Tinjauan Pustaka

Recombinant Human Erythropoietin:

A Review of Pharmacology and Therapeutic
Potential in Anemias

MC Gupta, Savita Verma, Harmeet Singh

Departments of Pharmacology and Radiotherapy,
Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, India

Abstract: Epoetin alfa (EPO) is a biosynthetic form of the glycoprotein hormone. Erythropoietin
has been shown to be highly effective in prevention of anemia, i.e anemia due to renal failure,
anemia of AIDS and anemia of cancer with patients responding with increase in hematocrit, Hb
levels and improvement in quality of life. Various clinical trials have shown to be effective in
anemia of prematurity, treatment of postural hypotension in anemic type 1 diabetic patients with
autonomic neuropathy, treatment of anemia in inflammatory bowel disease, the anemia of primary autonomic failure, hematopoietic stem cell disorders, and acceleration of erythroid
repopulation after bone marrow transplantation (BMT). This review discusses pharmacological and therapeutic potential of recombinant human erythropoietin in anemias.
Key words: Recombinant Human Erythropoietin, pharmacology, anemia

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A Review of Pharmacology and Therapeutic Potential in Anemias

Eritropoetin Manusia Rekombinan:

Tinjauan Farmakologi dan Potensi Terapeutik pada Anemia
MC Gupta, Savita Verma, Harmeet Singh
Departments of Pharmacology and Radiotherapy,
Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, India

Abstrak: Epoetin alfa (EPO) adalah bentuk biosintetik hormon glikoprotein. Hormon tersebut
menunjukkan efektivitas yang tinggi dalam pencegahan anemia, antara lain anemia karena gagal
ginjal, anemia pada AIDS dan anemia yang berhubungan dengan keganasan. Keberhasilan
pemberian hormon tersebut tampak pada meningkatnya hematokrit, dan kadar hemoglobin yang
berakibat peningkatan kwalitas hidup pasien. Berbagai uji klinik memperlihatkan efektivitasnya
pada anemia akibat prematuritas, hipotensi postural akibat anemia pada diabetes melitus tipe 1
dengan neuropati otonom, anemia pada peradangan usus besar, anemia akibat kegagalan primer
otonom, kerusakan pada stem cell hematopoetik. Selain itu juga mempercepat perbanyakan
eritroid setelah transplantasi sumsum tulang. Makalah ini akan membahas aspek farmakologi
dan potensi terapeutik hormon eritropoetin rekombinan pada anemia.
Kata kunci: Eritropoetin Manusia Rekombinan, farmakologi, anemia.

Introduction
Erythropoietin is a naturally occurring hormone, produced by the kidneys, which stimulates the body to produce red blood cells. It is used to treat anemia, which can be
a disease in its own right or a symptom of another disease,
like kidney failure. It can be given to people with cancer who
have anemia, either because of the disease or their chemotherapy treatment. It has also become more widely known as
a drug used by athletes to increase their hemoglobin levels
(blood-doping) and improve performance; but its use in sport
is illegal and it can be detected by drug tests.1
Recombinant human erythropoietin (rHuEpo) became
available for clinical trials in 1985 and was introduced into
clinical practice for correction of anemia of renal failure in
1989.2 A synthetic form of Erythropoietin (EPO), human recombinant EPO, has been successfully used to treat anemia
in patients with chronic renal failure and AIDS. EPO has also
been used in anemia related to cancer.1
Erythropoietin Production
EPO is primarily synthesized by the kidney under the
control of a single gene on human chromosome 7.1 Endogenous human erythropoietin, a growth factor, is a glycosylated protein hormone that appears to be secreted principally by renal peritubular interstitial cells outside the tubular
basement membrane in the cortex and outer medulla of the
kidney; however approximately 10% is produced in the liver
and possibly at other extrarenal sites in adults. Fetal ery-

Maj Kedokt Indon, Volum: 57, Nomor: 1, Januari 2007

thropoietin production occurs mainly in the liver. Secretion

of the hormone occurs principally in response to reductions
in arterial and/or venous oxygen tension and tissue oxygenation in the kidney.
With anemia or hypoxemia, renal synthesis of EPO rapidly increases 100-fold or more, serum EPO levels rise and
marrow progenitor cell survival, proliferation and maturation
are dramatically increased.1 Factors other than tissue hypoxia might also be involved in the regulation of EPO production or may influence serum concentration. Abnormally
high EPO levels have been reported in patients with aplastic
anemia, and dramatic changes in serum levels have been
described after chemotherapy3 and during vitamin B12 or
iron replacement therapy.4
Chemistry
Epoetin alfa is a biosynthetic form of the glycoprotein
hormone erythropoietin. The amino acid sequence and biologic properties of epoetin alfa are identical to those of endogenous human erythropoietin extracted from the urine of
patients with aplastic anemia. The drug is prepared from cultures of genetically modified mammalian (Chinese hamster
ovary) cells using recombinant DNA technology.1 The molecular weight of the functional, 165-amino acid erythropoietin protein (excluding carbohydrate moieties) is approximately 18,400 daltons. Epoetin alfa contains two internal disulfide bonds linking positions 7 and 161 and positions 29
and 33; these bonds are necessary for the hormones biologic activity.5
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A Review of Pharmacology and Therapeutic Potential in Anemias

