Erythropoietin: Difference between revisions

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'''Erythropoietin''' ({{IPAc-en|ɪ|ˌ|r|ɪ|θ|r|oʊ|ˈ|p|ɔɪ|.|ᵻ|t|ɪ|n|,_|-|r|ə|-|,_|-|p|ɔɪ|ˈ|ɛ|t|ɪ|n|,_|-|ˈ|iː|t|ɪ|n}};{{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 }}}} '''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
|hasBlackBoxWarning=Yes
|adverseReactions=hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection, cough, rash, and 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 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 PROCRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions.


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 Medicine | volume = 45 | issue = 4 | pages = 517–31 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 }}</ref> It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of [[posttranslational modification]].


<i><span style="color:#FF0000;">Cancer:</span></i>
==Pharmacology==
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).
== Function ==


*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.
=== Red blood cell production ===
*Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense PROCRIT 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.
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.
*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.
*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>
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.


*Due to increased risk of Deep Venous Thrombosis (DVT), DVT prophylaxis is recommended.
=== 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 | date = July 2012 | pmid = 22296650 | doi = 10.1016/j.clineuro.2012.01.007 }}</ref>


<!--Adult Indications and Dosage-->
== Mechanism of action ==
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 | date = May 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 | date = November 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]] signalling 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.com/?id=orVuGH_nrSMC&pg=PP1|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 | vauthors = Hodges VM, Rainey S, Lappin TR, Maxwell AP | title = Pathophysiology of anemia and erythrocytosis | journal = Critical Reviews in Oncology/Hematology | volume = 64 | issue = 2 | pages = 139–58 | date = November 2007 | pmid = 17656101 | doi = 10.1016/j.critrevonc.2007.06.006 }}</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}}


<!--FDA-Labeled Indications and Dosage (Adult)-->
== Synthesis and regulation ==
|fdaLIADAdult=====Anemia Due to Chronic Kidney Disease====
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 | date = March 1957 | pmid = 13418752 | doi = 10.1038/179633a0 | bibcode = 1957Natur.179..633J }}</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 | date = October 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 | vauthors = Ji P | title = Pericytes: new EPO-producing cells in the brain | journal = Blood | volume = 128 | issue = 21 | pages = 2483–2485 | date = November 2016 | pmid = 27884833 | 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 | date = March 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>{{cite journal | vauthors = Jelkmann W | title = Regulation of erythropoietin production | journal = The Journal of Physiology | volume = 589 | issue = Pt 6 | pages = 1251–8 | date = March 2011 | pmid = 21078592 | pmc = 3082088 | doi = 10.1113/jphysiol.2010.195057 }}</ref>


PROCRIT 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.
== 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 | date = February 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>


* Dosing Information
== 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=978-0-387-30010-8 |oclc=64571745 }}{{page needed|date=April 2016}}</ref>


:* Dosage
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 | date = August 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 | date = January 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 | date = November 1985 | pmid = 3865178 | pmc = 391376 | doi = 10.1073/pnas.82.22.7580 | bibcode = 1985PNAS...82.7580L }}</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>


====Anemia Due to Zidovudine in HIV-infected Patients====
==Usage as doping product==
EPO has been banned since the early 1990s, but a first test was not available until the [[2000 Summer Olympics]].<ref name="WADA">{{cite web|url=https://www.wada-ama.org/en/questions-answers/epo-detection|title=EPO DETECTION|publisher=[[World Anti-Doping Agency]]|date=December 2014}}</ref> Before this test was available, no athletes were sanctioned after positive tests, but it happened that they were sanctioned after confessing to having used EPO, for example in the [[Festina affair]], when a car with doping products for the Festina cycling team was found.


