


Complete blood count and
Platelet count    (recommended periodically because increases in white blood cell and platelet counts have been reported {01} {09} {11}, although the counts have generally remained within the normal range {01} {09} {11})


Fluid and electrolyte balance{01}
» Hematocrit    (determinations recommended prior to initiation of therapy, then twice a week during therapy in chronic renal failure patients and once a week in HIV and cancer patients as a guide to efficacy and dosage of epoetin; because a too-rapid rise in hematocrit may be associated with an increased risk of adverse effects in patients with chronic renal failure, it is recommended that epoetin dosage be reduced if the hematocrit increases by more than 4 points in a 2-week period; after the hematocrit has been stabilized in the target range [30 to 36% for chronic renal failure patients {44} and 36 to 40% for both HIV and cancer patients {44}], the frequency of monitoring may be decreased; however, after each dosage adjustment, determinations should be performed twice a week in chronic renal failure patients and once a week in HIV and cancer patients for at least 2 to 6 weeks, until the hematocrit has stabilized at the new level; for hematocrit-related dosage adjustment information based on the indication, see Usual adult and adolescent dose section)


» Iron status, including:
Serum ferritin
Transferrin saturation    (determination recommended prior to initiation of therapy, because epoetin"s efficacy is decreased when the available iron is insufficient to support erythropoiesis; serum ferritin should be at least 100 nanograms per mL, and transferrin saturation at least 20%, before therapy is initiated {01})

    (monitoring recommended at regular intervals throughout therapy to determine whether iron supplementation should be initiated or increased, because incorporation of iron into hemoglobin may decrease iron stores to the point of functional iron deficiency {01} {02} {04} {20} {21} {25}, leading to a decrease or loss of epoetin efficacy {01} {02} {04} {20} {25})


Neurologic evaluation    (recommended periodically, especially during the first 90 days of therapy, to detect premonitory signs indicative of a risk of seizures; although a causal association between a rapid rise in hematocrit and seizures has not been established, it is recommended that epoetin dosage be reduced if the hematocrit increases by more than 4 points within 2 weeks {01})


» Renal function, including:
Blood urea nitrogen (BUN) and
Serum creatinine and
Serum phosphorous and
Serum potassium and
Serum sodium and
Serum uric acid     (close monitoring recommended in patients with renal function impairment to determine the need for initiating or increasing dialysis {01}; however, whether the increases in concentrations of these substances that have been reported during epoetin therapy are caused by a direct effect of the hormone on renal function or the efficacy of dialysis and/or by noncompliance with dietary restrictions required by patients with chronic renal failure, which may occur when improvement of anemia produces increased appetite and feeling of well-being, has not been established {01} {04} {05} {07} {16} {20})




Side/Adverse Effects

Note: Some of the side effects listed below are known sequelae of chronic renal failure; therefore, a causal association with epoetin therapy has not always been established {01}.
Menses have resumed during treatment in some female patients. Therefore, the risk of pregnancy should be evaluated and an appropriate method of contraception instituted if necessary {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
For treatment of anemia in chronic renal failure patients
Incidence more frequent
    
Chest pain
    
edema (swelling of face, fingers, ankles, feet, or lower legs; weight gain)
    
headache —may rarely indicate hypertensive encephalopathy {05} {25}
    
increased blood pressure {01} {04} {05} {07} {08} {09} {11} {20} {21} — may reach hypertensive levels {01} {10} {20} and, rarely, lead to cerebral ischemia {07} or to hypertensive encephalopathy {01} {02} {04} {05} {25} (blurred vision or other change in vision {25} , grand mal seizures {04} {05} {25} , headache {05} {25} )
    
polycythemia {01} —may lead to hyperviscosity {05} {07} {08} resulting in increased peripheral vascular resistance {05} {07} {08} , hypertension {07} {08} , and thrombotic complications, e.g., clotting of arteriovenous (AV) shunts {01} {02} {07} {09} {20} and/or dialyzer {05} {09} {11} , and, rarely, transient ischemic attacks or cerebrovascular accident or myocardial infarction

Incidence rare
    
Skin rash or hives


For treatment of anemia in chronic renal failure requiring dialysis(in addition to those listed above)
Incidence more frequent
    
Fever
    
hyperkalemia{01}
    
shortness of breath{01}
    
tachycardia{01} (fast heartbeat )
    
upper respiratory tract infection{01} (cough, fever, sneezing, or sore throat)