Pharmacology
Mechanism of Action
Erythropoietin induces the production of erythrocytes
(i.e., stimulates erythropoiesis) principally by stimulating the
proliferation and differentiation of committed erythroid precursors (i.e., burst-forming units-erythroid [BFU-E], colonyforming units-erythroid [CFU-E]). Other marrow precursors,
including colony-forming units: CFU-megakaryocytic (CFUMK), CFU-granulocytic-monocytic (CFU-GM), and pluripotent stem cells may also be increased with in vivo administration of erythropoietin. Stimulation of CFU-E and BFU-E
appears to be direct, while stimulation of CFU-MK and CFUGM may occur as indirect feedback responses.6
Pharmacokinetics
Epoetin alfa cannot be given orally as it is destroyed in
the GI tract because of its protein nature, and must be administered parenterally (i.e., via IV infusion, subcutaneous
injection, intra peritoneal injection). Systemic absorption of
epoetin alfa is delayed and incomplete following subcutaneous injection or intra peritoneal injection. However, while
serum concentrations peak sooner and are substantially
higher with IV than subcutaneous injection of epoetin alfa,
they are less sustained, and the IV route of administration
generally offers no clinical advantage over the subcutaneous route.7
The distribution of epoetin alfa and the endogenous
hormone in humans remains to be fully elucidated. Epoetin
alfa appears to distribute into a single compartment with an
apparent volume of distribution that approximates or slightly
exceeds plasma volume (about 45% of body weight).7
The elimination characteristics of epoetin alfa and endogenous erythropoietin in humans remain to be fully established. Subcutaneous administration of rHuEpo induces
lower peak plasma EPO concentrations, with an elimination
half-life of about 19 to 22 hours compared to the 4 to 5 hours
of IV rHuEpo.7 Subcutaneous administration of smaller doses
of rHuEpo more closely resembles the physiology of Epo
production and leads to greater efficacy than IV administration of larger doses. Therefore, rHuEpo should routinely be
administered subcutaneously.
Indications
Recombinant human erythropoietin can be effective in
a number of anemias. EPO has been shown to be highly
effective in prevention of anemia, i.e. anemia due to renal failure, anemia of AIDS and anemia of cancer. Various clinical
trials have shown to be effective in anemia of prematurity,
treatment of postural hypotension in anemic type 1 diabetic
patients with autonomic neuropathy, treatment of anemia in
inflammatory bowel disease, the anemia of primary autonomic
failure, hematopoietic stem cell disorders, and acceleration
of erythroid repopulation after bone marrow transplantation (BMT).
28

Prevention of Anemia
Patients facing surgery or cancer chemotherapy are at a
risk of developing anemia. Some of these patients may benefit from the prophylactic use of rHuEpo. rHuEpo may be
used to enhance the collection of autologous blood in patients facing elective surgery, to correct anemia before surgery, and to accelerate postoperative erythropoietic response. The primary aim is to avoid the risks of blood transfusion from donors.8
Anemia due to Renal Failure
Epoetin alfa has been used for the treatment of anemia
associated with chronic renal failure. Clinical studies indicate that the drug increases and/or maintains hemoglobin
concentrations and hematocrit and decreases the need for
transfusions in dialysis-dependent patients with chronic renal failure as well as in those who do not yet require maintenance dialysis (predialysis patients).9 Therapy with epoetin
alfa is also associated with subjective improvements in these
patients, including a perceived general increase in feeling of
well-being and quality of life. Many clinicians currently consider epoetin alfa as first-line therapy for anemia of chronic
renal failure. Therapy with epoetin alfa may eliminate the
need for maintenance red blood cell transfusions, though it
should not be used as a substitute for emergency transfusion. The speed and level of response depends on the individual patient and the level of iron supply. Although iron
absorption can increase several folds when rHuEpo is used,
oral iron supplementation may be insufficient in matching
iron demands by the rHuEpo-expanded erythroid marrow.7
Anemia Caused by AIDS
Anemia is found in about two thirds of patients with
acquired immunodeficiency syndrome (AIDS) and generally
worsens during treatment with zidovudine. Dosages of
rHuEpo of 100 to 300 IU/kg administered IV or SC three times
a week induce increase in hematocrit and reduction of transfusion requirements in patients with baseline serum Epo levels less than 500 mU/mL1. HIV-infected patients with endogenous pretreatment (pretransfusion) serum erythropoietin
concentrations of up to 500 mU/mL who are receiving weekly
cumulative zidovudine dosages of 4.2 g or less are more likely
to respond to epoetin alfa therapy than patients with higher
endogenous pretreatment erythropoietin concentrations (i.e.,
exceeding 500 mU/mL). During the initial eight weeks of
therapy with epoetin alfa, the hematocrit should be monitored weekly and dosage of epoetin alfa adjusted accordingly.
Anemia of Cancer
Anemia is a frequent occurrence in patients with cancer
and may be due to different causes. In untreated subjects,
the most common type is anemia of chronic disease, which is
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A Review of Pharmacology and Therapeutic Potential in Anemias

