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ERYTHROPOIETINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Erythropoietin is a glycosylated protein hormone normally produced in the kidneys and is responsible for the stimulation of red blood cell production.
    B) Epoetin alfa, epoetin beta, and epoetin gamma are derived via recombinant DNA techniques; the amino acid sequence is identical to that of endogenous erythropoietin. Although all have the same 165 amino acid sequence, they differ in the glycosylation pattern.
    C) Darbepoetin alfa is an analogue of epoetin alfa with a longer plasma half-life. The longer half-life of darbepoetin alfa is an advantage over epoetin alfa, enabling less frequent dosing.
    D) Peginesatide binds to and activates the human erythropoietin receptor and stimulates erythropoiesis in human red cell precursors in vitro. As of February 2013, peginesatide has been voluntarily withdrawn from the US market due to reports of serious and fatal hypersensitivity reactions.

Specific Substances

    1) Epoetin alfa
    2) Epoetin beta
    3) Epoetin gamma
    4) BI-71.052
    5) BM-06.019
    6) EPO
    7) EPOCH
    8) CAS 113427-24-0 (epoetin alfa)
    9) CAS 122312-54-3 (epoetin beta)
    10) CAS 130455-76-4 (epoetin gamma)
    11) Darbepoetin alfa
    12) Novel erythropoiesis-stimulating protein
    13) NESP
    14) Peginesatide
    1.2.1) MOLECULAR FORMULA
    1) PEGINESATIDE: C2031-H3950-N62-O958-S6 (free base)

Available Forms Sources

    A) FORMS
    1) DARBEPOETIN ALFA
    a) SINGLE-DOSE PREFILLED SYRINGES: 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg /mL (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    b) SINGLE-DOSE VIALS: 25, 40, 60, 100, 200, 300, and 500 mcg/mL, and 150 mcg/0.75 mL (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    2) EPOETIN ALFA
    a) SINGLE-DOSE VIAL: 2000, 3000, 4000, and 10,000 Units/mL (Prod Info Epogen(R) intravenous injection, subcutaneous injection, 2014).
    b) MULTIDOSE VIAL: 20,000 Units/2 mL and 20,000 Units/mL, containing benzyl alcohol (Prod Info Epogen(R) intravenous injection, subcutaneous injection, 2014).
    3) PEGINESATIDE
    a) Available in 1 mg/0.5 mL, 2 mg/0.5 mL, 3 mg/0.5 mL, 4 mg/0.5 mL, 5 mg/0.5 mL, 6 mg/0.5 mL single use vials and in multiple use vials of 10 mg/mL, and 20 mg/2mL solutions for injection (Prod Info OMONTYS(R) injection solution, 2012).
    B) USES
    1) DARBEPOETIN ALFA is indicated for the treatment of anemia in patients with chronic kidney disease who are on dialysis or not on dialysis. It is also indicated for the treatment of anemia at the initiation of or secondary to concomitant myelosuppressive chemotherapy (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015). The acquisition cost of the drug will be a large factor in determining the extent of its clinical use (Joy, 2001).
    2) EPOETIN ALFA is indicated for the treatment of anemia due to chronic renal failure, zidovudine administration (in HIV-infected patients), and chemotherapy administration. It is also indicated to reduce the need for blood transfusions in anemic patients undergoing elective, noncardiac, or nonvascular surgery (Prod Info Epogen(R) intravenous injection, subcutaneous injection, 2014).
    3) PEGINESATIDE is indicated for the treatment of anemia related to chronic kidney disease in adults receiving dialysis (Prod Info OMONTYS(R) injection solution, 2012).
    a) VOLUNTARY WITHDRAWAL: As of February 2013, peginesatide has been voluntarily withdrawn from the US market due to reports of serious and fatal hypersensitivity reactions. There have been 19 reports to the FDA of anaphylaxis from dialysis centers in the US. The FDA recommends that healthcare providers stop using the product and return it to Takeda Pharmaceuticals (U.S. Food and Drug Administration (FDA), 2013).
    4) POTENTIAL FOR ABUSE: These drugs have the potential for misuse by elite athletes in an attempt to enhance performance by increasing oxygen carrying capacity (ie, blood doping).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) EPOETIN ALFA: Hypertension, headache, confusion (rare) and seizures have been associated with erythropoietin administration, particularly in those with poor renal function. Hypertensive crisis with encephalopathy-like symptoms have also been reported.
    2) OTHER ADVERSE EFFECTS: Thrombosis at vascular access sites and clotting in the dialyzer, transient thrombocytosis, iron deficiency, flu-like symptoms including chills and arthralgia, hyperkalemia, skin rashes, and increased mortality with higher hematocrit (greater than 36). Red cell aplasia, thought to be immune-mediated, has rarely been reported.
    3) DARBEPOETIN ALFA: Hypertension, hypotension, myalgia, headache, diarrhea, fever, nausea, and chest pain are the most frequently reported adverse effects.
    4) PEGINESATIDE: The most common adverse events are dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication. Hypertension, hypotension arthralgia, headache and pyrexia have also occurred.
    B) WITH POISONING/EXPOSURE
    1) Overdose data are limited. There have been reports of severe hypertension following overdose of erythropoiesis-stimulating agents.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Epoetin alfa, darbepoetin alfa, and peginesatide are classified as Food and Drug Administration pregnancy category C. It is not known if epoetin alfa, darbepoetin alfa, or peginesatide are excreted into human breast milk.