PROCRIT 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.
The first doping test in cycling was used in the [[2001 La Flèche Wallonne]]. The first rider to test positive in that race was [[Bo Hamburger]], although he was later acquitted because his B-sample was not conclusive.<ref>{{Cite news|url=http://news.bbc.co.uk/sport2/hi/other_sports/1483975.stm|publisher=BBC|date=10 August 2001|title=Hamburger cleared of EPO use}}</ref>


* Dosing Information
A 2007 study showed that EPO has a significant effect on exercise performance,<ref>{{cite journal | vauthors = Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C | title = Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity | journal = European Journal of Applied Physiology | volume = 101 | issue = 4 | pages = 481–6 | date = November 2007 | pmid = 17668232 | doi = 10.1007/s00421-007-0522-8 }}</ref><ref name="PEDs in sports review" /> but a 2017 study showed that the effects of EPO administered to amateur cyclists was not distinguishable from a placebo.<ref>{{cite journal | vauthors = Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF | title = Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial | journal = The Lancet. Haematology | volume = 4 | issue = 8 | pages = e374-e386 | date = August 2017 | pmid = 28669689 | doi = 10.1016/S2352-3026(17)30105-9 }}</ref>


:* Dosage
== See also ==
* [[Hemopoietic growth factors]]
* [[Jehovah's Witnesses and blood transfusions]]


====Anemia Due to Chemotherapy in Patients With Cancer====
== References ==
{{Reflist|30em}}


PROCRIT is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
== Further reading ==
{{refbegin|35em}}
* {{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 | date = September 1991 | pmid = 1820196 | doi = 10.1093/glycob/1.4.337 }}
* {{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 | date = August 2002 | pmid = 12192960 | doi = 10.1177/089033440201800307 }}
* {{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 | date = December 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 | date = March 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 | date = June 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 | date = March 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 | date = March 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 | date = July 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}}{{Self-published inline|certain=yes|date=December 2017}}
{{refend}}


* Dosing Information
== External links ==
{{Wikiquote}}
* {{Cite news |last=Schmeck |first=Harold M., Jr. |date=January 8, 1987 |title=Synthesized Drug Eases Kidney Ills |url=https://query.nytimes.com/gst/fullpage.html?res=9B0DE2D81138F93BA35752C0A961948260 |work=[[The New York Times]] |page=A00021 |access-date=7 August 2018 |postscript=. (Announcement of Epogen's clinical success)}}
* [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000372/WC500054472.pdf "European Public Assessment Report (EPAR): Dynepo: EPAR summary for the public" (EMEA/H/C/372)] (PDF)—[[European Medicines Agency]]


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====Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery====
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PROCRIT is indicated to reduce the need for allogeneic 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. PROCRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.
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{{Hormones}}
* Dosing Information
{{Renal physiology}}
 
{{Colony-stimulating factors}}
:* Dosage
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{{Growth factor receptor modulators}}
====Limitations of Use====
{{Cytokine receptor modulators}}
 
*PROCRIT has not been shown to improve quality of life, fatigue, or patient well-being.
 
*PROCRIT is not indicated for use:
 
:*In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant 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 or vascular surgery.
:*As a substitute for RBC transfusions in patients who require immediate correction of anemia.
 
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|offLabelPedGuideSupport======Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport======Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Contraindications-->
|contraindications=PROCRIT is contraindicated in patients with:
 
    Uncontrolled hypertension [see Warnings and Precautions (5.4)]
    Pure red cell aplasia (PRCA) that begins after treatment with PROCRIT or other erythropoietin protein drugs [see Warnings and Precautions (5.7)]
    Serious allergic reactions to PROCRIT [see Warnings and Precautions (5.8)]
 
PROCRIT 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 PROCRIT is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol [see Use in Specific Populations (8.1, 8.3, 8.4)].
 
|warnings=5.1 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), PROCRIT and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other 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 [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. 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, PROCRIT 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]]
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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 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 (see Table 1), 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 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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.5)].
 
Increased mortality was observed in a randomized, placebo-controlled study of PROCRIT in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to PROCRIT 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.
 
5.2 Prescribing and Distribution Program for PROCRIT in Patients With Cancer
 
In order to prescribe and/or dispense PROCRIT 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. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prior to each new course of PROCRIT in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of PROCRIT.
 
5.3 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]]
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Decreased Overall Survival
 
Study 1 was described in the previous section [see Warnings and Precautions (5.1)]. 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 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 to15.5 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).
 