characterized by excessive release of inflammatory cytokines
and variable degrees of defective endogenous Epo production.10 Chemotherapy and radiotherapy frequently cause or
exacerbate anemia in patients with cancer due to their suppressive effects on either erythropoiesis or renal production
of Epo. Epo has been found to be both safe and effective at
increasing Hb levels in anemic patients receiving radiation
therapy alone or combined with chemotherapy.
Anemia of Prematurity
Prematurely born infants, who are otherwise healthy,
undergo an exaggerated decrease in hemoglobin concentration compared with term infants. Multiple factors play a role
in determining the anemia of prematurity, including a defective Epo response to decreasing Hb levels11. Data from various clinical trials indicate that the use of rHuEpo reduces
transfusions in premature infants weighing more than 1000
g. In infants weighing less than 1000 g or requiring artificial
ventilation, the reduction in transfusion needs is less impressive, which may be due to poor Epo responsiveness or
insufficient iron supplements. There is no benefit in using
rHuEpo for infants weighing more than 1300 g, because they
rarely require transfusion.
Treatment of Postural Hypotension in Patients with Autonomic Neuropathy
Postural hypotension is a feature of autonomic failure
that may result from various causes and can be very difficult
to treat. It has been have shown that some patients with
severe symptomatic autonomic neuropathy from type 1 diabetes have a normocytic anemia associated with erythropoietin (EPO) deficiency. The treatment of these patients with
EPO rapidly corrects their anemia and improves their overall
well-being.12
Treatment of Anemia in Inflammatory Bowel Disease
Some patients with inflammatory bowel disease have
anemia that is not responsive to iron administration and not
due to folate or B12 deficiency. One hypothesis is that inflammatory cytokines decrease erythropoietin production
and create resistance to the effect of erythropoietin, leading
to a relative deficiency of this hormone. Studies have shown
that rHuEpo treatment can increase Hb levels in patients
with inflammatory bowel disease and anemia refractory to
treatment with oral iron and vitamins.13
The Anemia of Primary Autonomic Failure
The sympathetic nervous system stimulates erythropoiesis in humans because anemia is a frequent occurrence
in patients with severe autonomic failure and is associated
with a blunted erythropoietin response. This anemia has been
shown to be improved with rHuEPO administration.14

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Anemia of Hematopoietic Stem Cell Disorders

Anemia is a major clinical problem in conditions such as
aplastic anemia, sickle cell anemia, myelodysplastic syndromes (MDS), and idiopathic myelofibrosis. Many patients
are adversely affected by transfusion-dependency and secondary hemochromatosis. There is no evidence of any effect
in severe aplastic anemia, whereas occasional patients with
pure RBC aplasia may respond despite elevated endogenous
Epo levels. The response rate to rHuEpo increases to approximately 40% when rHuEpo and granulocyte-colonystimulating factor (G-CSF) are used in combination in MDS
patients.15
Acceleration of Erythroid Repopulation After Bone Marrow Transplantation (BMT)
Endogenous Epo production is frequently inadequate
in recipients of allogenic BMT and this may delay erythropoietic recovery. A pilot study showed that rHuEpo administration can accelerate erythroid reconstitution after allogeneic BMT with no stem cell competition effect. Three randomized clinical trials have confirmed that rHuEpo in high
doses reduces transfusion requirements during the first 2
months after BMT, whereas low doses are poorly effective.16
Adverse Effect Profile
Hypertension
The most frequent adverse effect observed in patients
receiving epoetin alfa for anemia of chronic renal failure is
development or exacerbation of hypertension. The risk of
hypertensive episodes appears to be low to nonexistent in
patients with normal renal function compared with that in
patients receiving the drug for anemia of chronic renal failure.7
Hematologic Effects
Increased in partial or complete clotting at the site of
vascular access has been observed in renal dialysis patients
receiving epoetin alfa. Patients with chronic renal failure (both
dialysis and predialysis patients) experience other types of
thrombotic events like myocardial infarction, cerebrovascular accident, transient ischemic attacks.7
Nervous System Effects
Seizures [tonic-clonic (grand mal)] have been reported
occasionally in patients receiving epoetin alfa. Hypertensive encephalopathy also has been observed. Seizures also
have been reported in HIV-infected patients receiving epoetin
alfa for the treatment of anemia associated with zidovudine
therapy; however, seizure activity in these patients appears
to be related to underlying pathology (e.g., meningitis, cerebral neoplasm) or other concomitant drug therapy rather than
to therapy with epoetin alfa.17