Laboratory Monitoring

    A) No laboratory studies are necessary in an asymptomatic patient after a single acute overdose. Hematocrit is not expected to rise until 2 to 6 weeks after drug administration.
    B) Monitor blood pressure and CBC with differential/platelet count in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive.
    B) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

Range Of Toxicity

    A) EPOETIN ALFA and DARBEPOETIN ALFA - A minimum toxic dose has not been established. An inadvertent overdose is anticipated to result in excessive and/or rapid increase in hemoglobin concentration, and to be an extension of adverse events reported with these agents.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Clotting of the arteriovenous fistula has been reported to occur at an annualized rate of 0.25 events per patient-year on erythropoietin therapy. Other thrombotic events, such as myocardial infarction, cerebrovascular accident, and transient ischemic attacks, have occurred (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000; Brown et al, 1993; Anon, 1987; Casati et al, 1987; Eschbach et al, 1987; Winearls et al, 1986).
    b) Thrombosis of the sagittal and transverse sinus was reported in a 37-year-old end-stage renal disease patient receiving epoetin alfa. The patient was treated with intravenous heparin sodium and analgesics, and an uneventful recovery ensued (Finelli & Carley, 2000).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: A functional iron deficiency developed following erythropoietin doses of 15 units/kg or more in 72% (13 of 18) of patients responding to therapy. Intravenous iron dextran restored erythropoiesis for 12 of the patients, and the additional patient responded to oral iron therapy (Brown et al, 1993; Eschbach et al, 1987).
    1) The authors felt that with these erythropoietin doses, the demand for hemoglobin synthesis exceeded the ability of the reticuloendothelial system to release iron to transferrin. The functional iron deficiency was preceded by a drop in the reticulocyte count and transferrin saturation (to less than 20%) (Brown et al, 1993; Eschbach et al, 1987).
    b) Thirteen of 14 patients receiving erythropoietin required iron supplementation because of a decrease in plasma iron from baseline (p=0.0006) (Casati et al, 1987). The authors hypothesized that this increased requirement for iron was due to the rapid increase in hemoglobin synthesis upon erythropoietin administration.
    C) PURE RED CELL APLASIA
    1) WITH THERAPEUTIC USE
    a) A pure red cell aplasia, thought to be immune-mediated, has been reported (primarily in Europe) (Locatelli & Del Veccio, 2003; Fearon & Weinthal, 2003).
    D) THROMBOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Median platelet counts increased from 209 to 239 X 10(9)/L in 13 anemic patients with chronic renal failure receiving erythropoietin. Initially, patients received bolus injections of 24 units/kg with a doubling of the dose every other week to 96 or 192 units/kg. The thrombocytosis was first noticed during the second week of therapy and became statistically significant by the fifth week of therapy. However, thrombocytosis was not observed in 2 clinical trials comprising a total of 35 anemic patients with end-stage renal disease (Eschbach et al, 1987; Winearls et al, 1986).
    E) ERYTHROCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Erythropoietin can result in polycythemia if the hematocrit is not carefully monitored and the dose appropriately adjusted. If the target hematocrit range (30% to 36%) is exceeded, erythropoietin may be withheld until the hematocrit is lowered; therapy should then be resumed at a lower dosage. Phlebotomy may occasionally be indicated to decrease the hematocrit to within an acceptable range (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Angina, polycythemia (hematocrit 70.4), worsening of hypertension, and exacerbation of chronic lung disease were reported in a 62-year-old delusional man without anemia after daily self-injections of recombinant human erythropoietin (rHuEpo) (doses not reported). Although most patients with polycythemia (associated with erythropoietin use) experience hypertension, this patient also experienced hypotension due to pneumonia-associated sepsis during his hospital stay. In addition, his chronic obstructive lung disease was probably exacerbated by the rHuEpo-induced erythrocytotic increases in pulmonary artery pressure. His condition required endotracheal intubation with mechanical ventilation, intravenous hydration, and serial phlebotomy (Brown et al, 1993).
    b) CASE SERIES: There have been numerous deaths associated with polycythemia thought to be due to erythropoietin abuse/misuse in athletes, including a case series of 18 Belgian and Dutch cyclists (Eichner, 1992).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Among 10 patients with end-stage renal failure and anemia given erythropoietin, 4 (40%) complained of a feeling of COLDNESS and SWEATING without fever (Winearls et al, 1986). The symptoms presented approximately 2 hours following injections and persisted for periods up to 12 hours; however, in no case did they necessitate discontinuation of therapy.
    B) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: It appears that the excipients in the formulation of epoetin alfa (notably the citrate buffer) are responsible for the pain upon subcutaneous administration (Markam & Bryson, 1995).
    b) DARBEPOETIN ALFA: Injection-site pain or discomfort has been more common with subcutaneous darbepoetin alfa than subcutaneous epoetin alfa in chronic renal failure patients (Anon, 2001). However, specific incidence data are unavailable.
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) DARBEPOETIN ALFA: Pruritus has been reported in less than 10% of patients (Prod Info Aranesp(TM), darbepoetin alfa , 2001). This complication was reported in 7% of nonmyeloid cancer patients in one study (Glaspy et al, 2001).
    b) CASE REPORTS
    1) EPOETIN BETA: A 66-year-old man on hemodialysis for chronic renal failure developed widespread suberythrodermic eczema (dermal biopsy revealed infiltrate of histocytes, neutrophils, lymphocytes, and eosinophils) 10 weeks after starting erythropoietin EPO-beta 2000 units 3 times weekly subcutaneously. He experienced pruritus and an itchy maculopapular eczema 4 weeks and 6 weeks, respectively, after starting the treatment. Rechallenge with 2000 units of EPO-alfa subcutaneously caused a relapse of the dermatitis (Hardwick & King, 1993).
    D) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Pseudoporphyria cutanea tarda, a photosensitivity disorder with findings similar to porphyria cutanea tarda, but without the associated biochemical markers, was reported in 2 children undergoing peritoneal dialysis and receiving erythropoietin (Harvey et al, 1992).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: In 3 double-blind, controlled studies of adult chronic kidney disease patients on dialysis, arthralgia was reported in 16.2% of patients who received epoetin alfa (n=148). In pediatric chronic kidney disease patients on dialysis, adverse reactions were similar to those found in adults (Prod Info Epogen(R) subcutaneous injection solution, intravenous injection solution, 2011; Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    b) PEGINESATIDE: Arthralgia was reported in 10.7% of patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).
    B) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: A 40% incidence (4 of 10) of bone pain, specifically aching in the limbs and pelvis, beginning 2 hours postinjection has been reported with erythropoietin. The symptoms persisted for periods up to 12 hours, but did not necessitate discontinuation of therapy (Winearls et al, 1986).
    C) ACQUIRED MUSCULOSKELETAL DEFORMITY
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: A 15-month-old boy developed a thickened cranium after 3 months of erythropoietin therapy for renal failure-associated chronic anemia. The frontal and temporal regions were predominantly affected, with an expanded diploic bone marrow cavity presumably due to increased erythrogenesis. The brain itself remained normal (Castillo & Davis, 1998).