5.4 Hypertension
 
PROCRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of PROCRIT, 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 PROCRIT.
 
Appropriately control hypertension prior to initiation of and during treatment with PROCRIT. Reduce or withhold PROCRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].
 
5.5 Seizures
 
PROCRIT increases the risk of seizures in patients with CKD. During the first several months following initiation of PROCRIT, 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.
 
5.6 Lack or Loss of Hemoglobin Response to PROCRIT
 
For lack or loss of hemoglobin response to PROCRIT, 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 [see Warnings and Precautions (5.7)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to PROCRIT therapy [see Dosage and Administration (2.2)].
 
5.7 Pure Red Cell Aplasia
 
Cases of PRCA 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 PROCRIT. This has been reported predominantly in patients with 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 PROCRIT is not approved).
 
If severe anemia and low reticulocyte count develop during treatment with PROCRIT, withhold PROCRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) to perform assays for binding and neutralizing antibodies. Permanently discontinue PROCRIT in patients who develop PRCA following treatment with PROCRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.
 
5.8 Serious Allergic Reactions
 
Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with PROCRIT. Immediately and permanently discontinue PROCRIT and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
 
5.9 Albumin (Human)
 
PROCRIT contains albumin, a derivative of human blood [see Description (11)]. 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.
 
5.10 Dialysis Management
 
Patients may require adjustments in their dialysis prescriptions after initiation of PROCRIT. Patients receiving PROCRIT may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.
 
5.11 Laboratory Monitoring
 
Evaluate transferrin saturation and serum ferritin prior to and during PROCRIT treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [see Dosage and Administration (2.1)]. 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 [see Warnings and Precautions (5.1)]
    Increased mortality and/or increased risk of tumor progression or recurrence in Patients With Cancer [see Warnings and Precautions (5.3)]
    Hypertension [see Warnings and Precautions (5.4)]
    Seizures [see Warnings and Precautions (5.5)]
    PRCA [see Warnings and Precautions (5.7)]
    Serious allergic reactions [see Warnings and Precautions (5.8)]
 
6.1 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 PROCRIT. 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 PROCRIT. 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 PROCRIT-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]]
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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% PROCRIT and 1% placebo) [see Warnings and Precautions (5.1)].
 
The adverse reactions with a reported incidence of ≥ 5% in PROCRIT-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]]
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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% PROCRIT and 0% placebo) and myocardial infarction (0.8% PROCRIT and 0% placebo) [see Warnings and Precautions (5.1)].
 
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 PROCRIT and 153 (52%) patients were randomly assigned to receive placebo. PROCRIT was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
 
For the combined PROCRIT 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 PROCRIT 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 PROCRIT were:
 
[[File:Erythropoietin table 5.png|600px|thumbnail|left]]
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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 PROCRIT 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 PROCRIT-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 PROCRIT-treatment group was 158 white (94%) and 10 black (6%). PROCRIT 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 PROCRIT-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]]
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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 PROCRIT and 103 (22%) patients were randomly assigned to receive placebo. PROCRIT 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 PROCRIT 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 PROCRIT 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 PROCRIT-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]]
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6.3 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 PROCRIT 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 PROCRIT:
 
    Seizures [see Warnings and Precautions (5.5)]
    PRCA [see Warnings and Precautions (5.7)]
    Serious allergic reactions [see Warnings and Precautions (5.8)]
    Injection site reactions, including irritation and pain
|drugInteractions=No formal drug interaction studies have been conducted with PROCRIT.
|useInPregnancyFDA=8.1 Pregnancy
 
The multidose vials are formulated with benzyl alcohol. Do not administer PROCRIT from multidose vials, or PROCRIT from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with PROCRIT is needed during pregnancy, use a benzyl alcohol-free formulation [see Dosage and Administration (2) and Contraindications (4)].
 
Pregnancy Category C (single-dose vials only)
 
There are no adequate and well-controlled studies of PROCRIT use during pregnancy. There are limited data on PROCRIT 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 PROCRIT 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 PROCRIT. 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 PROCRIT 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 PROCRIT only during organogenesis, no teratogenic effects were observed in the offspring.
 
