Erythropoietin: Difference between revisions

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'''Erythropoietin''' ('''EPO'''), also known as '''hematopoietin''' or '''hemopoietin''', is a [[glycoprotein]] [[cytokine]] secreted by the kidney in response to cellular [[Hypoxia (medical)|hypoxia]]; it stimulates [[red blood cell]] production ([[erythropoiesis]]) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any [[anemia]], and [[hypoxemia]] due to chronic lung disease.  
|genericName=Erythropoietin
 
|aOrAn=a
Erythropoietin is produced by interstitial [[fibroblast]]s in the kidney in close association with the [[peritubular capillary]] and [[proximal convoluted tubule]].  It is also produced in [[Perisinusoidal space|perisinusoidal]] cells in the [[liver]]. Liver production predominates in the fetal and perinatal period; renal production  predominates in adulthood.
|drugClass=[[glycoprotein]] hormone
|indicationType=treatment
|indication=[[anemia]] due to [[chronic kidney disease]] (CKD) in patients on [[dialysis]] and not on [[dialysis]], [[zidovudine]] in [[hiv|HIV-infected]] patients, the effects of concomitant [[Myelosuppression|myelosuppressive]] [[chemotherapy]],and reduction of [[allogeneic]] [[blood transfusion|RBC transfusions]] in patients undergoing elective, noncardiac, nonvascular [[surgery]].
|hasBlackBoxWarning=Yes
|adverseReactions=[[hypertension]], [[arthralgia]], [[muscle spasm]], [[pyrexia]], [[dizziness]], medical device malfunction, [[vascular occlusion]], and [[upper respiratory tract infection]], [[cough]], [[rash]], and [[Injection site reaction|injection site irritation]], [[nausea]], [[vomiting]], [[myalgia]], [[stomatitis]], [[cough]], weight decrease, [[leukopenia]], bone pain, [[hyperglycemia]], [[insomnia]], [[headache]], [[depression]], [[dysphagia]], [[hypokalemia]], and [[thrombosis]], [[pruritus]], [[headache]], [[Injection site reaction|injection site pain]], [[chills]] and [[deep vein thrombosis]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE</span>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Chronic Kidney Disease:: </span></i>


* In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL.
[[Exogeny|Exogenous]] erythropoietin, '''recombinant human erythropoietin''' (rhEPO) is produced by [[recombinant DNA technology]] in [[cell culture]] and are collectively called [[erythropoiesis-stimulating agent]]s (ESA): two examples are [[epoetin alfa]] and [[epoetin beta]]. ESAs are used in the treatment of [[anemia]] in [[chronic kidney disease]], anemia in [[myelodysplasia]], and in anemia from [[cancer]] [[chemotherapy]]. Risks of therapy include death, [[myocardial infarction]], [[stroke]], [[venous thromboembolism]], and tumor recurrence.  Risk increases when EPO treatment raises hemoglobin levels over 11&nbsp;g/dL to 12&nbsp;g/dL: this is to be avoided.
*No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
*Use the lowest Erythropoietin dose sufficient to reduce the need for red blood cell (RBC) transfusions.


<i><span style="color:#FF0000;">Cancer:</span></i>
rhEPO has been used illicitly as a [[performance-enhancing drug]].<ref name="PEDs in sports review">{{cite journal | vauthors = Momaya A, Fawal M, Estes R | title = '''Performance-enhancing substances''' in sports: a review of the literature | journal = Sports Med. | volume = 45 | issue = 4 | pages = 517–531 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 | quote = }}</ref> It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of [[posttranslational modification]].


*ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
==Pharmacology==
*Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Erythropoietin to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance.
EPO is highly [[glycosylation|glycosylated]] (40% of total molecular weight), with half-life in blood around 5&nbsp;h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).
*To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
*Use ESAs only for anemia from myelosuppressive chemotherapy.
== Function ==
*ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
*Discontinue following the completion of a chemotherapy course.


<i><span style="color:#FF0000;">Perisurgery:</span></i>
=== Red blood cell production ===
Erythropoietin is an essential hormone for red blood cell production. Without it, definitive [[erythropoiesis]] does not take place. Under [[hypoxia (medical)|hypoxic]] conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting [[CFU-E]], pro[[erythroblast]] and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from [[apoptosis]], or cell death.


*Due to increased risk of Deep Venous Thrombosis (DVT), DVT prophylaxis is recommended.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., [[interleukin 3|IL-3]], [[Interleukin 6|IL-6]], [[glucocorticoid]]s, and [[stem cell factor|SCF]]) involved in the development of [[erythroid]] lineage from [[stem cell|multipotent progenitors]]. The burst-forming unit-erythroid ([[BFU-E]]) cells start [[erythropoietin receptor]] expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid ([[CFU-E]]), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.


<!--Adult Indications and Dosage-->
=== Nonhematopoietic roles ===
Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including [[vasoconstriction]]-dependent [[hypertension]], stimulating [[angiogenesis]], and promoting cell survival via activation of Epo receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect.<ref name="pmid22848149">{{cite journal |vauthors=Elliott S, Sinclair AM |title=The effect of erythropoietin on normal and neoplastic cells |journal=Biologics |volume=6 |issue= |pages=163–89 |year=2012 |pmid=22848149 |pmc=3402043 |doi=10.2147/BTT.S32281 }}</ref> It is also inconsistent with the low levels of Epo receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.<ref>{{cite journal |vauthors=Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S |title=Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure |journal=Clinical Neurology and Neurosurgery |volume=114 |issue=6 |pages=663–7 |year=2012 |pmid=22296650 |doi=10.1016/j.clineuro.2012.01.007 }}</ref>


<!--FDA-Labeled Indications and Dosage (Adult)-->
== Mechanism of action ==
|fdaLIADAdult=====Anemia Due to Chronic Kidney Disease====
Erythropoietin has been shown to exert its effects by [[protein-protein interaction|binding]] to the [[erythropoietin receptor]] (EpoR).<ref name="pmid10318834">{{cite journal |vauthors=Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK |title=Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide |journal=The Journal of Biological Chemistry |volume=274 |issue=20 |pages=14163–9 |year=1999 |pmid=10318834 |doi=10.1074/jbc.274.20.14163 }}</ref><ref name="pmid9808045">{{cite journal |vauthors=Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA |title=An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation |journal=Nature Structural Biology |volume=5 |issue=11 |pages=993–1004 |year=1998 |pmid=9808045 |doi=10.1038/2965 }}</ref> EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a [[janus kinase 2|JAK2]] signaling cascade. This initiates the [[STAT5]], [[Phosphoinositide 3-kinase|PIK3]] and [[MAPK/ERK pathway|Ras MAPK]] pathways. This results in differentiation, survival and proliferation of the erythroid cell.<ref>{{Cite book|url=https://books.google.co.uk/books?hl=en&lr=&id=orVuGH_nrSMC&oi=fnd&pg=PP1&dq=the+cytokine+handbook&ots=Qi9qjk9sB0&sig=r9GgJGxiPVuc-tnlrIwjU1-z6hI#v=onepage&q=the%20cytokine%20handbook&f=false|title=The Cytokine Handbook, Two-Volume Set|last=Thomson|first=Angus W.|last2=Lotze|first2=Michael T.|date=2003-04-22|publisher=Gulf Professional Publishing|isbn=9780080518794|language=en}}</ref> SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.<ref>{{Cite journal|last=Hodges|first=Vivien M.|last2=Rainey|first2=Susan|last3=Lappin|first3=Terence R.|last4=Maxwell|first4=A. Peter|date=2007-11-01|title=Pathophysiology of anemia and erythrocytosis|journal=Critical Reviews in Oncology/Hematology|volume=64|issue=2|pages=139–158|doi=10.1016/j.critrevonc.2007.06.006|issn=1040-8428|pmid=17656101}}</ref> High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies. In controlled experiments, EPO receptor is not detected in those tissues. In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.{{citation needed|date=April 2016}}