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) EPOETIN ALFA: Hypertension, headache, confusion (rare) and seizures have been associated with erythropoietin administration, particularly in those with poor renal function. Hypertensive crisis with encephalopathy-like symptoms have also been reported.
    2) OTHER ADVERSE EFFECTS: Thrombosis at vascular access sites and clotting in the dialyzer, transient thrombocytosis, iron deficiency, flu-like symptoms including chills and arthralgia, hyperkalemia, skin rashes, and increased mortality with higher hematocrit (greater than 36). Red cell aplasia, thought to be immune-mediated, has rarely been reported.
    3) DARBEPOETIN ALFA: Hypertension, hypotension, myalgia, headache, diarrhea, fever, nausea, and chest pain are the most frequently reported adverse effects.
    4) PEGINESATIDE: The most common adverse events are dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication. Hypertension, hypotension arthralgia, headache and pyrexia have also occurred.
    B) WITH POISONING/EXPOSURE
    1) Overdose data are limited. There have been reports of severe hypertension following overdose of erythropoiesis-stimulating agents.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in therapeutic use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) DARBEPOETIN ALFA: In clinical trials (n=1598), fever was reported in 6% of patients (Prod Info Aranesp(TM), darbepoetin alfa , 2001).
    2) EPOETIN ALFA: In clinical trials with epoetin alfa (n=297), pyrexia was reported in 38% of zidovudine-treated HIV-infected patients compared to 29% placebo-treated patients (Prod Info Epogen(R), epoetin alfa, 1999).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CONJUNCTIVITIS: Five of 14 patients receiving erythropoietin IV 3 times weekly reported conjunctival inflammation similar to RED EYE SYNDROME seen in uremic patients (Casati et al, 1987).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Increased risk of death, myocardial infarction, stroke, congestive heart failure, venous thromboembolism, and thrombosis of vascular access has been reported in controlled clinical trials of erythropoiesis-stimulating agents in patients with chronic kidney disease who were dosed to a target hemoglobin concentration of 13 to 14 g/dL as compared with those dosed to a target hemoglobin concentration of 9 to 11.3 g/dL. Targeting hemoglobin levels of greater than 11 g/dL or rises of greater than 1 g/dL over 2 weeks may increase the risks of these events (Prod Info OMONTYS(R) injection solution, 2012; Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011; Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    b) A randomized, open-label design trial (n=1432) ("Correction of Hemoglobin and Outcomes in Renal Insufficiency" (CHOIR)) of patients with anemic chronic kidney disease (CKD), demonstrated increases in serious and potentially life-threatening cardiovascular events when epoetin alfa (Procrit) was administered to reach higher target hemoglobin levels (13.5 g/dL (g/dL)) than lower target hemoglobin levels (11.3 g/dL). The cardiovascular events reported include death, myocardial infarction, hospitalization for congestive heart failure, and stroke (Singh et al, 2006; US Food and Drug Administration, 2006).
    c) DARBEPOETIN ALFA: Hypertension (23%) or hypotension (22%), vascular-access thrombosis (8%), peripheral edema (11%), cardiac dysrhythmias/arrest (10%), congestive heart failure (6%) and angina (8%) are relatively common adverse effects of darbepoetin alfa therapy in chronic renal failure patients (n=1598) (Prod Info Aranesp(TM), darbepoetin alfa , 2001; Anon, 2001; Joy, 2001; Macdougall, 2001; Macdougall, 2000).
    d) EPOETIN ALFA: Increases in cardiac output, stroke volume and ejection fractions, as well as decreased peripheral resistance have been reported in patients receiving erythropoietins (Paganini et al, 1989; Verbeelen et al, 1989).
    1) Thrombotic events, such as myocardial infarction, cerebrovascular accident, and transient ischemic attacks, have occurred (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    e) PEGINESATIDE: Among patients with chronic kidney disease who were NOT on dialysis, 22% of patients receiving peginesatide and 17% of patients receiving darbepoetin alfa experienced a composite safety endpoint (death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia) in 2 randomized, active-controlled, open-label, multi-center trials (n=983) (Prod Info OMONTYS(R) injection solution, 2012).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: An excessive rise in hematocrit has been associated with an exacerbation of hypertension. The dose of erythropoietin should be reduced in patients who experience a rapid increase in hematocrit (more than 4 points in any 2-week period) (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000; Markham & Bryson, 1995; Brown et al, 1993; Eschbach et al, 1987; Bommer et al, 1987; Erslev, 1987).
    1) In 8 of 14 previously hypertensive patients, an increase in blood pressure occurred, requiring an increase in antihypertensive medication when erythropoietin was administered to maintain the Hgb at 12 g/dL Blood pressure levels dropped when erythropoietin dosages were reduced to maintain a target Hgb of 10 to 12 g/dL (Casati et al, 1987).
    2) Several authors have noted increases in mean arterial pressure, total peripheral resistance index and decrease in cardiac index and left ventricular ejection fraction suggesting a reversal of the hemodynamic adaptions seen in patients with anemia (Akiba T, Kurihara S & Katoh H et al, 1988; Mayer et al, 1988; Schwartz et al, 1988; Buckner et al, 1988).
    3) A single case report of HYPERTENSIVE ENCEPHALOPATHY occurred in a patient receiving erythropoietin therapy. The hemoglobin was 9.3 g/dL and the blood pressure rose to 220/140 mmHg (systolic/diastolic) from a previous value of 170/90 mmHg. Erythropoietin was discontinued, and within 3 weeks the hemoglobin decreased to pretreatment values, allowing for reinstitution of the erythropoietin at a lower dose (96 units/kg) with clinical benefit. It was determined that the patient's blood pressure had been poorly controlled prior to the institution of therapy with erythropoietin. The elevated hematocrit may have increased peripheral resistance and therefore contributed to the hypertension (Winearls et al, 1986).
    b) PEGINESATIDE: Hypertension was reported in 13.2% of patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).
    2) WITH POISONING/EXPOSURE
    a) There have been reports of severe hypertension following overdose of erythropoiesis-stimulating agents (Prod Info OMONTYS(R) injection solution, 2012).
    C) ANGINA
    1) WITH THERAPEUTIC USE