When healthy pregnant rats received PROCRIT 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 [see Nonclinical Toxicology (13.3)].
 
|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 PROCRIT are formulated with benzyl alcohol. Do not administer PROCRIT from multidose vials, or PROCRIT from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with PROCRIT is needed in nursing women, use a benzyl alcohol-free formulation [see Dosage and Administration (2) and Contraindications (4)].
 
It is not known whether PROCRIT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT from single-dose vials is administered to a nursing woman.
|useInPed=The multidose vials are formulated with benzyl alcohol. Do not administer PROCRIT from multidose vials, or PROCRIT from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with PROCRIT is needed in neonates and infants, use a benzyl alcohol-free formulation [see Dosage and Administration (2) and Contraindications (4)].
 
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
 
PROCRIT 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 [see Clinical Studies (14.1)].
 
The safety data from these studies are similar to those obtained from the studies of PROCRIT in adult patients with CKD [see Warnings and Precautions (5) and Adverse Reactions (6.1)].
 
Pediatric Cancer Patients on Chemotherapy
 
PROCRIT 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 [see Clinical Studies (14.3)]. The safety data from these studies are similar to those obtained from the studies of PROCRIT in adult patients with cancer [see Warnings and Precautions (5) and Adverse Reactions (6.1)].
 
Pediatric Patients With HIV Infection Receiving Zidovudine
 
Published literature has reported the use of PROCRIT 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 PROCRIT 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 PROCRIT 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 [see Dosage and Administration (2)].
 
Among 778 patients enrolled in the 3 clinical studies of PROCRIT for the treatment of anemia due to concomitant chemotherapy, 419 received PROCRIT and 359 received placebo. Of the 419 who received PROCRIT, 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 PROCRIT in geriatric and younger patients within the 3 studies were similar.
 
Among 1731 patients enrolled in the 6 clinical studies of PROCRIT for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received PROCRIT and 646 received placebo or standard of care treatment. Of the 1085 patients who received PROCRIT, 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 PROCRIT 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 PROCRIT for the treatment of zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.
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|overdose=PROCRIT overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of PROCRIT dosage and/or with phlebotomy, as clinically indicated [see Pharmacodynamics (12.2)]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.4)].
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|mechAction=PROCRIT stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
|structure=PROCRIT (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.
 
PROCRIT 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=PROCRIT 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 PROCRIT 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 PROCRIT 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 PROCRIT 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 PROCRIT in children and adolescents appeared similar to that of adults.
 
The pharmacokinetics of PROCRIT has not been studied in patients with HIV infection.
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
 
Carcinogenicity
 
The carcinogenic potential of PROCRIT has not been evaluated.
 
Mutagenicity
 
PROCRIT was not mutagenic or clastogenic under the conditions tested: PROCRIT 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 PROCRIT 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.
 
13.3 Reproductive and Developmental Toxicology
 
When pregnant rats were administered intravenous PROCRIT, 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 PROCRIT 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 PROCRIT-related effects were apparent for their offspring (F2 generation fetuses).
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[[Category:Drug]]
[[Category:Cytokines]]
[[Category:Growth factors]]
[[Category:Hormones of the kidneys]]
[[Category:Nephrology procedures]]
[[Category:World Anti-Doping Agency prohibited substances]]

Latest revision as of 13:04, 4 January 2019

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Erythropoietin (/ɪˌrɪθroʊˈpɔɪ.ɪtɪn, -rə-, -pɔɪˈɛtɪn, -ˈiːtɪn/;[1][2][3] 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.[4] 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.[5] 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.[6]

Mechanism of action

Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR).[7][8] EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signalling cascade. This initiates the STAT5, PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell.[9] SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.[10] 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,[11][12][13] and the pericytes in the brain.[14] Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.[15] 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.[16]

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)[17] 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.[18]

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 [19] 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.[15][20]

In 1977, Goldwasser and Kung purified EPO.[21] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[15] Synthetic EPO was first successfully used to correct anemia in 1987.[22] In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.[23] In 1989, the US Food and Drug Administration approved the hormone Epogen for use in certain anemias.[24]

Usage as doping product

EPO has been banned since the early 1990s, but a first test was not available until the 2000 Summer Olympics.[25] Before this test was available, no athletes were sanctioned after positive tests, but it happened that they were sanctioned after confessing to having used EPO, for example in the Festina affair, when a car with doping products for the Festina cycling team was found.