*Erythropoietin is indicated for the treatment of [[anemia]] due to [[chronic kidney disease]] (CKD), including patients on [[dialysis]] and not on dialysis to decrease the need for red blood cell (RBC) transfusion.
== Synthesis and regulation ==
Erythropoietin levels in blood are quite low in the absence of anemia, at around 10&nbsp;mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10&nbsp;000&nbsp;mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the [[renal cortex]], with additional amounts being produced in the liver,<ref name=Jacobson1957>{{cite journal |vauthors=Jacobson LO, Goldwasser E, Fried W, Plzak L |title=Role of the kidney in erythropoiesis |journal=Nature |volume=179 |issue=4560 |pages=633–4 |year=1957 |pmid=13418752 |doi=10.1038/179633a0 }}</ref><ref name=Fisher1996>{{cite journal |vauthors=Fisher JW, Koury S, Ducey T, Mendel S |title=Erythropoietin production by interstitial cells of hypoxic monkey kidneys |journal=British Journal of Haematology |volume=95 |issue=1 |pages=27–32 |year=1996 |pmid=8857934 |doi=10.1046/j.1365-2141.1996.d01-1864.x }}</ref><ref name=sinharaja2002>{{cite book |editor1-first=Kim E. |editor1-last=Barrett |editor2-first=Susan M. |editor2-last=Barman |editor3-first=Scott |editor3-last=Boitano |editor4-first=Heddwen |editor4-last=Brooks |title=Ganong's review of Medical Physiology |edition=24th |publisher=McGraw Hill |isbn=978-1-25-902753-6 |page=709 }}</ref> and the [[pericytes]] in the [[brain]].<ref>{{cite journal|last1=Ji|first1=P.|title=Pericytes: new EPO-producing cells in the brain|journal=Blood|date=24 November 2016|volume=128|issue=21|pages=2483–2485|doi=10.1182/blood-2016-10-743880}}</ref> Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.<ref name=pmid17253966>{{cite journal |vauthors=Jelkmann W |title=Erythropoietin after a century of research: younger than ever |journal=European Journal of Haematology |volume=78 |issue=3 |pages=183–205 |year=2007 |pmid=17253966 |doi=10.1111/j.1600-0609.2007.00818.x }}</ref> Constitutively synthesized transcription factors for EPO, known as [[hypoxia-inducible factors]], are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia [[GATA2]] inhibits the promoter region for EPO. [[GATA2]] levels decrease during hypoxia and allow the promotion of EPO production.<ref>Jelkmann, W., 2011. Regulation of erythropoietin production.&nbsp;The Journal of physiology,&nbsp;589(6), pp.1251-1258.</ref>


* Dosing Information
== Medical uses ==
{{main article|Erythropoiesis-stimulating agent}}
Erythropoietins available for use as [[Biologic medical product|therapeutic agents]] are produced by [[recombinant DNA technology]] in [[cell culture]], and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating [[anemia]] resulting from [[chronic kidney disease]], chemotherapy induced anemia in patients with cancer, [[inflammatory bowel disease]] ([[Crohn's disease]] and [[ulcerative colitis]])<ref>{{cite journal |vauthors=Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J |title=Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study |journal=Nutrition in Clinical Practice |volume=28 |issue=1 |pages=120–7 |year=2013 |pmid=23064018 |doi=10.1177/0884533612462744 }}</ref> and [[Myelodysplastic syndrome|myelodysplasia]] from the treatment of [[cancer]] ([[chemotherapy]] and [[radiation]]). The [[package insert]]s include [[boxed warning]]s of increased risk of death, [[myocardial infarction]], [[stroke]], [[Venous thrombosis|venous thromboembolism]], and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11&nbsp;g/dL to 12&nbsp;g/dL.<ref name="url_Epogen_Procrit _FDA">{{cite web |url=http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm |title=Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa) |work=MedWatch: The FDA Safety Information and Adverse Event Reporting Program |date=August 11, 2011 |publisher=United States Food and Drug Administration }}</ref>


:* In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered [[erythropoiesis-stimulating agent|erythropoiesis-stimulating agents]] (ESAs) to target a [[hemoglobin]] level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Erythropoietin sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious [[cardiovascular]] adverse events.
== History ==
In 1905, [[Paul Carnot]] proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to [[bloodletting]], Carnot and his graduate student Clotilde-Camille Deflandre <ref>{{cite journal|last1=Carnot|first1=P|last2=Deflandre|first2=Cl|title=Sur l'activite hematopoietique du serum au cours de la regeneration du sang|journal=Compt. Rend. Acad. Sci.|date=1906|volume=143|pages=384–386}}</ref> attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev  demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase [[hematocrit]]. This substance was purified and confirmed as erythropoietin.<ref name="pmid17253966" /><ref>{{cite book |first=Ahmet |last=Höke |name-list-format=vanc |title=Erythropoietin and the Nervous System  |publisher=Springer |location=Berlin |year=2005 |pages= |isbn=0-387-30010-4 |oclc=64571745 }}{{page needed|date=April 2016}}</ref>


*For all patients with CKD:
In 1977, Goldwasser and Kung purified EPO.<ref name="pmid18467">{{cite journal |vauthors=Miyake T, Kung CK, Goldwasser E |title=Purification of human erythropoietin |journal=The Journal of Biological Chemistry |volume=252 |issue=15 |pages=5558–64 |year=1977 |pmid=18467 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18467 }}</ref> Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.<ref name="pmid17253966" /> Synthetic EPO was first successfully used to correct anemia in 1987.<ref name="pmid3537801">{{cite journal |vauthors=Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW |title=Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial |journal=The New England Journal of Medicine |volume=316 |issue=2 |pages=73–8 |year=1987 |pmid=3537801 |doi=10.1056/NEJM198701083160203 }}</ref> In 1985, Lin ''et al'' isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.<ref name="pmid3865178">{{cite journal |vauthors=Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z |title=Cloning and expression of the human erythropoietin gene |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=82 |issue=22 |pages=7580–4 |year=1985 |pmid=3865178 |pmc=391376 |doi=10.1073/pnas.82.22.7580 }}</ref> In 1989, the [[US Food and Drug Administration]] approved the hormone [[Epogen]] for use in certain anemias.<ref>{{cite web|url=http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf|title=Epogen Prescribing Information}}</ref>


*When initiating or adjusting therapy, monitor [[hemoglobin]] levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
==Pronunciation==
It is pronounced {{IPAc-en|ɪ|ˌ|r|ɪ|θ|r|oʊ|ˈ|p|ɔɪ|ᵻ|t|ən}} or {{IPAc-en|ɪ|ˌ|r|ɪ|θ|r|oʊ|p|oʊ|ˈ|ɛ|t|ɪ|n|,_|-|r|ə|-|,_|-|ˈ|iː|-|,_|-|t|ən}}.{{refn|{{MerriamWebsterDictionary|Erythropoietin}}}}{{refn|{{Dictionary.com|Erythropoietin}}}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/erythropoietin |title=erythropoietin – definition of erythropoietin in English from the Oxford dictionary |publisher=[[OxfordDictionaries.com]] |access-date=2016-01-20 }}}}


:*Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
== See also ==
:*If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Erythropoietin by 25% or more as needed to reduce rapid responses.
* [[Hemopoietic growth factors]]
:*For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
* [[Jehovah's Witnesses and blood transfusions]]
:*For patients who do not respond adequately over a 12-week escalation period, increasing the Erythropoietin dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of [[anemia]]. Discontinue Erythropoietin if responsiveness does not improve.


