Epoetin Alfa

The most common adverse effects of epoetin alfa include hypertension, arthralgia, injection site pain, headache, nausea, vomiting, cough, and fever. Rare but more serious adverse effects include severe allergic reactions, anaphylaxis, and severe cutaneous reactions such as Stevens-Johnson Syndrome.

/HUMAN EXPOSURE STUDIES/ In double-blind, placebo-controlled studies in cancer patients with chemotherapy-induced anemia, 2 patients receiving epoetin alfa (3 times weekly) and 8 patients receiving placebo had thrombotic events (e.g., pulmonary embolism, cerebrovascular accident). Clinically important thrombotic events (e.g., deep-vein thrombosis requiring anticoagulant therapy, pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure, thrombotic microangiopathy) also were reported in 6% of evaluable patients receiving once-weekly dosages of epoetin alfa and 3.6% of patients receiving placebo in another study. However, a definitive relationship between the rate of hemoglobin increase and the occurrence of clinically important thrombotic events could not be evaluated because of the limited schedule of hemoglobin measurements in this study.

/HUMAN EXPOSURE STUDIES/ In a placebo-controlled study in patients undergoing coronary artery bypass graft surgery (CABG), thrombotic/vascular events occurred in 23 or 29% of patients treated with epoetin alfa or placebo, respectively; 7 deaths occurred in patients treated with perioperative epoetin alfa versus no deaths among those receiving placebo. All deaths that occurred during the time of epoetin alfa therapy (4 of 7 deaths) were associated with thrombotic events.

/HUMAN EXPOSURE STUDIES/ Limited data are available on the acute toxicity of epoetin alfa. The maximum single dose of epoetin alfa that can be administered safely has not been determined, but patients have received iv doses of up to at least 1600 units/kg without unusual adverse effects.

/HUMAN EXPOSURE STUDIES/ Increased mortality has been reported in hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure) who received epoetin alfa with a goal of achieving and maintaining a target hematocrit of 42% compared with that in similar patients treated to a target hematocrit of 30%. Although the reason for the increased mortality is not known, the incidences of nonfatal MI, vascular access thrombosis, and all other thrombotic events were higher in those treated to a target hematocrit of 42%. Likewise, the incidence of fatal thrombotic vascular events (1.1 versus 0.2%) and death attributed to disease progression (6 versus 2.8%) during the first 4 months after randomization were both higher in women with metastatic breast cancer who received epoetin alfa with a goal of achieving and maintaining hemoglobin concentrations of 12-14 g/dL (hematocrit 36-42%) than in those who received placebo. Based on Kaplan-Meier estimates, the proportion of these patients who survived 1 year after randomization was lower in the epoetin alfa group than in the placebo group (70% vs 76%). However, due to insufficient monitoring and data collection, reliable comparisons cannot be made concerning the effect of epoetin alfa on overall time to disease progression, progression-free survival, and overall survival.

For more Human Toxicity Excerpts (Complete) data for EPOETIN ALFA (21 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Epoetin alfa

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of up to 500 Units per kg of body weight male rabbits from Day 6 to Day 16 of gestation produced no adverse effects.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of 500 Units per kg of body weight male rat 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.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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.

/GENOTOXICITY/ Epoetin alfa does not induce bacterial gene mutation (Ames test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene ion at the HGPRT locus.

Epoetin alfa is contraindicated in patients with uncontrolled hypertension, and the manufacturers state that the drug also is contraindicated in patients with known sensitivity to mammalian cell-derived products. The use of epoetin alfa also is contraindicated in patients with known hypersensitivity to albumin human.

The most frequent adverse effect observed in patients receiving epoetin alfa for anemia of chronic renal failure is development or exacerbation of hypertension. The risk of hypertensive episodes is greatest in patients with chronic renal failure who have preexisting hypertension or a history of hypertensive disease...

**Healthy volunteers:*

Elimination /half-life/ may average 4 to 13 hours following intravenous or subcutaneous administration. The elimination half-life is generally higher after the first few doses (> 7.5 hours) than after 2 or more weeks treatment (6.2 hours after 7 doses; 4.6 hours after 24 doses).

The elimination half-life of epoetin alfa following iv administration in healthy individuals and in adults and children with chronic renal failure ranges from 4-16 hours. There is some evidence that the elimination half-life of epoetin alfa may increase with increasing dosage, but a reduction in half-life during continuous dosing also has been reported. The half-life of epoetin alfa is similar in adults older or younger than 65 years of age. In patients with impaired renal function, a prolongation in elimination half-life relative to that in patients with normal renal function may occur; however, the elimination half-life does not appear to be affected by hemodialysis.

With continuous dosing at iv doses of 15-500 units/kg administered up to 3 times weekly, the elimination half-life of epoetin alfa may decrease over time. In patients undergoing hemodialysis, mean elimination half-life was reduced by 20-40% after several weeks to months of such dosing; no further reductions generally were observed beyond 3-4 months of continued therapy. Similar reductions in half-life with multiple dosing have been observed in predialysis patients; the mean half-life of the drug decreased by 40% after 8 weeks of therapy in one study. Although it has been suggested that this decrease in half-life may be related to increased clearance of the drug as more erythroid precursors are formed and increased numbers of erythropoietin receptors are made available, other studies have not found reductions in elimination half-life after continuous dosing.