For treatment of zidovudine-treated HIV-infected patients
Incidence more frequent
    
Fever{01}
    
headache{01}
    
shortness of breath{01}
    
skin rash or hives{01}

Incidence less frequent or rare
    
Seizures{01} (convulsions)—may be related to underlying pathology{01}


For treatment of cancer patients on chemotherapy
Incidence more frequent
    
Edema{01} (swelling of face, fingers, ankles, feet, or lower legs; weight gain)
    
fever{01}
    
shortness of breath{01}
    
upper respiratory tract infection{01} (cough, fever, sneezing, or sore throat)


For treatment of surgical patients
Incidence more frequent
    
Deep venous thrombosis{01} (swelling or pain in leg)
    
edema{01} (swelling of face, fingers, ankles, feet, or lower legs; weight gain)
    
fever{01}
    
headache{01}
    
increased blood pressure{01}
    
skin rash or hives{01}
    
urinary tract infection{01} (blood in urine ; lower back pain; pain or burning while urinating)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea{01}
    
dizziness{01}
    
nausea and vomiting{01}

For treatment of anemia in chronic renal failure patients (in addition to those listed above)
    
Administration site reaction{01} (itching or stinging at site of injection)
    
asthenia{01} (loss of strength or energy; muscle pain or weakness)
    
fatigue{01} (general feeling of tiredness and weakness)
    
influenza-like syndrome, mild{01} (bone or joint pain; muscle aches; chills; shivering; sweating)— may appear 1 to 2 hours after intravenous administration and persist for up to 12 hours {01} {02} {05} {07}

For treatment of anemia in chronic renal failure patients requiring dialysis(in addition to those listed above)
    
Constipation
    
cough
    
peritonitis (abdominal pain and swelling; fever; weight loss)—in children receiving peritoneal dialysis
    
pharyngitis ( sore throat)

For treatment of zidovudine-treated HIV-infected patients
    
Administration site reaction{01} (itching or stinging at site of injection)
    
asthenia{01} (loss of strength or energy; muscle pain or weakness)
    
cough{01}
    
congestion, respiratory{01}
    
fatigue{01} (general feeling of tiredness and weakness)

For treatment of cancer patients on chemotherapy
    
Asthenia{01} (loss of strength or energy; muscle pain or weakness)
    
fatigue{01} (general feeling of tiredness and weakness)
    
paresthesia{01} (tingling, burning, or prickly sensation)

For treatment of surgical patients
    
Administration site reaction{01} (itching or stinging at site of injection)
    
anxiety{01}
    
constipation{01}
    
dyspepsia{01} (stomach discomfort, upset, or pain; heartburn; belching; acid or sour stomach)
    
insomnia{01} (inability to sleep)
    
skin pain{01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Epoetin (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Other medical problems, especially hypertension and a history of hypersensitivity to albumin or to mammalian cell–derived products

Proper use of this medication
» Proper injection technique (if dispensed for home use)

» Proper dosing
Administering as soon as possible; not administering if almost time for next dose; not doubling doses

» Proper storage

Precautions while receiving this medication
Risk of seizures, especially during the first 90 days of treatment; avoiding activities that may be hazardous should a seizure occur

» Importance of keeping medical and dialysis appointments

» Importance of compliance with antihypertensive regimen (medications and diet), if prescribed, and dietary restrictions pertinent to patients with chronic renal failure

» Importance of compliance with iron or other vitamin supplementation


Side/adverse effects
Signs of potential side effects, especially chest pain, edema, headache, increased blood pressure, polycythemia, skin rash or hives, fever, hyperkalemia, shortness of breath, tachycardia, upper respiratory tract infection, seizures, deep venous thrombosis, and urinary tract infection


General Dosing Information
Epoetin alfa is administered intravenously or subcutaneously {01} {19} {21} {29}. In general, it is given intravenously to patients with an available intravenous access, i.e., patients receiving hemodialysis {01}, and either intravenously or subcutaneously to other patients {01} {19} {21} {29}.

An increase in dosage may be required if aluminum intoxication, which is not uncommon in patients with chronic renal failure, is present {07} {12} {20}.