*For patients with CKD on dialysis:
== References ==
{{Reflist|30em}}


*Initiate Erythropoietin treatment when the hemoglobin level is less than 10 g/dL.
== Further reading ==
*If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Erythropoietin.
{{refbegin|35em}}
*The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.  
*{{cite journal |vauthors=Takeuchi M, Kobata A |title=Structures and functional roles of the sugar chains of human erythropoietins |journal=Glycobiology |volume=1 |issue=4 |pages=337–46 |year=1991 |pmid=1820196 |doi=10.1093/glycob/1.4.337 }}
*For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended.  
*{{cite journal |vauthors=Semba RD, Juul SE |title=Erythropoietin in human milk: physiology and role in infant health |journal=Journal of Human Lactation |volume=18 |issue=3 |pages=252–61 |year=2002 |pmid=12192960 |doi=10.1177/089033440201800307 }}
*The intravenous route is recommended for patients on [[hemodialysis]].
*{{cite journal |vauthors=Ratcliffe PJ |title=From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway |journal=Blood Purification |volume=20 |issue=5 |pages=445–50 |year=2002 |pmid=12207089 |doi=10.1159/000065201 }}
*{{cite journal |vauthors=Westenfelder C |title=Unexpected renal actions of erythropoietin |journal=Experimental Nephrology |volume=10 |issue=5-6 |pages=294–8 |year=2002 |pmid=12381912 |doi=10.1159/000065304 }}
*{{cite journal |vauthors=Becerra SP, Amaral J |title=Erythropoietin--an endogenous retinal survival factor |journal=The New England Journal of Medicine |volume=347 |issue=24 |pages=1968–70 |year=2002 |pmid=12477950 |doi=10.1056/NEJMcibr022629 }}
*{{cite journal |vauthors=Genc S, Koroglu TF, Genc K |title=Erythropoietin and the nervous system |journal=Brain Research |volume=1000 |issue=1-2 |pages=19–31 |year=2004 |pmid=15053948 |doi=10.1016/j.brainres.2003.12.037 }}
*{{cite journal |vauthors=Fandrey J |title=Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression |journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume=286 |issue=6 |pages=R977–88 |year=2004 |pmid=15142852 |doi=10.1152/ajpregu.00577.2003 }}
*{{cite journal |vauthors=Juul S |title=Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models |journal=Clinics in Perinatology |volume=31 |issue=1 |pages=129–42 |year=2004 |pmid=15183662 |doi=10.1016/j.clp.2004.03.004 }}
*{{cite journal |vauthors=Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G |title=Brain and cancer: the protective role of erythropoietin |journal=Medicinal Research Reviews |volume=25 |issue=2 |pages=245–59 |year=2005 |pmid=15389732 |doi=10.1002/med.20012 }}
*{{cite journal |vauthors=Sytkowski AJ |title=Does erythropoietin have a dark side? Epo signaling and cancer cells |journal=Science's STKE |volume=2007 |issue=395 |pages=pe38 |year=2007 |pmid=17636183 |doi=10.1126/stke.3952007pe38 }}
*  {{cite book |last=Goldwasser |first=Eugene |title=A Bloody Long Journey: Erythropoietin and the Person Who Isolated It |publisher=Xlibris |date=2011 |isbn=978-1-4568-5737-0}}
{{refend}}


*For patients with CKD not on dialysis:
== External links ==
* [https://query.nytimes.com/gst/fullpage.html?res=9B0DE2D81138F93BA35752C0A961948260&sec=&spon=&partner=permalink&exprod=permalink NYT – 1987 announcement of Epogen's clinical success]
* [http://www.ema.europa.eu/humandocs/PDFs/EPAR/dynepo/H-372-PI-en.pdf Dynepo EPAR <sup>(European Public Assessment Report)</sup>, PDF format]{{dead link|date=September 2017 |bot=InternetArchiveBot |fix-attempted=yes }}, credit [[European Medicines Agency]]


*Consider initiating Erythropoietin treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
{{Navboxes
:*The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
|title=Articles and topics related to Erythropoietin
:*Reducing the risk of [[alloimmunization]] and/or other RBC transfusion-related risks is a goal
|state=collapsed
*If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Erythropoietin, and use the lowest dose of Erythropoietin sufficient to reduce the need for RBC transfusions.
|list1=</span>
*The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
{{PDB Gallery|geneid=2056}}
*When treating patients who have [[chronic kidney disease]] and [[cancer]], physicians should refer to warnings and precautions.
{{Hormones}}
 
{{Renal physiology}}
*Refer patients who self-administer Erythropoietin to the Instructions for Use.*
{{Colony-stimulating factors}}
 
{{B03, B05, B06}}
====Anemia Due to Zidovudine in HIV-infected Patients====
{{Growth factor receptor modulators}}
 
{{Cytokine receptor modulators}}
*Erythropoietin is indicated for the treatment of anemia due to [[zidovudine]] administered at ≤ 4200 mg/week in HIV-infected patients with endogenous serum Erythropoietin levels of ≤ 500 mUnits/mL.
 
* Dosing Information
 
:* Starting Dose
 
*The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
 
*Dose Adjustment
 
:*If hemoglobin does not increase after 8 weeks of therapy, increase Erythropoietin dose by approximately 50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
:*Withhold Erythropoietin if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
 
*Discontinue Erythropoietin if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
 
====Anemia Due to Chemotherapy in Patients With Cancer====
 
*Erythropoietin is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant [[myelosuppression|myelosuppressive]] [[chemotherapy]], and upon initiation, there is a minimum of two additional months of planned chemotherapy.
 
* Dosing Information
 
:* Initiate Erythropoietin in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
 
*Use the lowest dose of Erythropoietin necessary to avoid RBC transfusions.
 
*Recommended Starting Dose:
 
*Adults:
 
:*150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
:*40,000 Units subcutaneously weekly until completion of a chemotherapy course.
 
*Pediatric Patients (5 to 18 years):
 
:*600 Units/kg intravenously weekly until completion of a chemotherapy course.
 
*Dose Reduction:
 
*Reduce dose by 25% if:
 
:*Hemoglobin increases greater than 1 g/dL in any 2-week period or
:*Hemoglobin reaches a level needed to avoid RBC transfusion.
 
*Withhold dose if hemoglobin exceeds a level needed to avoid [[blood transfusion|RBC transfusion]]. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
 
*Dose Increase:
 
*After the initial 4 weeks of Erythropoietin therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
 
:*300 Units/kg three times per week in adults or
:*60,000 Units weekly in adults
    900 Units/kg (maximum 60,000 Units) weekly in children
 
*After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Erythropoietin.
 
====Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery====
 
*Erythropoietin is indicated to reduce the need for allogeneic [[blood transfusion|RBC transfusions]] among patients with perioperative hemoglobin > 10 to ≤ 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular [[surgery]]. Erythropoietin is not indicated for patients who are willing to donate [[autologous]] blood pre-operatively.
 
* Dosing Information
 
:*The recommended Erythropoietin regimens are:
 
:*300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
:*600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
 
*[[Deep venous thrombosis]] prophylaxis is recommended during Erythropoietin therapy.
 
====Limitations of Use====
 
*Erythropoietin has not been shown to improve quality of life, fatigue, or patient well-being.
 
*Erythropoietin is not indicated for use:
 
:*In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant [[myelosuppresion|myelosuppressive]] [[chemotherapy]].
:*In patients with [[cancer]] receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
:*In patients scheduled for surgery who are willing to donate [[autologous]] blood.
:*In patients undergoing [[cardiac surgery|cardiac]] or [[vascular surgery]].
:*As a substitute for [[blood transfusion|RBC transfusions]] in patients who require immediate correction of [[anemia]].
 
<!--Off-Label Use and Dosage (Adult)-->
 
<!--Guideline-Supported Use (Adult)-->
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Pediatric Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Erythropoietin in pediatric patients.
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Erythropoietin in pediatric patients.
|contraindications=Erythropoietin is contraindicated in patients with:
 
*Uncontrolled [[hypertension]]
*[[Pure red cell aplasia]] (PRCA) that begins after treatment with Erythropoietin or other Erythropoietin protein drugs
*Serious [[allergic reactions]] to Erythropoietin
 
Erythropoietin from multidose vials contains benzyl alcohol and is contraindicated in:
 
*Neonates, infants, pregnant women, and nursing mothers. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. When therapy with Erythropoietin is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol.
|warnings='''Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism'''
 
*In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 – 11.3 g/dL), Erythropoietin and other ESAs increased the risk of death, [[myocardial infarction]], [[stroke]], [[congestive heart failure]], [[thrombosis]] of [[hemodialysis]] vascular access, and other [[thromboembolic event|thromboembolic events]] in the higher target groups.
*Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent [[cardiovascular disease]] and [[stroke]]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
*In controlled clinical trials of patients with cancer, Erythropoietin and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included [[myocardial infarction]] and [[stroke]].
*In controlled clinical trials, ESAs increased the risk of death in patients undergoing [[coronary artery bypass graft surgery]] (CABG) and the risk of [[deep venous thrombosis]] (DVT) in patients undergoing orthopedic procedures.
 