    a) DARBEPOETIN: Angina was reported in 8% of patients with chronic kidney disease administered darbepoetin (n=766; median weight adjusted dose, 0.5 mcg/kg) based on pooled data from 5 randomized, active-controlled studies (Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Angina, polycythemia, worsening of hypertension, and exacerbation of chronic lung disease were reported in a 62-year-old delusional man without anemia after daily self-injections of recombinant human erythropoietin (rHuEpo) (doses not reported). Although most patients with polycythemia (associated with erythropoietin use) experience hypertension, this patient also experienced hypotension due to pneumonia-associated sepsis during his hospital stay. In addition, his chronic obstructive lung disease was probably exacerbated by the rHuEpo-induced erythrocytotic increases in pulmonary artery pressure. He required endotracheal intubation with mechanical ventilation, intravenous hydration, and serial phlebotomy (Brown et al, 1993).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) DARBEPOETIN: Procedural hypotension was reported in 10% of patients with chronic kidney disease administered darbepoetin (n=766; median weight adjusted dose, 0.5 mcg/kg) based on pooled data from 5 randomized, active-controlled studies (Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011).
    b) EPOETIN: Hypotension was reported in 14.6% of patients with chronic kidney disease on dialysis who received epoetin 1 to 3 times/week (n=542; median weight adjusted dose, 113 units/week/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).
    c) PEGINESATIDE: Hypotension was reported in 14.2% of patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) DARBEPOETIN ALFA: In clinical trials (n=1598), upper respiratory tract infection (14%), dyspnea (12%) cough (10%) and bronchitis (6%) were reported (Prod Info Aranesp(TM), darbepoetin alfa , 2001).
    1) Dyspnea occurred in 21% of dialysis patients receiving darbepoetin alfa 0.45 mcg/kg weekly in one study, which was higher than in the epoetin alfa group (6%); this study employed lower doses of darbepoetin alfa (based on peptide mass) (Joy, 2001).
    b) PEGINESATIDE: Dyspnea (18.4%) and cough (15.9%) were reported in patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Increased risk of seizures has been reported in patients with chronic kidney disease during the first several months of therapy with erythropoiesis-stimulating agents (Prod Info OMONTYS(R) injection solution, 2012; Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011; Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    b) EPOETIN ALFA: Seizures have been reported in patients with chronic renal failure receiving erythropoietin. In patients on dialysis, there is a higher incidence of seizures during the first 90 days of therapy (2.5% of patients) (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000; Brown et al, 1993).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Aphasia and confusion possibly related to an ischemic lesion in the brain, were reported in 1 patient receiving erythropoietin (Casati et al, 1987). Erythropoietin was discontinued and the symptoms disappeared within 10 days. Erythropoietin was reintroduced at a lower dose without further complications.
    b) DARBEPOETIN ALFA: In clinical trials (n=1598), headache was seen in 16% of patients, with fatigue and dizziness each occurring in less than 10% (Prod Info Aranesp(TM), darbepoetin alfa , 2001).
    c) DARBEPOETIN ALFA: Fatigue and asthenia were frequent adverse effects of darbepoetin alfa in nonmyeloid cancer patients not receiving chemotherapy (incidence not provided) (Smith et al, 2001).
    d) EPOETIN ALFA: Thrombotic events, such as cerebrovascular accident and transient ischemic attacks, have occurred (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Severe headache secondary to thrombosis of the sagittal and transverse sinuses was reported in a 37-year-old end-stage renal disease patient receiving epoetin alfa. The patient was treated with intravenous heparin sodium and analgesics, and an uneventful recovery ensued (Finelli & Carley, 2000).
    b) PEGINESATIDE: Headache was reported in 15.4% of patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) in pooled data from 2 randomized, active-controlled, open-label trials (Prod Info OMONTYS(R) injection solution, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) DARBEPOETIN ALFA: In one study, nausea (32%) and vomiting (20%) were observed in dialysis patients receiving once-weekly therapy; these incidences were higher than reported for epoetin alfa given three times weekly (Joy, 2001). The dose of darbepoetin alfa in this study was lower than that of epoetin alfa based on peptide mass.
    b) EPOETIN ALFA: Nausea (11%), vomiting (8%), and diarrhea (9%) have been reported with erythropoietin in double-blind placebo-controlled trials involving over 300 patients. Corresponding rates in patients receiving placebo were 9%, 5%, and 6%, respectively (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    c) PEGINESATIDE: In pooled data from 2 randomized, active-controlled, open-label trials, diarrhea (18.4%), nausea (17.4%), and vomiting (15.3%) were reported in patients with chronic kidney disease on dialysis who received peginesatide once monthly (n=1066; median weight adjusted dose, 0.07 mg/kg) (Prod Info OMONTYS(R) injection solution, 2012).
    B) SPLENOMEGALY
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Two patients with myeloproliferative disorders experienced aggravation of splenomegaly after erythropoietin administration (Sweetman, 2002; Iki et al, 1991). An 8-year-old boy with aplastic anemia experienced splenic infarction after erythropoietin therapy (Imashuku et al, 1993).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) EPOETIN ALFA: Transient urticaria has occasionally been reported with erythropoietin (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    b) In Japan, a case of anaphylaxis was reported in association with the administration of epoetins alfa and beta. A 44-year-old woman received a dose of epoetin alfa that contained BOVINE GELATIN as a stabilizer and immediately experienced a severe anaphylactic reaction (hypotension, airway obstruction, cough). She recovered completely after treatment with dopamine, hydrocortisone, and oxygen therapy. Afterwards she received conventional epoetin alfa (with human serum albumin) and showed no reaction. Upon rechallenge with epoetin beta containing bovine gelatin, the patient developed signs of anaphylaxis. The investigators found that the patient had antigelatin IgE suggesting that anaphylaxis to erythropoietin products was associated with hypersensitivity to gelatin included in the products (Sakaguchi et al, 1999).
    c) PURE RED CELL APLASIA
    1) There is an increasing incidence of this rare effect, primarily reported in Europe. It is thought to be due to antibodies against recombinant human erythropoietin that cross-react with endogenous and exogenously administered erythropoietin (Locatelli & Del Vecchio, 2003).

