NEODOSE

Indications

Hypoxic-ischemic Encephalopathy (HIE): Multiple high-doses of erythropoietin resulted in significantly improved short-term (12 months) motor outcomes in one, but not both, neurodevelopment assessment tests in newborns (mean gestational age, 38.7 weeks) undergoing hypothermia for moderate to severe HIE in a phase II double-blind, placebocontrolled trial (n=50). Less MRI brain injury was observed at a mean age of 5.2 days in the erythropoietin group compared with placebo group. Dosage of erythropoietin was 1000 units/kg IV on days 1, 2, 3, 5, and 7 (total, 5 doses) starting within the first 24 hours of life . In term neonates with moderate or severe HIE who received 5 doses of erythropoietin 500 units/kg initiated by 6 hours of age without hypothermia therapy (n=100), composite death or moderate or severe disability at 19 months of age was significantly reduced by 43% (95% CI, 15% to 62%) and survival without neurological abnormality was significantly improved by 35% (95% CI, 6% to 55%; p=0.016) compared with placebo. However, there was no significant difference from placebo for death or disability in those with severe encephalopathy . Neurocognitive Development – Prematurity: Summary: Erythropoietin may provide a benefit in mental development but not other areas such as cerebral palsy, vision, or hearing in preterm newborns . The benefit in preterm newborns may be limited to newborns 28 weeks or older gestation . •There was no significant difference between high-dose erythropoietin and placebo administered to extremely preterm newborns (24 weeks to 27 weeks 6 days gestation) in the primary outcome of death or severe neurodevelopment impairment at 22 to 26 months postmenstrual age in a double-blind, randomized trial (N=941). The relative risk for severe neurodevelopment impairment was 0.79 (95% CI, 0.51 to 1.22); 11% in the erythropoietin group and 14% in the placebo group. Severe neurodevelopment was defined as the presence of severe cerebral palsy or a Bayley III Scales of Infant Development motor or cognitive score of less than 70. For moderate neurodevelopment impairment, there was no clinical difference between groups. Adverse events (severe bronchopulmonary dysplasia, medically or surgically treated patent ductus arteriosus, intracranial hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity) were not different between the groups. The dosages of erythropoietin were 1000 units/kg IV every 48 hours for 6 doses, then 400 units/kg subQ 3 times a week through 32 weeks 6 days of postmenstrual age . •In a meta-analysis including 4 randomized studies with 1133 preterm infants, prophylactic erythropoietin significantly reduced the incidence of a mental development index (MDI; Bayley Scales of Infant Development) of less than 70 at 18 to 24 months’ corrected age compared with placebo or no treatment (odds ratio, 0.51; 95% CI, 0.31 to 0.81). However, there was no significant difference in psychomotor development index of less than 70, or in development of cerebral palsy, visual impairment, or hearing impairment. With limited data in infants less than 28 weeks’ gestation, no significant difference in MDI less than 70 was observed . In one of the included studies that showed no difference in neurodevelopmental outcomes at 2 years’ corrected age in infants with a mean gestational age of 29 weeks (n=450), the dosage was erythropoietin 3000 international units/kg/dose (max 4500 international units/dose for weight 1.5 kg or greater) IV within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth [10]. Another of the studies included in the metaanalysis showed neurocognitive outcomes that were minimally better in preterm infants treated with erythropoiesis stimulating agents (ESA) (erythropoietin or darbepoetin) compared with placebo, at 18 to 22 months of age (n=80) at high-altitude institutions. The study only used the Bayley Scales of Infant Development III to evaluate the infants. ESAs were continued until 35 weeks’ gestation was completed; 400 units/kg/dose subQ 3 times weekly for erythropoietin and 10 mcg/kg/dose subQ once weekly for darbepoetin . At 2.5 to 4 years of age the same children (n=53) had significantly higher cognitive scores and improved executive function in the ESA group compared with placebo. When compared with term infants without complications, the cognitive performance in the ESA group were lower. Dosages were erythropoietin 400 units/kg/dose subQ 3 times a week and darbepoetin 10 mcg/kg/dose subQ once weekly until 35 completed weeks’s gestation, discharge, transfer to another hospital, or death . Anemia of prematurity Early administration (before 8 days of age): Although there was a reduction in the use of RBC transfusions (RR 0.79 (95% CI 0.74 to 0.85)), volume of RBCs transfused, and number of donor exposures, with erythropoiesis-stimulating agents (ESAs; mostly epoetin alfa) compared with placebo, the differences were not clinically significant. This was demonstrated in a meta-analysis (n=34 studies; 3643 preterm and/or very low birthweight infants). ESAs did not have a significant effect on mortality. Retinopathy of prematurity (stage 3 or more) was not different between the 2 groups. There were conflicting results for neuroprotection, neurodevelopmental outcomes, intraventricular hemorrhage (grades III and IV), periventricular leukomalacia, and necrotizing enterocolitis . Late administration: Although, the use of late administration (between 8 to 28 days of age) reduced the number of RBC transfusion per infant (by less than 1 transfusion/infant) the total volume of RBC transfused/infant was not reduced. Furthermore, most infants received blood transfusions prior to erythropoietin administration. Clinically significant adverse outcomes did not increase or decrease with late administration .

Administration

Note: Do not use epoetin alfa from multidose vials in neonates or infants; contains benzyl alcohol. Do not use single-dose vials admixed with bacteriostatic saline containing benzyl alcohol in neonates and infants

Administer subQ, or IV over at least 4 hours (even continuously in total parenteral nutrition).

Contraindications/Precautions

Contraindicated in patients with a known hypersensitivity to mammalian cell-derived products or albumin (human), patients with uncontrolled hypertension, or in patients with pure red cell aplasia that develops with epoetin or other erythropoietin protein drugs. Multidose vials contains benzyl alcohol; use single-dose vials in neonates. Benzyl alcohol: Multidose vial contains benzyl alcohol which has been associated with fatal gasping syndrome in neonates and infants . Dermatologic: Blistering and skin exfoliation reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported; discontinue use immediately if suspected.

Adverse Effects

An adverse effect in premature neonates is neutropenia, which occurs rarely and resolves with discontinuation of the drug. Although data are conflicting, erythropoietin may be associated with retinopathy of prematurity (ROP). The risk may be reduced for stage greater than 3 ROP if erythropoietin is initiated before 8 days of age . Treatment of preterm infants (median gestational age, 29 weeks) with epoetin was associated with an increased risk of infantile hemangiomas in a retrospective study; hazard ratio of 2.82 (n=2563).

Black Box Warning

Adult patients with chronic kidney disease treated with erythropoiesis-stimulating agents (ESAs) to target a hemoglobin levels greater than 11 g/dL had a greater risk of serious cardiovascular reactions, stroke, and death. In addition, ESAs reduced survival and increased the risk of tumor progression or recurrence in studies of adult patients with cancers of the breast, non-small cell lung, head and neck, lymphoid, and cervix. No clinical trial has identified a risk-free hemoglobin target level, ESA dose, or dosing strategy. The manufacturer recommends the lowest epoetin alpha dose needed to reduce RBC transfusion requirements for both chronic kidney disease and cancer indications. Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe and dispense epoetin alpha to patients with cancer. In patients with cancer, use ESAs only to treat anemia associated with myelosuppressive therapy, and discontinue treatment when a chemotherapy course is completed. ESAs are not indicated with myelosuppressive therapy for patients with cancer with a high probability of cure. Due to an increased risk of DVT, presurgical prophylaxis is recommended. These findings have unknown relevance in the neonatal population.

Monitoring

Weekly CBC to check for neutropenia and monitor RBC response..