Binding of erythropoietin and epoetin alfa to EPO-R leads to cellular internalization, which involves the degradation of the ligand. Erythropoietin and epoetin alfa may also be degraded by the reticuloendothelial scavenging pathway or lymphatic system.

The metabolic fate of endogenous erythropoietin and the recombinant hormone (i.e., epoetin alfa) is poorly understood. Although some in vitro and animal data suggest that the kidney may be involved in erythropoietin metabolism, limited evidence in humans suggests otherwise. It also has been suggested that the physicochemical characteristics of the glycoprotein would impede access to potential sites of renal metabolism, thus limiting any contribution of the kidney in the degradation of the endogenous and recombinant hormones. Current evidence from studies in animals suggests that hepatic metabolism contributes only minimally to elimination of the intact hormone, but desialylated epoetin alfa (i.e., terminal sialic acid groups removed) appears to undergo substantial hepatic clearance via metabolic pathways and/or binding. Desialylation and/or removal of the oligosaccharide side chains of erythropoietin appear to occur principally in the liver; bone marrow also may have a role in catabolism of the hormone. Elimination of desialylated drug by the kidneys, bone marrow, and spleen also may occur; results of animal studies suggest that proximal renal tubular secretion may be involved in renal elimination.

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ERYTHROPOIETIN

Established Pharmacologic Class [EPC] - Erythropoiesis-stimulating Agent

Chemical Structure [CS] - Erythropoietin

Physiologic Effects [PE] - Increased Erythroid Cell Production

Erythropoietin is an Erythropoiesis-stimulating Agent. The physiologic effect of erythropoietin is by means of Increased Erythroid Cell Production.

The time to reach peak concentration is slower via the subcutaneous route than the intravenous route which ranges from 20 to 25 hours, and the peak is always well below the peak achieved using the intravenous route (5–10% of those seen with IV administration). The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40%. **Adult and paediatric patients with CRF:** Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours. **Cancer patients receiving cyclic chemotherapy:** The average time to reach peak plasma concentration was approximately 13.3 ± 12.4 hours after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The Cmax is expected be 3- to 7- fold higher and the Tmax is expected to be 2- to 3-fold longer in patients receiving a 40,000 Units SC weekly dosing regimen.

Erythropoietin and epoetin alfa are cleared via uptake and degradation via the EPO-R-expressing cells, and may also involve other cellular pathways in the interstitium, probably via cells in the reticuloendothelial scavenging pathway or lymphatic system. Only a small amount of unchanged epoetin alfa is found in the urine.

In healthy volunteers, the volume of distribution of intravenous epoetin alfa was generally similar to the plasma volume (range of 40–63.80 mL/kg), indicating limited extravascular distribution.

**Healthy volunteers: *

Because of its protein nature, epoetin alfa is destroyed in the GI tract and must be administered parenterally (e.g., via IV infusion, subcutaneous injection, intraperitoneal instillation). Systemic absorption of epoetin alfa is delayed and incomplete following subcutaneous injection or intraperitoneal instillation. However, while serum concentrations peak sooner and are substantially higher with iv than subcutaneous injection of epoetin alfa, they are less sustained, and the iv route of administration generally offers no clinical advantage over the subcutaneous route except in patients with existing accessible iv sites (e.g., hemodialysis patients). In fact, limited evidence suggests that subcutaneous injection of epoetin alfa 3 times weekly can produce a hemoglobin response similar to that with iv administration but at lower dosages; other evidence indicates that dosages of epoetin alfa required for maintenance therapy generally are lower with subcutaneous than iv injection. The decreased and variable systemic absorption of subcutaneously administered epoetin alfa relative to iv administration may result from the lipophilicity and/or relatively large size of the molecule; degradation by peptidases in the skin also may be responsible. With usual epoetin alfa dosages of 50-300 units/kg 3 times weekly given either subcutaneously or iv, detectable serum concentrations of erythropoietin are maintained for at least 24 hours.

Serum erythropoietin concentrations exhibit considerable interindividual variation with a given epoetin alfa dose and route of administration. Peak serum erythropoietin concentrations following iv administration of 80, 120, or 150 units/kg of epoetin alfa reportedly range from 1200-1800, 3200-4700, or 3000-5000 mU/mL, respectively, in patients with chronic renal failure; in healthy adults, peak serum concentrations following iv administration of 150 or 300 units/kg of the drug average 3500 or 7300 mU/mL, respectively. Peak serum erythropoietin concentrations after subcutaneous injection of 50, 150, or 300 units/kg of epoetin alfa in healthy individuals averaged 36 (corrected for endogenous serum erythropoietin concentration), 144-226, or 285-288 mU/mL. Peak serum erythropoietin concentrations are achieved within 4-24 hours following subcutaneous injection of usual therapeutic doses of epoetin alfa, and serum erythropoietin concentrations generally remain above baseline for 2-4 days. Following iv doses of 50-300 units/kg of exogenous erythropoietin, serum erythropoietin concentrations generally decline to baseline levels within 1-3 days.