Reproductive

    3.20.1) SUMMARY
    A) Epoetin alfa, darbepoetin alfa, and peginesatide are classified as Food and Drug Administration pregnancy category C. It is not known if epoetin alfa, darbepoetin alfa, or peginesatide are excreted into human breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) EPOETIN ALFA: Animal studies with rats using doses 5 times the human dose have resulted in decreases in body weight gain, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae. No adequate well-controlled studies have been performed with erythropoietin in pregnant women. Erythropoietin should only be used during pregnancy if the potential benefits justify the potential risks to the fetus (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    2) DARBEPOETIN ALFA: In animal studies, reduced fetal weight was observed after high doses, but there was no evidence of teratogenic effects (Prod Info Aranesp(TM), darbepoetin alfa , 2001).
    3) PEGINESATIDE: Peginesatide was teratogenic and produced embryofetal lethality in animals at doses and/or exposures that resulted in polycythemia. Embryofetal toxicity and malformations, including reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones, were observed in rats and rabbits administered IV peginesatide every third (5 doses) and fifth (3 doses) day, respectively, during organogenesis (0.01 to 50 mg/kg/dose). In rats, embryofetal toxicity was reported with peginesatide doses of 1 mg/kg or greater and malformations (cleft palate and sternoschisis, and variations in blood vessels) usually occurred with doses of 10 mg/kg or greater. The dose of 1 mg/kg is approximately equal to the human exposure after IV doses of 0.35 mg/kg in dialysis patients. Reduced fetal weight and delayed/reduced ossification were also noted with peginesatide doses of 0.25 mg/kg in rats and 0.5 mg/kg/dose or greater in rabbits. In other rabbit studies, peginesatide doses as low as 0.25 mg/kg (5% to 50% of the recommended human dose of 0.35 mg/kg) produced an increased incidence of fetal adverse events, including fused sternebrae (Prod Info OMONTYS(R) injection solution, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) EPOETIN ALFA: US Food and Drug Administration's pregnancy category C (Prod Info Procrit(R), epoetin alpha, 2000; Prod Info Epogen(R), epoetin alfa, 1999)
    2) DARBEPOETIN ALFA: US Food and Drug Administration's pregnancy category C (Prod Info Aranesp(TM), darbepoetin alfa , 2001)
    3) PEGINESATIDE: US Food and Drug Administration's pregnancy category C (Prod Info OMONTYS(R) injection solution, 2012)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) EPOETIN ALFA: It is not known if epoetin alfa is excreted into human breast milk (Prod Info Epogen(R), epoetin alfa, 1999).
    2) DARBEPOETIN ALFA: It is not known if darbepoetin alfa is excreted into human breast milk (Prod Info Aranesp(TM), darbepoetin alfa , 2001).
    3) PEGINESATIDE: It is not known if peginesatide is excreted into human breast milk (Prod Info OMONTYS(R) injection solution, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) PEGINESATIDE: Fertility was reduced in male and female rats administered IV peginesatide doses of 0.1 mg/kg or greater (approximately 5% of the dose of 0.35 mg/kg in patients) at weekly intervals prior to and during mating. Reduced fertility was most evident with doses of 1 mg/kg or greater. Reduced weight of seminal vesicles and prostate were noted in male rats and decreased viable fetuses due to pre- and post-implantation losses were noted with doses of 0.1 mg/kg or greater in female rats.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No laboratory studies are necessary in an asymptomatic patient after a single acute overdose. Hematocrit is not expected to rise until 2 to 6 weeks after drug administration.
    B) Monitor blood pressure and CBC with differential/platelet count in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No laboratory studies are necessary in an asymptomatic patient after a single acute overdose. Hematocrit is not expected to rise until 2 to 6 weeks after drug administration.
    2) In patients with chronic overuse of erythropoietins, monitor hematocrit twice a week until stabilization. The suggested target hematocrit range for a patient with chronic anemia is 30% to 36%. (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000). Because of the length of time required for erythropoiesis (several days for erythroid progenitors to mature and be released into the circulation), a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients (Prod Info Epogen(R), epoetin alfa, 1999).