*The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.
 
[[File:Erythropoietin table 1.png|600px|thumbnail|left]]
{{clear}}
 
'''Patients with Chronic Kidney Disease'''
 
*Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with [[chronic kidney disease]] on [[dialysis]] with documented evidence of [[congestive heart failure]] or [[ischemic heart disease]] was designed to test the hypothesis that a higher target [[hematocrit]] (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to [[epoetin alfa]] treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high [[hematocrit]] target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR = 1.27; 95% CI (1.04, 1.54); p = 0.018. The incidence of nonfatal [[myocardial infarction]], vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
 
*CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to [[epoetin alfa]] treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, [[myocardial infarction]], [[stroke]], or hospitalization for [[congestive heart failure]]) occurred in 125 of the 715 patients (18%) in the higher [[hemoglobin]] group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p = 0.03].
 
*TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on [[dialysis]] (eGFR of 20 – 60 mL/min), [[anemia]] (hemoglobin levels ≤ 11 g/dL), and [[Diabetes mellitus type 2|type 2 diabetes mellitus]], patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event ([[myocardial ischemia]], [[CHF]], [[MI]], and [[CVA]]) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment, but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
 
'''Patients with Cancer'''
 
*An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
 
*In a randomized, placebo-controlled study (Study 1 in Table 2 [see Warnings and Precautions (5.3)]) of 939 women with [[breast cancer|metastatic breast cancer]] receiving [[chemotherapy]], patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
 
'''Patients Having Surgery'''
 
*An increased incidence of [[deep venous thrombosis]] (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated. In a randomized, controlled study, 680 adult patients, not receiving prophylactic [[anticoagulation]] and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients.
 
*Increased mortality was observed in a randomized, placebo-controlled study of Erythropoietin in adult patients who were undergoing [[Coronary artery bypass graft surgery|CABG surgery]] (7 deaths in 126 patients randomized to Erythropoietin versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.
 
'''Prescribing and Distribution Program for Erythropoietin in Patients With Cancer'''
 
*In order to prescribe and/or dispense Erythropoietin to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program requirements. Additionally, prior to each new course of Erythropoietin in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Erythropoietin.
 
'''Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer'''
 
*ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 2). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8).
 
[[File:Erythropoietin table 2.png|600px|thumbnail|left]]
{{clear}}
 
'''Decreased Overall Survival'''
 
*Study 1 was described in the previous section. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
 
*Study 2 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
 
*Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced [[non small cell lung cancer|non-small cell lung cancer]] receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain [[hemoglobin]] levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
 
*Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive [[chemotherapy]] or [[radiation therapy]]. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).
 
'''Decreased Progression-free Survival and Overall Survival'''
 
*Study 3 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant [[breast cancer]] treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
 
*Study 4 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
 
*Study 5 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
 
'''Decreased Locoregional Control'''
 
*Study 6 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to 15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
 
'''Hypertension'''
 
*Erythropoietin is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of Erythropoietin, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; [[hypertensive encephalopathy]] and [[seizures]] have been reported in patients with [[CKD]] receiving Erythropoietin.
 
*Appropriately control [[hypertension]] prior to initiation of and during treatment with Erythropoietin. Reduce or withhold Erythropoietin if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.
 
'''Seizures'''
 
*Erythropoietin increases the risk of seizures in patients with [[CKD]]. During the first several months following initiation of Erythropoietin, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.
 
'''Lack or Loss of Hemoglobin Response to Erythropoietin'''
 
*For lack or loss of hemoglobin response to Erythropoietin, initiate a search for causative factors (e.g., [[iron deficiency]], [[infection]], [[inflammation]], [[bleeding]]). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Erythropoietin therapy.
 
'''Pure Red Cell Aplasia'''
 
*Cases of [[pure red cell aplasia]] and of severe [[anemia]], with or without other cytopenias that arise following the development of neutralizing antibodies to Erythropoietin have been reported in patients treated with Erythropoietin. This has been reported predominantly in patients with [[chronic kidney disease|CKD]] receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to [[hepatitis C]] treatment (an indication for which Erythropoietin is not approved).
 
*If severe anemia and low reticulocyte count develop during treatment with Erythropoietin, withhold Erythropoietin and evaluate patients for neutralizing antibodies to Erythropoietin. Permanently discontinue Erythropoietin in patients who develop PRCA following treatment with Erythropoietin or other Erythropoietin protein drugs. Do not switch patients to other ESAs.
 
'''Serious Allergic Reactions'''
 
*Serious [[allergic reactions]], including [[anaphylactic reactions]], [[angioedema]], [[bronchospasm]], [[rash|skin rash]], and [[urticaria]] may occur with Erythropoietin. Immediately and permanently discontinue Erythropoietin and administer appropriate therapy if a serious allergic or [[anaphylactic reaction]] occurs.
 
'''Albumin (Human)'''
 
*Erythropoietin contains [[albumin]], a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of [[Creutzfeldt-Jakob disease]] (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
 
'''Dialysis Management'''
 
*Patients may require adjustments in their dialysis prescriptions after initiation of Erythropoietin. Patients receiving Erythropoietin may require increased anticoagulation with [[heparin]] to prevent clotting of the extracorporeal circuit during [[hemodialysis]].
 
'''Laboratory Monitoring'''
 
*Evaluate [[transferrin saturation]] and [[ferritin|serum ferritin]] prior to and during Erythropoietin treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.
 
<!--Adverse Reactions-->
 
<!--Clinical Trials Experience-->
|clinicalTrials=The following serious adverse reactions are discussed in greater detail in other sections of the label:
 
*Increased Mortality, [[myocardial infarction]], [[stroke]], and [[thromboembolism]]
*Increased mortality and/or increased risk of tumor progression or recurrence in patients With [[cancer]]
*[[Hypertension]]
*[[Seizures]]
*PRCA
*Serious [[allergic reactions]]
 
'''Clinical Trial Experience'''
 
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
 
'''Patients with Chronic Kidney Disease'''
 
'''Adult Patients'''
 
*Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Erythropoietin. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.
 
*Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to Erythropoietin. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.
 
*The adverse reactions with a reported incidence of ≥ 5% in Erythropoietin-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
 
[[File:Erythropoietin table 3.png|600px|thumbnail|left]]
{{clear}}
 
*An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% Erythropoietin and 1% placebo).
 
*The adverse reactions with a reported incidence of ≥ 5% in Erythropoietin-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
 
[[File:Erythropoietin table 4.png|600px|thumbnail|left]]
{{clear}}
 
*Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% Erythropoietin and 0% placebo) and myocardial infarction (0.8% Erythropoietin and 0% placebo).
 
'''Pediatric Patients'''
 
*In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.
 
'''Zidovudine-treated HIV-infected Patients'''
 
*A total of 297 [[zidovudine]]-treated [[HIV]]-infected patients were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Erythropoietin and 153 (52%) patients were randomly assigned to receive placebo. Erythropoietin was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
 
*For the combined Erythropoietin treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined Erythropoietin treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.
 
*In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Erythropoietin were:
 
[[File:Erythropoietin table 5.png|600px|thumbnail|left]]
{{clear}}
 
'''Cancer Patients on Chemotherapy'''
 
*The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to Erythropoietin received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly Erythropoietin-treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the Erythropoietin-treatment group was 158 white (94%) and 10 black (6%). Erythropoietin was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).
 
*The adverse reactions with a reported incidence of ≥ 5% in Erythropoietin-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
 
[[File:Erythropoietin table 6.png|600px|thumbnail|left]]
{{clear}}
 
'''Surgery Patients'''
 
*Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive Erythropoietin and 103 (22%) patients were randomly assigned to receive placebo. Erythropoietin was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.
 