Diet/Nutrition
Failure to achieve an adequate response to the medication, or loss of efficacy during therapy, may indicate a lack of sufficient iron to support erythropoiesis. Iron supplementation should be initiated or increased as needed {01} {02} {04} {10} {20} {25}. Also, folic acid and/or vitamin B 12 deficiency may reduce or delay the response to the medication {01}; supplementation with these nutrients may also be required.

Correction of anemia often results in increased appetite and a feeling of well-being, which, in turn, may lead to noncompliance with dietary restrictions (e.g., regulated protein, sodium, and potassium intake) that are necessary in patients with chronic renal failure. Noncompliance with such restrictions may require institution of, or an increase in, dialysis. {01} {04} {05} {16} {20}

For treatment of adverse effects
Recommended treatment consists of the following

   • For clotting of arteriovenous (AV) shunt and/or dialyzer—Clotting complications should be managed according to the dialysis center's policy and procedures {36}. AV shunts may be cleared by use of a syringe with heparinized saline solution. If this is unsuccessful, a thrombolytic agent (streptokinase or urokinase) may be used, after allowing the effects of prior anticoagulation to diminish. {31} Increasing heparin dosage helps prevent recurrent clotting complications.
   • For hypertension—Instituting or increasing administration of antihypertensive medications. In some patients, a decrease in dosage or temporary withdrawal of epoetin and/or phlebotomy may be needed.
   • For polycythemia—Decreasing the dosage of, or temporarily suspending therapy with, epoetin. In some patients, phlebotomy may be needed.


Parenteral Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to categories of use and/or indications or dosages that are not included in U.S. product labeling.

EPOETIN ALFA, RECOMBINANT, INJECTION

Usual adult and adolescent dose
Anemia associated with chronic renal failure
Initial: Intravenous or subcutaneous, 50 to 100 Units per kg of body weight three times a week. Dosage may be increased if, after eight weeks of therapy, the hematocrit has not increased by five to six points and is still below the desired range (30 to 36%).{01}{44}
Note: Some clinicians begin therapy with lower doses, e.g., 40 Units per kg of body weight three times a week{38}.
An interval of at least four weeks should elapse between dosage adjustments, unless clinical circumstances dictate otherwise, because the response to a change in dosage may require two to six weeks{01}{44}.
Because of a possible risk of hypertensive and/or thrombotic complications, it is recommended that dosage be decreased if the hematocrit increases by more than four points in a two-week period.
Administration of epoetin should be discontinued temporarily if the hematocrit reaches or exceeds the maximum recommended level of 36%. When the hematocrit has returned to the desired range, therapy may be resumed.{01}



Maintenance: Dosage should be decreased gradually to the lowest dose that will maintain the hematocrit at the desired level (30 to 36%){01}.
Note: Although maintenance doses of up to 525 Units per kg of body weight three times a week have been administered{01}{20}, the maximum maintenance dose recommended by the manufacturer is 300 Units per kg of body weight three times a week{01}.
Once-weekly subcutaneous administration of the entire week's dosage requirement may be sufficient to maintain some patients at the desired hematocrit range{21}{37}.



Anemia in zidovudine-treated HIV-infected patients
Initial: Intravenous or subcutaneous, 100 Units per kg of body weight three times a week for eight weeks for patients with serum erythropoietin levels £ 500 milliUnits per mL and who are receiving a dose of zidovudine £ 4200 mg per week. Dosage may be increased if, after eight weeks of therapy, a satisfactory increase in hematocrit or reduction of transfusion requirements is not obtained. The dose can be increased by 50 to 100 Units per kg of body weight three times a week, with weekly monitoring of the hematocrit. Thereafter, the response should be evaluated every four to eight weeks, with the dose adjusted accordingly by 50 to 100 Units per kg of body weight three times a week. Patients who do not have a satisfactory response to a dose of 300 Units per kg of body weight three times a week are unlikely to respond to higher doses.{01}{44}
Note: Prior to beginning treatment with epoetin, it is recommended that the endogenous serum erythropoietin level be determined. Available evidence suggests that patients receiving zidovudine who have endogenous serum erythropoietin levels > 500 mUnits/mL are unlikely to respond to therapy with epoetin.{01}{44}



Maintenance: Dosage should be titrated to maintain the desired response and should be based on factors such as variations in zidovudine dose and the presence of intercurrent infectious or inflammatory episodes. Treatment should be discontinued if the hematocrit exceeds 40%. When the hematocrit drops to 36%, treatment may be resumed at a dose 25% less than the previous dose and then titrated accordingly.{01}{44}