    3) Platelet count: Monitor on a regular basis in patients with chronic use or overuse (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).
    4) Monitor serum ferritin and transferrin saturation in patients with chronic overuse or use of erythropoietins (Prod Info Epogen(R), epoetin alfa, 1999; Prod Info Procrit(R), epoetin alpha, 2000).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No laboratory studies are necessary in an asymptomatic patient after a single acute overdose. Hematocrit is not expected to rise until 2 to 6 weeks after drug administration.
    B) Monitor blood pressure and CBC with differential/platelet count in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.

Oral Exposure

    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) PERITONEAL DIALYSIS
    1) EPOETIN ALFA: MINIMAL - Following doses of 120 U/kg of erythropoietin by IV bolus injection to patients on continuous ambulatory peritoneal dialysis (CAPD), approximately 1.7% to 3% of the total dose was recovered in the dialysate fluid after 24 hours(MacDougall et al, 1989).
    2) DARBEPOETIN ALFA: There is no information regarding the effectiveness of peritoneal dialysis for the removal of darbepoetin alfa from plasma.
    B) HEMODIALYSIS
    1) DARBEPOETIN ALFA: There is no information regarding the effectiveness of hemodialysis for the removal of darbepoetin alfa from plasma.

Range Of Toxicity

Summary

    A) EPOETIN ALFA and DARBEPOETIN ALFA - A minimum toxic dose has not been established. An inadvertent overdose is anticipated to result in excessive and/or rapid increase in hemoglobin concentration, and to be an extension of adverse events reported with these agents.

Therapeutic Dose

    7.2.1) ADULT
    A) DARBEPOETIN ALFA
    1) PATIENTS WITH CHRONIC KIDNEY DISEASE ON DIALYSIS: The recommended starting dose is 0.45 mcg/kg IV or subQ once weekly, or 0.75 mcg/kg IV or subQ once every 2 weeks as appropriate (Prod Info Aranesp(R) intravenous injection, subcutaneous injection, 2015).
    2) PATIENTS WITH CHRONIC KIDNEY DISEASE NOT ON DIALYSIS: The recommended starting dose is 0.45 mcg/kg IV or subQ given once every 4 weeks as appropriate (Prod Info Aranesp(R) intravenous injection, subcutaneous injection, 2015).
    3) For patients with chronic kidney disease on dialysis who are converting from epoetin alfa, the usual darbepoetin alfa dose is 6.25 to 200 mcg/week IV or subQ, depending on the previous epoetin alfa dose (Prod Info Aranesp(R) intravenous injection, subcutaneous injection, 2015).
    B) EPOETIN ALFA
    1) The recommended dose is 50 to 300 units/kg 3 times/week IV or subQ. Doses up to 60,000 units/week have been used (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    2) In surgery patients, the recommended dose is 300 to 600 units/kg/day (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    C) PEGINESATIDE
    1) VOLUNTARY WITHDRAWAL: As of February 2013, peginesatide has been voluntarily withdrawn from the US market due to reports of serious and fatal hypersensitivity reactions (U.S. Food and Drug Administration (FDA), 2013).
    a) The recommended starting dose is 0.04 mg/kg IV or subQ once monthly (Prod Info OMONTYS(R) injection solution, 2012).
    7.2.2) PEDIATRIC
    A) DARBEPOETIN ALFA
    1) CANCER CHEMOTHERAPY
    a) Safety and efficacy have not been established (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    2) CHRONIC KIDNEY DISEASE
    a) ON DIALYSIS, GREATER THAN 1 YEAR OF AGE: When converting from epoetin alfa, 6.25 to 200 mcg/week IV or subQ, depending on the previous weekly epoetin dose (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    b) ON DIALYSIS, AS INITIAL TREATMENT: Safety and efficacy have not been established in pediatric patients (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    c) NOT ON DIALYSIS: Safety and efficacy have not been established in pediatric patients (Prod Info ARANESP(R) intravenous injection, subcutaneous injection, 2015).
    B) EPOETIN ALFA
    1) CANCER CHEMOTHERAPY
    a) 5 TO 18 YEARS OF AGE: The recommended dose is 600 to 900 units/kg IV weekly. MAXIMUM DOSE: 60,000 units/week (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    b) LESS THAN 5 YEARS OF AGE: Safety and efficacy have not been established (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    2) CHRONIC KIDNEY DISEASE
    a) 1 MONTH TO 16 YEARS OF AGE: The recommended starting dose is 50 units/kg IV or subQ 3 times/week for patients on dialysis (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    b) LESS THAN 1 MONTH OF AGE: Safety and efficacy have not been established (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).