*For the combined Erythropoietin treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Erythropoietin treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.
 
*The adverse reactions with a reported incidence of ≥ 1% in Erythropoietin-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
 
[[File:Erythropoietin table 7.png|600px|thumbnail|left]]
{{clear}}
 
'''Immunogenicity'''
 
*As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to epoetin alfa that cross-react with endogenous Erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.7)].
 
*The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erythropoietin with the incidence of antibodies to other products may be misleading.
|postmarketing=*Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
 
*The following adverse reactions have been identified during postmarketing use of Erythropoietin:
 
:*[[Seizures]]
:*[[Pure Red Cell Aplasia]]
:*Serious [[allergic reactions]]
:*[[Injection site reaction]], including irritation and pain
|drugInteractions=* No formal drug interaction studies have been conducted with Erythropoietin.
|useInPregnancyFDA='''Pregnancy'''
 
*The multidose vials are formulated with benzyl alcohol. Do not administer Erythropoietin from multidose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with Erythropoietin is needed during pregnancy, use a benzyl alcohol-free formulation.
 
'''Pregnancy Category C (single-dose vials only)'''
 
*There are no adequate and well-controlled studies of Erythropoietin use during pregnancy. There are limited data on Erythropoietin use in pregnant women. In animal reproductive and developmental toxicity studies, adverse fetal effects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses. Single-dose formulations of Erythropoietin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 
*There are reports of at least 33 pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received Erythropoietin. Polyhydramnios and intrauterine growth restriction were reported in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum and hypospadias following exposure during the first trimester. Due to the limited number of exposed pregnancies and multiple confounding factors (such as underlying maternal conditions, other maternal medications, and gestational timing of exposure), these published case reports and studies do not reliably estimate the frequency or absence of adverse outcomes.
 
*When healthy rats received Erythropoietin at doses of 100 Units/kg/day during mating and through early pregnancy (dosing stopped prior to organogenesis), there were slight increases in the incidences of pre- and post-implantation loss, and a decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When healthy pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of Erythropoietin only during organogenesis, no teratogenic effects were observed in the offspring.
 
*When healthy pregnant rats received Erythropoietin at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis), offspring had decreased number of caudal vertebrae and growth delays.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
 
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=*The multidose vials of Erythropoietin are formulated with benzyl alcohol. Do not administer Erythropoietin from multidose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with Erythropoietin is needed in nursing women, use a benzyl alcohol-free formulation.
 
*It is not known whether Erythropoietin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Erythropoietin from single-dose vials is administered to a nursing woman.
|useInPed=*The multidose vials are formulated with benzyl alcohol. Do not administer Erythropoietin from multidose vials, or Erythropoietin from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with Erythropoietin is needed in neonates and infants, use a benzyl alcohol-free formulation.
 
*Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
 
*Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
 
'''Pediatric Patients on Dialysis'''
 
*Erythropoietin is indicated in pediatric patients, ages 1 month to 16 years of age, for the treatment of anemia associated with CKD requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established.
 
*The safety data from these studies are similar to those obtained from the studies of Erythropoietin in adult patients with CKD.
 
'''Pediatric Cancer Patients on Chemotherapy'''
 
*Erythropoietin is indicated in patients 5 to 18 years old for the treatment of anemia due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in pediatric patients less than 5 years of age have not been established. The safety data from these studies are similar to those obtained from the studies of Erythropoietin in adult patients with cancer.
 
'''Pediatric Patients With HIV Infection Receiving Zidovudine'''
 
*Published literature has reported the use of Erythropoietin in 20 zidovudine-treated, anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts and decreases in or elimination of RBC transfusions were observed.
 
'''Pharmacokinetics in Neonates'''
 
*Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous Erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
|useInGeri=*Of the 4553 patients who received Erythropoietin in the 6 studies for treatment of anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over, while 1418 (31%) were 75 years and over. Of the 757 patients who received Erythropoietin in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and over, while 100 (13%) were 75 years and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hemoglobin.
 
*Among 778 patients enrolled in the 3 clinical studies of Erythropoietin for the treatment of anemia due to concomitant chemotherapy, 419 received Erythropoietin and 359 received placebo. Of the 419 who received Erythropoietin, 247 (59%) were age 65 years and over, while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Erythropoietin in geriatric and younger patients within the 3 studies were similar.
 
*Among 1731 patients enrolled in the 6 clinical studies of Erythropoietin for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received Erythropoietin and 646 received placebo or standard of care treatment. Of the 1085 patients who received Erythropoietin, 582 (54%) were age 65 years and over, while 245 (23%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Erythropoietin in geriatric and younger patients within the 4 studies using the 3 times weekly schedule and 2 studies using the weekly schedule were similar.
 
*Insufficient numbers of patients age 65 years or older were enrolled in clinical studies of Erythropoietin for the treatment of zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.
|useInGender=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
 
<!--Administration and Monitoring-->
|administration='''Evaluation of Iron Stores and Nutritional Factors'''
 
*Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Erythropoietin.
 
'''Patients with Chronic Kidney Disease'''
 
*In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Erythropoietin sufficient to reduce the need for RBC transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
For all patients with CKD:
 
*When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
 
:*Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
:*If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Erythropoietin by 25% or more as needed to reduce rapid responses.
:*For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
:*For patients who do not respond adequately over a 12-week escalation period, increasing the Erythropoietin dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. *Discontinue Erythropoietin if responsiveness does not improve.
 
*For patients with CKD on dialysis:
 
*Initiate Erythropoietin treatment when the hemoglobin level is less than 10 g/dL.
*If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Erythropoietin.
*The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
 
*For patients with CKD not on dialysis:
 
*Consider initiating Erythropoietin treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
:*The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
:*Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
:*If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Erythropoietin, and use the lowest dose of Erythropoietin sufficient to reduce the need for RBC transfusions.
:*The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
 
*When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.
 
*Refer patients who self-administer Erythropoietin to the Instructions for Use.
 
'''Zidovudine-treated HIV-infected Patients'''
 
Starting Dose
 
*The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
 
Dose Adjustment
 
*If hemoglobin does not increase after 8 weeks of therapy, increase Erythropoietin dose by approximately 50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
*Withhold Erythropoietin if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
 
*Discontinue Erythropoietin if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
 
'''Patients on Cancer Chemotherapy'''
 
*Initiate Erythropoietin in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
 
*Use the lowest dose of Erythropoietin necessary to avoid RBC transfusions.
 
Recommended Starting Dose
 
Adults:
 
*150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
*40,000 Units subcutaneously weekly until completion of a chemotherapy course.
 
Pediatric Patients (5 to 18 years):
 
*600 Units/kg intravenously weekly until completion of a chemotherapy course.
 
Dose Reduction
 
*Reduce dose by 25% if:
 
:*Hemoglobin increases greater than 1 g/dL in any 2-week period or
:*Hemoglobin reaches a level needed to avoid RBC transfusion.
 
*Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
 
Dose Increase
 
*After the initial 4 weeks of Erythropoietin therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
 
:*300 Units/kg three times per week in adults or
:*60,000 Units weekly in adults
:*900 Units/kg (maximum 60,000 Units) weekly in children
 
*After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Erythropoietin.
 
'''Surgery Patients'''
 
*The recommended Erythropoietin regimens are:
 
:*300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
:*600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
 
*Deep venous thrombosis prophylaxis is recommended during Erythropoietin therapy.
 
'''Preparation and Administration'''
 
*Do not shake. Do not use Erythropoietin that has been shaken or frozen.
*Protect vials from light.
*Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
*Discard unused portions of Erythropoietin in preservative-free vials. Do not re-enter preservative-free vials.
*Store unused portions of Erythropoietin in multidose vials at 36°F to 46°F (2°C to 8°C). Discard 21 days after initial entry.
*Do not dilute. Do not mix with other drug solutions except for admixing as described below:
*Preservative-free Erythropoietin from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and nursing mothers.
 