Anemia in cancer patients on chemotherapy
Initial: Subcutaneous, 150 Units per kg of body weight three times a week. If the initial dose causes a very rapid rise in hematocrit (i.e., an increase of more than four points in a two-week period), the dose should be reduced. Dosage may be increased if, after eight weeks of therapy, a satisfactory increase in hematocrit or reduction of transfusion requirements is not obtained. The dose can be increased up to 300 Units per kg of body weight three times a week. Patients who do not have a satisfactory response to a dose of 300 Units per kg of body weight three times a week are unlikely to respond to higher doses. [ Alternatively, a dose of 40,000 to 60,000 Units once weekly may be used.]1{49}{50}{51} Treatment should be discontinued if the hematocrit exceeds 40%. When the hematocrit drops to 36%, treatment may be resumed at a dose 25% less than the previous dose and then titrated accordingly.{01}{44}

Note: Treatment of patients with grossly elevated serum erythropoietin levels (e.g., > 200 mUnits/mL) is not recommended{01}{44}.


Reduction of allogeneic blood transfusion in anemic surgery patients
Subcutaneous, 300 Units per kg of body weight per day for ten days prior to surgery, on the day of surgery, and for four days after surgery. Alternatively, subcutaneous, 600 Units per kg of body weight once a week, twenty-one, fourteen, and seven days prior to surgery, and on the day of surgery.{01}{44}

Note: Prior to treatment with epoetin, it should be established that the patient's hemoglobin is > 10 and £ 13 grams per deciliter{01}{44}.



Usual pediatric dose
Anemia associated with chronic renal failure requiring dialysis
Initial: Intravenous or subcutaneous, 50 Units per kg of body weight three times a week. Dosage may be increased if, after eight weeks of therapy, the hematocrit has not increased by five to six points and is still below the desired range (30 to 36%). Dosage should be reduced if the hematocrit approaches 36% or if the hematocrit increases by > four points in any two-week period.{01}

Maintenance: Dosage should be decreased gradually to the lowest dose that will maintain the hematocrit at the desired level (30 to 36%). {01}

Anemia associated with chronic renal failure not requiring dialysis
Children ages 3 months to 20 years: Doses of 50 to 250 Units per kg of body weight given intravenously or subcutaneously one to three times a week have been reported.{01}

Anemia in zidovudine-treated HIV-infected children
Children ages eight months to 17 years: Doses of 50 to 400 Units per kg of body weight given intravenously or subcutaneously two to three times a week have been reported.{01}

Anemia in cancer patients on chemotherapy
Children ages six months to 18 years: Doses of 25 to 300 Units per kg of body weight given intravenously or subcutaneously three to seven times a week have been reported.{01}


Strength(s) usually available
U.S.—



In 1-mL single-dose vials


2000 Units per mL (Rx) [Epogen (human albumin 2.5 mg)] [Procrit (human albumin 2.5 mg)]


3000 Units per mL (Rx) [Epogen (human albumin 2.5 mg)] [Procrit (human albumin 2.5 mg)]


4000 Units per mL (Rx) [Epogen (human albumin 2.5 mg)] [Procrit (human albumin 2.5 mg)]


10,000 Units per mL (Rx) [Epogen (human albumin 2.5 mg)] [Procrit (human albumin 2.5 mg )]


40,000 units per mL (Rx) [Epogen (human albumin 2.5 mg)] [Procrit (human albumin 2.5 mg)]



In multi-dose vials


10,000 Units per mL in 2-mL vials (Rx) [Epogen (human albumin 2.5 mg) (benzyl alcohol 1%)] [Procrit (human albumin 2.5 mg) (benzyl alcohol 1%)]


20,000 Units per mL in 1-mL vials (Rx) [Epogen (human albumin 2.5 mg) (benzyl alcohol 1%)] [Procrit (human albumin 2.5 mg) (benzyl alcohol 1%)]

Canada—



In 1-mL single-dose vials


2000 International Units (IU) per mL (Rx) [Eprex (human albumin 2.5 mg)]


4000 IU per mL (Rx) [Eprex (human albumin 2.5 mg)]


10,000 IU per mL (Rx) [Eprex (human albumin 2.5 mg)]