The first doping test in cycling was used in the 2001 La Flèche Wallonne. The first rider to test positive in that race was Bo Hamburger, although he was later acquitted because his B-sample was not conclusive.[26]

A 2007 study showed that EPO has a significant effect on exercise performance,[27][4] but a 2017 study showed that the effects of EPO administered to amateur cyclists was not distinguishable from a placebo.[28]

See also

References

  1. ↑ "Erythropoietin". Merriam-Webster Dictionary.
  2. ↑ "Erythropoietin". Dictionary.com Unabridged. Random House.
  3. ↑ "erythropoietin – definition of erythropoietin in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.
  4. ↑ 4.0 4.1 Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Medicine. 45 (4): 517–31. doi:10.1007/s40279-015-0308-9. PMID 25663250.
  5. ↑ 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.
  6. ↑ Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S (July 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.
  7. ↑ 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 (May 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.
  8. ↑ 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 (November 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.
  9. ↑ Thomson, Angus W.; Lotze, Michael T. (2003-04-22). The Cytokine Handbook, Two-Volume Set. Gulf Professional Publishing. ISBN 9780080518794.
  10. ↑ Hodges VM, Rainey S, Lappin TR, Maxwell AP (November 2007). "Pathophysiology of anemia and erythrocytosis". Critical Reviews in Oncology/Hematology. 64 (2): 139–58. doi:10.1016/j.critrevonc.2007.06.006. PMID 17656101.
  11. ↑ Jacobson LO, Goldwasser E, Fried W, Plzak L (March 1957). "Role of the kidney in erythropoiesis". Nature. 179 (4560): 633–4. Bibcode:1957Natur.179..633J. doi:10.1038/179633a0. PMID 13418752.
  12. ↑ Fisher JW, Koury S, Ducey T, Mendel S (October 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.
  13. ↑ 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.
  14. ↑ Ji P (November 2016). "Pericytes: new EPO-producing cells in the brain". Blood. 128 (21): 2483–2485. doi:10.1182/blood-2016-10-743880. PMID 27884833.
  15. ↑ 15.0 15.1 15.2 Jelkmann W (March 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.
  16. ↑ Jelkmann W (March 2011). "Regulation of erythropoietin production". The Journal of Physiology. 589 (Pt 6): 1251–8. doi:10.1113/jphysiol.2010.195057. PMC 3082088. PMID 21078592.
  17. ↑ Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (February 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.
  18. ↑ "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.
  19. ↑ 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.
  20. ↑ Höke A (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 978-0-387-30010-8. OCLC 64571745.[page needed]
  21. ↑ Miyake T, Kung CK, Goldwasser E (August 1977). "Purification of human erythropoietin". The Journal of Biological Chemistry. 252 (15): 5558–64. PMID 18467.
  22. ↑ Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 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.
  23. ↑ Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 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. Bibcode:1985PNAS...82.7580L. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178.
  24. ↑ "Epogen Prescribing Information" (PDF).
  25. ↑ "EPO DETECTION". World Anti-Doping Agency. December 2014.
  26. ↑ "Hamburger cleared of EPO use". BBC. 10 August 2001.
  27. ↑ Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C (November 2007). "Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity". European Journal of Applied Physiology. 101 (4): 481–6. doi:10.1007/s00421-007-0522-8. PMID 17668232.
  28. ↑ Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF (August 2017). "Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial". The Lancet. Haematology. 4 (8): e374–e386. doi:10.1016/S2352-3026(17)30105-9. PMID 28669689.

Further reading

  • Takeuchi M, Kobata A (September 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 (August 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 (December 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 (March 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 (June 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 (March 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 (March 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 (July 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.[self-published source]

External links

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