'''DOSAGE FORMS AND STRENGTHS'''
 
*Single-dose vials: 2000, 3000, 4000, 10,000, and 40,000 Units Erythropoietin /1 mL
 
*Multidose vials (contains benzyl alcohol): 20,000 Units Erythropoietin /2 mL and 20,000 Units Erythropoietin /1 mL
|monitoring=*Seizures: Erythropoietin increases the risk for seizures in patients with CKD. Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms.
*When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
*Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.
*Hypertension: Control hypertension prior to initiating and during treatment with Erythropoietin. Monitor for hypertension.
|IVCompat=*There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
 
<!--Overdosage-->
|overdose=*Erythropoietin overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Erythropoietin dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs.
|drugBox=[[File:Erythropoietin image.png|600px|thumbnail|left]]
{{clear}}
|mechAction=*Erythropoietin stimulates erythropoiesis by the same mechanism as endogenous Erythropoietin.
|structure=*Erythropoietin (epoetin alfa) is a 165-amino acid erythropoiesis-stimulating glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced by mammalian cells into which the human Erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural Erythropoietin.
 
*Erythropoietin is formulated as a sterile, colorless liquid in vials in multiple formulations. Single-dose vials, formulated with an isotonic sodium chloride/sodium citrate-buffered solution, are supplied in multiple strengths. Each 1 mL vial contains 2000, 3000, 4000, or 10,000 Units of epoetin alfa, Albumin (Human) (2.5 mg), citric acid (0.06 mg), sodium chloride (5.9 mg), and sodium citrate (5.8 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Single-dose 1 mL vials formulated with an isotonic sodium chloride/sodium phosphate buffer contain 40,000 Units of epoetin alfa albumin (human) (2.5 mg),citric acid (0.0068 mg), sodium chloride (5.8 mg), sodium citrate (0.7 mg), sodium phosphate dibasic anhydrate (1.8 mg), and sodium phosphate monobasic monohydrate (1.2 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Multidose, 2 mL vials contain 10,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), and sodium citrate (1.3 mg) per 1 mL Water for Injection, USP (pH 6.1 ± 0.3). Multidose 1 mL vials contain 20,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg), per 1 mL in Water for Injection, USP (pH 6.1 ± 0.3).
|PD=*Erythropoietin increases the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. The rate of hemoglobin increase varies among patients and is dependent upon the dose of Erythropoietin administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.
|PK=*In adult and pediatric patients with CKD, the elimination half-life (t1/2) of plasma Erythropoietin after intravenous administration of Erythropoietin ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t1/2 in adult patients with serum creatinine greater than 3 mg/dL was similar between those not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in Erythropoietin t1/2 among adult patients above or below 65 years of age.
 
*A pharmacokinetic study comparing 150 Units/kg subcutaneous 3 times weekly to 40,000 Units subcutaneous weekly dosing regimen was conducted for 4 weeks in healthy subjects (n = 12) and for 6 weeks in anemic cancer patients (n = 32) receiving cyclic chemotherapy. There was no accumulation of serum Erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3- to 7-fold), longer Tmax (2- to 3-fold), higher AUC0–168 h (2- to 3-fold) of Erythropoietin and lower clearance (CL) (50%) than the 150 Units/kg 3 times weekly regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg 3 times weekly dosing, the values of Tmax and CL were similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/hr/kg) between week 1 when patients were receiving chemotherapy (n = 14) and week 3 when patients were not receiving chemotherapy (n = 4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower CL (9.2 ± 4.7 mL/hr/kg) during week 1 when patients were receiving chemotherapy (n = 18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/hr/kg, respectively) during week 3 when patients were not receiving chemotherapy (n = 7).
 
*The pharmacokinetic profile of Erythropoietin in children and adolescents appeared similar to that of adults.
 
*The pharmacokinetics of Erythropoietin has not been studied in patients with HIV infection.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
 
'''Carcinogenicity'''
 
*The carcinogenic potential of Erythropoietin has not been evaluated.
 
'''Mutagenicity'''
 
*Erythropoietin was not mutagenic or clastogenic under the conditions tested: Erythropoietin was negative in the in vitro bacterial reverse mutation assay (Ames test), in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus), in an in vitro chromosomal aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.
 
'''Impairment of Fertility'''
 
*When administered intravenously to male and female rats prior to and during mating, and to females through the beginning of implantation (up to gestational day 7; dosing stopped prior to the beginning of organogenesis), doses of 100 and 500 Units/kg/day of Erythropoietin caused slight increases in pre-implantation loss, post-implantation loss and decreases in the incidence of live fetuses. It is not clear whether these effects reflect a drug effect on the uterine environment or on the conceptus. This animal dose level of 100 Units/kg/day approximates the clinical recommended starting dose, depending on the patient's treatment indication, but may be lower than the clinical dose in patients whose doses have been adjusted.
 
'''Reproductive and Developmental Toxicology'''
 
*When pregnant rats were administered intravenous Erythropoietin, 500 Units/kg/day, after the period of organogenesis (from day 17 of gestation through day 21 of lactation), their pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification. This animal dose level of 500 Units/kg/day is approximately 5-fold higher than the clinical recommended starting dose, depending on the patient's treatment indication.
 
*When Erythropoietin was administered intravenously during the period of organogenesis to pregnant rats (gestational days 7 to 17) and pregnant rabbits (gestational days 6 to 18), no evidence of teratogenic outcome was observed at the doses tested, up to 500 Units/kg/day. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Erythropoietin-related effects were apparent for their offspring (F2 generation fetuses).
|clinicalStudies='''Patients With Chronic Kidney Disease'''
 
'''Adult Patients on Dialysis'''
 
*Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion
 
*In clinical studies of CKD patients on dialysis, Erythropoietin increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving Erythropoietin for 3 months. In clinical studies at starting doses of 50 to 150 Units/kg 3 times weekly, adult patients responded with an average rate of hemoglobin rise as presented in Table 8.
 
[[File:Erythropoietin table 8.png|600px|thumbnail|left]]
{{clear}}
 
*The safety and efficacy of Erythropoietin were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 anemic patients on dialysis. Overall, more than 90% of the patients treated with Erythropoietin experienced improvement in hemoglobin concentrations. In the 3 largest of these clinical studies, the median maintenance dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 Units/kg 3 times weekly. More than 95% of patients were able to avoid RBC transfusions. In the largest US multicenter study, approximately 65% of the patients received doses of 100 Units/kg 3 times weekly or less to maintain their hemoglobin at approximately 11.7 g/dL. Almost 10% of patients received a dose of 25 Units/kg or less, and approximately 10% received a dose of more than 200 Units/kg 3 times weekly to maintain their hemoglobin at this level.
 
*In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).
 
'''Other ESA trials'''
 
*In a 26-week, double-blind, placebo-controlled study, 118 patients on dialysis with an average hemoglobin of approximately 7 g/dL were randomized to either Erythropoietin or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the Erythropoietin-treated patients and remained unchanged in patients receiving placebo. Erythropoietin-treated patients experienced improvements in exercise tolerance and patient-reported physical functioning at month 2 that were maintained throughout the study.
 
*A multicenter, unit-dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered Erythropoietin subcutaneously. Patients responded to Erythropoietin administered subcutaneously in a manner similar to patients receiving intravenous administration.
 
'''Pediatric Patients on Dialysis'''
 
*The safety and efficacy of Erythropoietin were studied in a placebo-controlled, randomized study of 113 children with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of Erythropoietin was 50 Units/kg intravenously or subcutaneously 3 times weekly. The dose of study drug was titrated to achieve either a hemoglobin of 10 to 12 g/dL or an absolute increase in hemoglobin of 2 g/dL over baseline.
 
*At the end of the initial 12 weeks, a statistically significant rise in mean hemoglobin (3.1 g/dL vs. 0.3 g/dL) was observed only in the Erythropoietin arm. The proportion of children achieving a hemoglobin of 10 g/dL, or an increase in hemoglobin of 2 g/dL over baseline, at any time during the first 12 weeks was higher in the Erythropoietin arm (96% vs. 58%). Within 12 weeks of initiating Erythropoietin therapy, 92.3% of the pediatric patients were RBC transfusion independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of Erythropoietin, hemodialysis patients received a higher median maintenance dose [167 Units/kg/week (n = 28) vs. 76 Units/kg/week (n = 36)] and took longer to achieve a hemoglobin of 10 to 12 g/dL (median time to response 69 days vs. 32 days) than patients undergoing peritoneal dialysis.
 