In multi-dose vials


20,000 IU per mL in 1-mL vials (Rx) [Eprex (human albumin 2.5 mg) (benzyl alcohol 1%)]



In single-dose, pre-filled syringes


1000 IU per 0.5 mL (Rx) [Eprex]


2000 IU per 0.5 mL (Rx) [Eprex]


3000 IU per 0.3 mL (Rx) [Eprex]


4000 IU per 0.4 mL (Rx) [Eprex]


10,000 IU per mL (Rx) [Eprex]

Packaging and storage:
Store at 2 to 8 °C (36 to 46 °F), unless otherwise specified by manufacturer. Protect from freezing. {01}

Stability:
Do not shake the vial of epoetin alfa, recombinant, injection. Shaking may denature the glycoprotein and render it biologically inactive. {01}

Because the single-dose injection contains no preservative, each vial should be used to administer one dose only. Any unused portion of the solution must be discarded. {01}

The multi-dose vials should be discarded 21 days after initial entry {01} {44}.

Incompatibilities:
It is recommended that epoetin alfa, recombinant, not be admixed with other medications {01}.

Auxiliary labeling:
   • Refrigerate, do not freeze.
   • Do not shake.

Additional information:
The multi-dose vials contain benzyl alcohol, which is not recommended for use in neonates. A fatal syndrome consisting of metabolic acidosis, central nervous system depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhage has been associated with the administration of benzyl alcohol to neonates.