Maximum Tolerated Exposure

    A) EPOETIN ALFA and DARBEPOETIN ALFA - A minimum toxic dose has not been established. An inadvertent overdose is anticipated to result in excessive and/or rapid increase in hemoglobin concentration, and to be an extension of adverse events reported with these agents (Prod Info EPOGEN(R) injection, 2007; Prod Info ARANESP(R) injection, 2007).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) EPOETIN ALFA
    1) EPOETIN ALFA: Recombinant human erythropoietin (epoetin alfa) is a polypeptide containing 165 amino acids (Prod Info Epogen(R) intravenous injection, subcutaneous injection, 2014; Anon, 1987; Erslev, 1987). The molecule is heavily glycosylated with a molecular weight of 34,000 daltons (Prod Info Epogen(R) intravenous injection, subcutaneous injection, 2014; Anon, 1987). Production of the hormone was made possible using recombinant DNA techniques. Following isolation of the human erythropoietin gene, it was inserted into and expressed by cultured mammalian cells, which are capable of synthesizing unlimited quantities of the hormone (Eschbach et al, 1987; Lin et al, 1985; Erslev, 1987).
    a) Erythropoietin is a hormone that is instrumental in the production of red cells from the erythroid tissues in the bone marrow. The majority of this hormone is produced in the kidney in response to hypoxia, with an additional 10% to 15% of synthesis occurring in the liver. Erythropoietin functions as a growth factor, stimulating the mitotic activity of the erythroid progenitor cells (erythrocyte burst-forming and colony-forming units) and early precursor cells (proerythroblasts) (Erslev, 1987).
    b) The hormone is also active as a differentiation factor that stimulates transformation of an erythrocyte colony-forming unit to a proerythroblast (Erslev, 1987). Although the precise location for the production of erythropoietin in the kidney tubule is not totally conclusive, it has been suggested that tubular or interstitial cells function as the main site for localization of the hormone and its mRNA (Schuster et al, 1986; Erslev, 1987). Preliminary work has also identified the liver as the major site of erythropoietin production for the fetus (Nathan, 1977).
    c) Erythropoietin significantly increases peripheral hemopoietic progenitor cells including BFU-E, CFU-GM and CFU-mix within one week of erythropoietin supplementation. An increase in hematocrit was noted within 3 to 4 weeks, depending on the dosage of erythropoietin. The latter progenitor cells (CFU-GM, CFU-mix) are not those normally associated with erythrocyte production. Thus, erythropoietin may effect both cell lineages (erythroid and myeloid) when given in therapeutic doses (Stockenhuber et al, 1990).
    d) EPOETIN ALFA-INDUCED HYPERTENSION
    1) MECHANISM: It is commonly believed that epoetin alfa (EPO)-induced hypertension is mediated by the associated increase in erythrocyte mass and hematocrit. However, there is evidence to the contrary. Data from animal and human subjects have revealed that blood transfusions fail to increase blood pressure despite achieving hematocrit values comparable to that of EPO administration. An increase in vasoconstrictor response to norepinephrine has been reported following EPO administration. In contrast, exposure to EPO does not alter the pressor response to angiotensin II in the rat model nor does it significantly increase plasma endothelin-1 concentrations in both rats and man. In vitro, EPO increases the release of the vasoconstrictive prostaglandins PGF2-alfa and thromboxane B2 and reduces the release of the vasodilatory prostaglandin, prostacyclin. However, in both human and animal models, no discernible increase in blood pressure or heart rate occurs after single injections of EPO suggesting a time-dependent, adaptive process. Chronic exposure to exogenous EPO results in resistance to the vasodilatory action of nitric oxide. This mechanism may explain the pathogenesis of EPO-induced hypertension. Additionally, elevated resting cytosolic calcium concentrations are a marker of hypertensive disorders and it has been found that these increased concentrations contribute to nitric oxide resistance. It has been found that EPO exerts a direct vasoconstrictive effect. In the short-term, this effect is countered by acute elevations of the vasodilators, nitric oxide and cGMP. EPO-induced hypertension does not appear to be caused by alterations in plasma levels of atrial natriuretic peptide or vasopressin. Finally, EPO promotes vascular smooth muscle cell growth which may result in vascular remodeling and medial hypertrophy thereby contributing to maintenance of hypertension. The author suggests that therapeutic strategies to restore normal cytosolic calcium are logical and desirable (Vaziri, 1999).
    2) The effect of erythropoietin therapy and the associated development of hypertension were evaluated in 13 chronic hemodialysis patients receiving erythropoietin therapy for at least one year. Blood viscosity increased in conjunction with hemoglobin in all patients receiving erythropoietin. However, only 3 patients developed hypertension. The authors suggest that, based on this observation, increased blood viscosity is not the only factor leading to hypertension in this population and a multifactorial approach to the mechanism of this side effect should be considered (Canaud et al, 1989).
    e) SEIZURES
    1) Seizures associated with erythropoietin therapy may be the result of a rapid increase in packed cell volume translating to both an increase in blood viscosity and loss of hypoxic vasodilatation. These combined events may lead to a rise in vascular resistance and, when associated with an abnormality in cerebral vasculature, may lead to hypertensive encephalopathy (Brown et al, 1989). Seizure events may also be the result of acute cerebral ischemia. Events occurring during dialysis may enhance autoregulation of vasoconstriction and decrease cerebral perfusion, leading to seizure activity (Temple et al, 1990).
    B) DARBEPOETIN ALFA
    1) The mechanism of stimulation of erythropoiesis by darbepoetin alfa is like that of epoetin alfa; both agents bind to the erythropoietin receptor on erythroid progenitor cells, stimulating production/differentiation of mature red cells (Macdougall, 2000; Joy, 2001). Although the binding affinity of darbepoetin alfa is lower than that of epoetin alfa or natural erythropoietin, this is offset by the longer half-life of darbepoetin which affords greater in vivo biological activity (Egrie & Browne, 2001; Macdougall, 2000).
    2) Darbepoetin alfa (novel erythropoiesis-stimulating protein) is a hyperglycosylated analogue of recombinant human erythropoietin (epoetin alfa) (Joy, 2001; Macdougall, 2000; Egrie & Browne, 2001). It contains five N-linked carbohydrate chains, two more than epoetin, imparting a higher sialic acid content and molecular weight, and a greater negative charge (Egrie & Browne, 2001).
    a) The enhanced sialic acid content of darbepoetin alfa results in slower plasma clearance, a longer plasma half-life, and greater in vivo biologic activity compared to epoetin alfa, enabling less frequent dosing (eg, once versus three times weekly) (Macdougall, 2001; Anon, 2001). In animal models and humans, the elimination half-life of darbepoetin alfa was up to 3-fold longer than that of epoetin alfa (Macdougall, 2001).
    b) Darbepoetin alfa has produced dose-dependent hematocrit increases in normal mice when given either intravenously, subcutaneously, or intraperitoneally (Egrie & Browne, 2001). In comparative studies in animals, the potency of darbepoetin alfa was about 3.5-fold that of epoetin alfa with respect to hematocrit increases when these agents were given three times weekly by any route; administration of darbepoetin alfa once-weekly or every other week was significantly more effective than epoetin alfa given in these dose frequencies (Macdougall, 2000; Egrie & Browne, 2001). Potency differences from animal studies indicated that similar efficacy could be achieved (hematocrit increases) with less frequent administration of darbepoetin alfa (Egrie & Browne, 2001).