'''Adult Patients With CKD Not Requiring Dialysis'''
 
*Four clinical studies were conducted in patients with CKD not on dialysis involving 181 patients treated with Erythropoietin. These patients responded to Erythropoietin therapy in a manner similar to that observed in patients on dialysis. Patients with CKD not on dialysis demonstrated a dose-dependent and sustained increase in hemoglobin when Erythropoietin was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when Erythropoietin was administered by either route.
 
'''Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion'''
 
*In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
 
'''ESA Effects on rates of death and other serious cardiac adverse events'''
 
*Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using Epogen/Erythropoietin/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile.
 
'''Zidovudine-treated Patients With HIV Infection'''
 
*The safety and efficacy of Erythropoietin were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV infection receiving concomitant therapy with zidovudine. In the subgroup of patients (89/125 Erythropoietin and 88/130 placebo) with pre-study endogenous serum Erythropoietin levels ≤ 500 mUnits/mL, Erythropoietin reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with Erythropoietin versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Erythropoietin therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with Erythropoietin (n = 51) compared to placebo-treated patients (n = 54) whose mean weekly zidovudine dose was ≤ 4200 mg/week.
 
*Approximately 17% of the patients with endogenous serum Erythropoietin levels ≤ 500 mUnits/mL receiving Erythropoietin in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose pre-study endogenous serum Erythropoietin levels were > 500 mUnits/mL, Erythropoietin therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.
 
'''Cancer Patients on Chemotherapy'''
 
*The safety and effectiveness of Erythropoietin was assessed in two multicenter, randomized (1:1), placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.
 
'''Study C1'''
 
*Study C1 was conducted in anemic patients (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin (< 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n = 174) or placebo (n = 170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.
 
*Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.
 
[[File:Erythropoietin table 9.png|600px|thumbnail|left]]
{{clear}}
 
'''Study C2'''
 
*Study C2 was conducted in 222 anemic patients, ages 5 to 18, receiving chemotherapy for the treatment of various childhood malignancies. Randomization was stratified by cancer type (solid tumors, Hodgkin's disease, acute lymphocytic leukemia, vs. non-Hodgkin's lymphoma); patients were randomized to receive epoetin alfa at 600 Units/kg maximum 40,000 Units (n = 111) or placebo (n = 111) as a weekly intravenous injection.
 
*Sixty-nine percent of patients were white, 55% were male, and the median age of patients was 12 years (range: 5 to 18 years). Two (2%) of placebo-treated patients and 3 (3%) of epoetin alfa-treated patients dropped out of the study prior to week 5. There were fewer RBC transfusions from week 5 through the end-of-study in epoetin-alfa treated patients [51% (57/111)] compared to placebo-treated patients [69% (77/111)]. There was no evidence of an improvement in health-related quality of life, including no evidence of an effect on fatigue, energy, or strength in patients receiving Erythropoietin as compared to those receiving placebo.
 
'''Pooled Analysis (Three Times Per Week Dosing)'''
 
*The results of 6 studies of similar design and that randomized 131 patients to epoetin alfa or placebo were pooled to assess the safety and effectiveness of epoetin alfa. Patients were randomized to receive epoetin alfa at 150 Units/kg (n = 63) or placebo (n = 68), subcutaneously three times per week for 12 weeks in each study. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Twelve patients (19%) in the epoetin alfa arm and 10 patients (15%) in the placebo-arm dropped out prior to week 6 and are excluded from efficacy analyses.
 
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'''Surgery Patients'''
 
*The safety and efficacy of Erythropoietin were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin [≤ 10 g/dL (n = 2), > 10 to ≤ 13 g/dL (n = 96), and > 13 to ≤ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg Erythropoietin, 100 Units/kg Erythropoietin, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.
 
*Treatment with Erythropoietin 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with Erythropoietin 300 Units/kg, 6/26 (23%) of patients treated with Erythropoietin 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between Erythropoietin (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if Erythropoietin is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per Erythropoietin-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with Erythropoietin.
 
*Erythropoietin was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of Erythropoietin (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.
 
*From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 × 106/mm3) compared to the daily group (0.17 × 106/mm3). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.
 
*The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group]. The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.
|howSupplied=*Single-dose, Preservative-free Vial: Each 1 mL of solution contains 2000 (NDC 59676-302-01), 3000 (NDC 59676-303-01), 4000 (NDC 59676-304-01), or 10,000 Units (NDC 59676-310-01) of epoetin alfa. Each strength is supplied in cartons, each carton containing 6 single-dose vials.
 
*Single-dose, Preservative-free Vial (Tray): Each 1 mL of solution contains 10,000 Units (NDC 59676-310-02) of epoetin alfa and is supplied in dispensing packs containing 25 single-dose vials.
 
*Single-dose, Preservative-free Vial (in phosphate-buffered formulation): Each 1 mL of solution contains 40,000 Units (NDC 59676-340-01) of epoetin alfa and is supplied in dispensing packs containing 4 single-dose vials.
 
*Multidose, Preserved Vial: 2 mL (20,000 Units total; 10,000 Units/mL). Each 1 mL of solution contains 10,000 Units (NDC 59676-312-04) of epoetin alfa and is supplied in dispensing packs containing 4 multidose vials.
 
*Multidose, Preserved Vial: 1 mL (20,000 Units/mL). Each 1 mL of solution contains 20,000 Units (NDC 59676-320-04) of epoetin alfa and is supplied in dispensing packs containing 4 multidose vials.
|storage=*Store at 36°F to 46°F (2°C to 8°C). Do not freeze.
 
*Do not shake. Protect from light; store Erythropoietin in the carton until use.
 
*Do not use Erythropoietin that has been shaken or frozen.
|packLabel=[[File:Erythropoietin pdp1.jpg|600px|thumbnail|left]]
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[[File:Erythropoietin label.png|600px|thumbnail|left]]
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|fdaPatientInfo=*See Medication Guide.
 
*Prior to treatment, inform patients of the risks and benefits of Erythropoietin.
 
*Inform patients with cancer that they must sign the patient-healthcare provider acknowledgment form before the start of each treatment course with Erythropoietin and that healthcare providers must enroll and comply with the ESA APPRISE Oncology Program in order to prescribe Erythropoietin.
 
*Inform patients:
 
:*To read the Medication Guide.
:*Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression.
:*To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions.
:*To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.
:*Of the need to have regular laboratory tests for hemoglobin.
:*Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and nursing mothers.
 
*Instruct patients who self-administer Erythropoietin of the:
 
:*Importance of following the Instructions for Use.
:*Dangers of reusing needles, syringes, or unused portions of single-dose vials.
:*Proper disposal of used syringes, needles, and unused vials, and of the full container.
 
[[File:Erythropoietin medication guide.png|600px|thumbnail|left]]
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
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[[Category:Drug]]
[[Category:Growth factors]]
[[Category:Chemotherapeutic agents]]
[[Category:Hormones of the kidneys]]
[[Category:Cytokines]]
[[Category:Nephrology procedures]]
[[Category:World Anti-Doping Agency prohibited substances]]

Revision as of 16:07, 25 November 2017

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Erythropoietin (EPO), also known as hematopoietin or hemopoietin, is a glycoprotein cytokine secreted by the kidney in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any anemia, and hypoxemia due to chronic lung disease.

Erythropoietin is produced by interstitial fibroblasts in the kidney in close association with the peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood.

Exogenous erythropoietin, recombinant human erythropoietin (rhEPO) is produced by recombinant DNA technology in cell culture and are collectively called erythropoiesis-stimulating agents (ESA): two examples are epoetin alfa and epoetin beta. ESAs are used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Risks of therapy include death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.

rhEPO has been used illicitly as a performance-enhancing drug.[1] It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of posttranslational modification.

Pharmacology

EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).

Function

Red blood cell production

Erythropoietin is an essential hormone for red blood cell production. Without it, definitive erythropoiesis does not take place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, proerythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from apoptosis, or cell death.

Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3, IL-6, glucocorticoids, and SCF) involved in the development of erythroid lineage from multipotent progenitors. The burst-forming unit-erythroid (BFU-E) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid (CFU-E), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.

Nonhematopoietic roles

Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including vasoconstriction-dependent hypertension, stimulating angiogenesis, and promoting cell survival via activation of Epo receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect.[2] It is also inconsistent with the low levels of Epo receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.[3]

Mechanism of action

Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR).[4][5] EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signaling cascade. This initiates the STAT5, PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell.[6] SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.[7] High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies. In controlled experiments, EPO receptor is not detected in those tissues. In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.[citation needed]

Synthesis and regulation

Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the renal cortex, with additional amounts being produced in the liver,[8][9][10] and the pericytes in the brain.[11] Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.[12] Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.[13]

Medical uses

Main article: Erythropoiesis-stimulating agent

Erythropoietins available for use as therapeutic agents are produced by recombinant DNA technology in cell culture, and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting from chronic kidney disease, chemotherapy induced anemia in patients with cancer, inflammatory bowel disease (Crohn's disease and ulcerative colitis)[14] and myelodysplasia from the treatment of cancer (chemotherapy and radiation). The package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.[15]

History

In 1905, Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and his graduate student Clotilde-Camille Deflandre [16] attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was purified and confirmed as erythropoietin.[12][17]

In 1977, Goldwasser and Kung purified EPO.[18] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[12] Synthetic EPO was first successfully used to correct anemia in 1987.[19] In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.[20] In 1989, the US Food and Drug Administration approved the hormone Epogen for use in certain anemias.[21]

Pronunciation

It is pronounced /ɪˌrɪθroʊˈpɔɪɪtən/ or /ɪˌrɪθroʊpoʊˈɛtɪn, -rə-, -ˈiː-, -tən/.[22][23][24]

See also

References

  1. ↑ Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250.
  2. ↑ Elliott S, Sinclair AM (2012). "The effect of erythropoietin on normal and neoplastic cells". Biologics. 6: 163–89. doi:10.2147/BTT.S32281. PMC 3402043. PMID 22848149.
  3. ↑ Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S (2012). "Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure". Clinical Neurology and Neurosurgery. 114 (6): 663–7. doi:10.1016/j.clineuro.2012.01.007. PMID 22296650.
  4. ↑ Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK (1999). "Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide". The Journal of Biological Chemistry. 274 (20): 14163–9. doi:10.1074/jbc.274.20.14163. PMID 10318834.
  5. ↑ Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA (1998). "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation". Nature Structural Biology. 5 (11): 993–1004. doi:10.1038/2965. PMID 9808045.
  6. ↑ Thomson, Angus W.; Lotze, Michael T. (2003-04-22). The Cytokine Handbook, Two-Volume Set. Gulf Professional Publishing. ISBN 9780080518794.
  7. ↑ Hodges, Vivien M.; Rainey, Susan; Lappin, Terence R.; Maxwell, A. Peter (2007-11-01). "Pathophysiology of anemia and erythrocytosis". Critical Reviews in Oncology/Hematology. 64 (2): 139–158. doi:10.1016/j.critrevonc.2007.06.006. ISSN 1040-8428. PMID 17656101.
  8. ↑ Jacobson LO, Goldwasser E, Fried W, Plzak L (1957). "Role of the kidney in erythropoiesis". Nature. 179 (4560): 633–4. doi:10.1038/179633a0. PMID 13418752.
  9. ↑ Fisher JW, Koury S, Ducey T, Mendel S (1996). "Erythropoietin production by interstitial cells of hypoxic monkey kidneys". British Journal of Haematology. 95 (1): 27–32. doi:10.1046/j.1365-2141.1996.d01-1864.x. PMID 8857934.
  10. ↑ Barrett, Kim E.; Barman, Susan M.; Boitano, Scott; Brooks, Heddwen (eds.). Ganong's review of Medical Physiology (24th ed.). McGraw Hill. p. 709. ISBN 978-1-25-902753-6.
  11. ↑ Ji, P. (24 November 2016). "Pericytes: new EPO-producing cells in the brain". Blood. 128 (21): 2483–2485. doi:10.1182/blood-2016-10-743880.
  12. ↑ 12.0 12.1 12.2 Jelkmann W (2007). "Erythropoietin after a century of research: younger than ever". European Journal of Haematology. 78 (3): 183–205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966.
  13. ↑ Jelkmann, W., 2011. Regulation of erythropoietin production. The Journal of physiology, 589(6), pp.1251-1258.
  14. ↑ Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (2013). "Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study". Nutrition in Clinical Practice. 28 (1): 120–7. doi:10.1177/0884533612462744. PMID 23064018.
  15. ↑ "Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa)". MedWatch: The FDA Safety Information and Adverse Event Reporting Program. United States Food and Drug Administration. August 11, 2011.
  16. ↑ Carnot, P; Deflandre, Cl (1906). "Sur l'activite hematopoietique du serum au cours de la regeneration du sang". Compt. Rend. Acad. Sci. 143: 384–386.
  17. ↑ Höke A (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 0-387-30010-4. OCLC 64571745.[page needed]
  18. ↑ Miyake T, Kung CK, Goldwasser E (1977). "Purification of human erythropoietin". The Journal of Biological Chemistry. 252 (15): 5558–64. PMID 18467.
  19. ↑ Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". The New England Journal of Medicine. 316 (2): 73–8. doi:10.1056/NEJM198701083160203. PMID 3537801.
  20. ↑ Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (1985). "Cloning and expression of the human erythropoietin gene". Proceedings of the National Academy of Sciences of the United States of America. 82 (22): 7580–4. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178.
  21. ↑ "Epogen Prescribing Information" (PDF).
  22. ↑ "Erythropoietin". Merriam-Webster Dictionary.
  23. ↑ "Erythropoietin". Dictionary.com Unabridged. Random House.
  24. ↑ "erythropoietin – definition of erythropoietin in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.

Further reading

  • Takeuchi M, Kobata A (1991). "Structures and functional roles of the sugar chains of human erythropoietins". Glycobiology. 1 (4): 337–46. doi:10.1093/glycob/1.4.337. PMID 1820196.
  • Semba RD, Juul SE (2002). "Erythropoietin in human milk: physiology and role in infant health". Journal of Human Lactation. 18 (3): 252–61. doi:10.1177/089033440201800307. PMID 12192960.
  • Ratcliffe PJ (2002). "From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway". Blood Purification. 20 (5): 445–50. doi:10.1159/000065201. PMID 12207089.
  • Westenfelder C (2002). "Unexpected renal actions of erythropoietin". Experimental Nephrology. 10 (5–6): 294–8. doi:10.1159/000065304. PMID 12381912.
  • Becerra SP, Amaral J (2002). "Erythropoietin--an endogenous retinal survival factor". The New England Journal of Medicine. 347 (24): 1968–70. doi:10.1056/NEJMcibr022629. PMID 12477950.
  • Genc S, Koroglu TF, Genc K (2004). "Erythropoietin and the nervous system". Brain Research. 1000 (1–2): 19–31. doi:10.1016/j.brainres.2003.12.037. PMID 15053948.
  • Fandrey J (2004). "Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 286 (6): R977–88. doi:10.1152/ajpregu.00577.2003. PMID 15142852.
  • Juul S (2004). "Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models". Clinics in Perinatology. 31 (1): 129–42. doi:10.1016/j.clp.2004.03.004. PMID 15183662.
  • Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G (2005). "Brain and cancer: the protective role of erythropoietin". Medicinal Research Reviews. 25 (2): 245–59. doi:10.1002/med.20012. PMID 15389732.
  • Sytkowski AJ (2007). "Does erythropoietin have a dark side? Epo signaling and cancer cells". Science's STKE. 2007 (395): pe38. doi:10.1126/stke.3952007pe38. PMID 17636183.
  • Goldwasser, Eugene (2011). A Bloody Long Journey: Erythropoietin and the Person Who Isolated It. Xlibris. ISBN 978-1-4568-5737-0.

External links

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