Revised: 12/26/2002



References
  1. Product Information: Epogen, epoetin alfa. Amgen, Thousand Oaks, CA, (PI revised 7/99) reviewed 2/2000
  1. Winearls CG, Oliver DO, Pippard MJ, et al. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic hemodialysis. Lancet 1986; 2: 1175-8.
  1. Zins B, Drueke T, Zingraff J, et al. Erythropoietin treatment in anaemic patients on haemodialysis [letter]. Lancet 1986; 2: 1329.
  1. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial. N Engl J Med 1987; 316: 73-8.
  1. Erythropoietin [editorial]. Lancet 1987; 1: 781-2.
  1. Moia M, Manucci PM, Vizzotto L, et al. Improvement in the haemostatic defect of uraemia after treatment with recombinant human erythropoietin. Lancet 1987; 2: 1227-9.
  1. Casati S, Passerini P, Campise MR, et al. Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having hemolysis. Br Med J 1987; 295: 1017-20.
  1. Raine AEG. Hypertension, blood viscosity, and cardiovascular mortality in renal failure: implications of erythropoietin therapy. Lancet 1988; 1: 97-100.
  1. Schaefer RM, Kuerner B, Zech M, et al. Treatment of the anemia of hemodialysis patients with recombinant human erythropoietin. Int J Artif Organs 1988; 11: 249-54.
  1. Stone WJ, Graber SE, Krantz SB, et al. Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebo-controlled trial. Am J Med Sci 1988; 296: 171-9.
  1. Akizawa T, Koshikawa S, Takaku F, et al. Clinical effect of recombinant human erythropoietin on anemia associated with chronic renal failure. A multi-institutional study in Japan. Int J Artif Organs 1988; 11: 343-50.
  1. Watson AJ, Spivak JL. Recombinant human erythropoietin therapy in end stage renal failure. J Clin Pharmacol 1988; 28: 1086-8.
  1. Zehnter E, Pollok M, Ziegenhagen D, et al. Urea kinetics in patients on regular dialysis treatment before and after treatment with recombinant human erythropoietin. Contr Nephrol 1988; 66: 149-55.
  1. Delano GB, Lundin AP, Galonsky R, et al. Dialyzer urea and creatinine clearances not significantly changed in r-HuEPO treated maintenance hemodialysis (MD) patients [abstract]. Kidney Int 1988; 33: 219.
  1. Stivelman J, VanWyck D, Kirlin L, et al. Use of recombinant erythropoietin (rHuEPO) with high flux dialysis (HFD) does not worsen azotemia or shorten access survival [abstract]. Kidney Int 1988; 33: 239.
  1. Paganini E, Garcia J, Ellis P, et al. Clinical sequellae of correction of anemia with recombinent (sic) human erythropoietin (r-HuEPO): urea kinetics, dialyzer function and reuse [abstract]. Am J Kidney Dis 1988; 11: 16.
  1. Egrie JC, Eschbach JW, McGuire T, et al. Pharmacokinetics of recombinant human erythropoietin (rHuEPO) administered to hemodialysis (HD) patients [abstract]. Kidney Int 1988; 33: 262.
  1. Lim VS, DeGowin RL, Zavala D, et al. Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial. Ann Int Med 1989; 110: 108-14.
  1. Macdougall IC, Roberts DE, Neubert P, et al. Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1989; 1: 425-7.
  1. Mohini R. Clinical efficacy of recombinant human erythropoietin in hemodialysis patients. Semin Nephrol 1989; 9 Suppl 1: 16-21.
  1. Sinai-Trieman L, Saalusky IB, Fine RN. Use of subcutaneous recombinant human erythropoietin in children undergoing continuous cycling peritoneal dialysis. J Pediatr 1989; 114: 550-4.
  1. Casati S, Campise M, Ponticelli C. Erythropoietin concentrations during treatment [letter]. Lancet 1989; 1: 1078.
  1. Zachee P, Staal GEJ, Rijksen G, et al. Pyruvate kinase deficiency and delayed clinical response to recombinant human erythropoietin treatment [letter]. Lancet 1989; 1: 1327-8.
  1. Food and Drug Administration announcement, June 26, 1989.
  1. Schwenk MH, Halstenson CE. Recombinant human erythropoietin. DICP 1989; 23: 528-36.
  1. Delano BG. Improvements in quality of life following treatment with r-HuEPO in anemic hemodialysis patients. Am J Kidney Dis 1989; 14 Suppl 1: 14-8.
  1. Gibilaro SD, Delano BG, Quinn R, et al. Improved quality of life while receiving recombinant erythropoietin (r-HuEPO) [abstract]. Kidney Int 1989; 35: 247.
  1. Wolcott DL, Schweitzer S, Nissenson AR. Recombinant erythropoietin (r-EPO) improves cognitive function (CF) and quality of life (QL) of chronic hemodialysis (CHD) patients (PTS) [abstract]. Kidney Int 1989; 35: 266.
  1. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989; 321: 158-63.
  1. Personal communication, Regulatory Affairs Officer, Geigy Canada, 10/25/89.
  1. Thrombolytic Agents (Systemic) monograph, USPDI 1990.
  1. Reviewers' responses to monograph revision.
  1. Panel comment, 12/1/89.
  1. Panel comment, 12/1/89.
  1. Reviewers" responses to monograph revision.
  1. Panel comment.
  1. Panel comment.
  1. Panel comment.
  1. Reviewers" responses to monograph revision of 12/89.
  1. Eprex prescribing information (Ortho—Canada), Rec 5/90; Rev 5/97, Rec 7/97.
  1. Henry DH, Rudnick SA, Bryant E, et al. Preliminary report of two double blind, placebo controlled studies using human recombinant erythropoietin (rHuEPO) in the anemia associated with cancer [abstract]. Blood 1989; 74 Suppl 7: 6a.
  1. Ludwig H, Fritz E, Kotzman H, Hocker P, Gisslinger H, Barnas U. Erythropoietin treatment for chronic anemia of malignancy [abstract]. Blood 1989; 74 Suppl 7: 16a.
  1. Reviewers' responses to panel ballot of 1/30/90.
  1. Procrit package insert (Ortho Biotech—US), Rev 2/97, Rec 5/97.
  1. Negrin RS, Stein R, Doherty K, et al. Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood 1996; 87: 4076-81.
  1. Stasi R, Brunetti M, Bussa S, et al. Response to recombinant human erythropoietin in patients with myelodysplastic syndromes. Clin Cancer Res 1997; 3: 733-9.
  1. Rose EH, Abels RI, Nelson RA, et al. The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS). Br J Haematol 1995; 89: 831-7.
  1. DePaoli L, Levis A, Isabella N, et al. Serum erythropoietin level and marrow erythroid infiltration predict response to recombinant human erythropoietin in myelodysplastic syndromes. Haematologica 1993; 78: 118-22.
  1. Reviewers' consensus on ballot of 10/28/2002.
  1. Cheung W, Minton N, Gunawardena K. Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol 2001; 57: 411-8.
  1. Gabrilove JL, Cleeland CS, Livingston RB, et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19: 2875-82.
Hide
(web3)