Physicochemical

Physical Characteristics

    A) DARBEPOETIN ALFA is a colorless solution (Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011).
    B) EPOETIN ALFA is a colorless liquid (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011).
    C) PEGINESATIDE is a colorless to slightly yellow solution (Prod Info OMONTYS(R) injection solution, 2012).

Ph

    A) DARBEPOETIN ALFA: 5.7 to 6.3 (albumin solution) (Prod Info ARANESP(R) injection, 2010); 6 to 6.4 (polysorbate solution) (Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011)
    B) EPOETIN ALFA: 6.6 to 7.2 (single-dose vials); 5.8 to 6.4 (multidose vials) (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011)
    C) PEGINESATIDE: 5.7 to 6.3 (single-dose vials); 4.9 to 5.9 (multidose vials) (Prod Info OMONTYS(R) injection solution, 2012)

Molecular Weight

    A) DARBEPOETIN ALFA: approximately 37,000 daltons (Prod Info Aranesp(R) intravenous injection subcutaneous injection, 2011)
    B) EPOETIN ALFA: approximately 30,400 daltons (Prod Info PROCRIT(R) IV, subcutaneous injection, 2011)
    C) PEGINESATIDE: approximately 45,000 daltons (Prod Info OMONTYS(R) injection solution, 2012)

References

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    51) Product Information: ARANESP(R) injection, darbepoetin alfa injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
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    55) Product Information: Aranesp(TM), darbepoetin alfa . Amgen Inc, Thousand Oaks, CA, 2001.
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    60) Product Information: OMONTYS(R) injection solution, peginesatide injection solution. Affymax, Inc. (Per FDA), Palo Alto, CA, 2012.
    61) Product Information: PROCRIT(R) IV, subcutaneous injection, epoetin alfa IV, subcutaneous injection. Centocor Ortho Biotech Products, L.P. (per FDA), Raritan, NJ, 2011.
    62) Product Information: Procrit(R), epoetin alpha. Ortho Biotech, Raritan, NJ, 2000.
    63) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    64) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    65) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    66) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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