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A Review of Pharmacology and Therapeutic Potential in Anemias

Renal and Electrolyte Effects
Predialysis increases in serum concentrations of potassium, blood urea nitrogen (BUN), creatinine, uric acid,
and phosphate have been reported with erythropoietin
therapy. Severe, recurrent hyperkalemia has been reported
infrequently with epoetin alfa. An increase in calcium-phosphate product associated with joint pain, inflammation, swelling, and periarticular calcification has also been observed.18
Flu-like Syndrome
A flu-like syndrome has been reported rarely in patients
receiving epoetin alfa, principally with IV infusion of the
drug, but also with subcutaneous administration. This flulike syndrome is characterized by the development of transient diaphoresis, chills, shivering, malaise, feeling of cold
or warmth, myalgia, bone pain and arthralgia of the limbs
and pelvis, generalized aches and pains (including chest,
back, and/or flank pain), fever, paresthesias, and/or abdominal pain/cramps. The reaction generally is self-limiting and
does not require dosage modification or preclude continued
administration of the drug.18
Other Adverse Effects
Nausea, vomiting, diarrhea, edema, arthralgias, and fatigue have been reported in more than 5% of chronic renal
failure patients receiving epoetin alfa. Tachycardia, cramps,
night sweats, visual disturbances, exacerbation of acne, skin
rash and urticaria, petechial
purpura, pruritus, transient
local pain and/or stinging at the subcutaneous injection site,
volume overload, shortness of breath, and conjunctival inflammation, redness, and/or injection have been reported
infrequently.18 Aggravation of splenomegaly has been reported occasionally in patients receiving the drug for anemia of myeloproliferative disorders.16 Adverse effects reported with epoetin alfa in HIV-infected individuals include
pyrexia, headache, cough, rash, respiratory congestion, nausea, vomiting, diarrhea, shortness of breath, hypertension,
fatigue, peripheral neuropathy, joint pain, pruritus, seizures,
myalgia, palpitation, and local reaction (e.g., burning, pain)
at the site of injection.19 Adverse effects reported with epoetin
alfa in cancer patients with chemotherapy-induced anemia
include pyrexia, diarrhea, nausea, vomiting, edema, asthenia, paresthesia, fatigue, shortness of breath, upper respiratory infection, dizziness, and trunk pain.16
Drug Interactions
Androgens
Androgens have been shown to increase the sensitivity of erythroid progenitors to endogenous erythropoietin
and possibly stimulate residual endogenous erythropoietin
secretion, these drugs have been used as an adjunct to epoetin alfa therapy in a few patients to decrease the total amount
of epoetin alfa required for the amelioration of anemia.20
30

Desmopressin
Concurrent therapy with epoetin alfa and desmopressin
has resulted in an additive effect in reducing the bleeding
time in a patient with end-stage renal disease who was receiving epoetin alfa for correction of uremia-induced increased bleeding time and epistaxis.21
Probenecid
Probenecid has been shown to inhibit renal tubular secretion of endogenous erythropoietin in animals.22
Precautions and Contraindications
The safety and efficacy of epoetin alfa have not been
established in patients with a preexisting seizure disorder,
and the drug should be used with caution in such patients.18
All patients receiving epoetin alfa should be observed closely
for signs of declining neurologic status, especially during
the first 3 months of therapy.
Frequent, periodic monitoring of blood pressure (up to
3 times weekly) is indicated in all patients receiving epoetin
alfa, including dialysis and nondialysis patients and cancer
patients, since development of hypertension may be associated with the rate or extent of increase in hematocrit. Blood
pressure monitoring is particularly important in patients with
an underlying history of hypertension or cardiovascular disease.23
Therapy with epoetin alfa should be discontinued immediately and appropriate therapy initiated if an anaphylactoid reaction should occur.
Stimulation of oncogenic hematologic cell lines by
epoetin alfa has not been documented to date; however, the
drug, like other growth factors, should be used with caution
in patients with a known neoplasm or leukemic disease.23
Renal function (as evaluated by measurement of BUN
and serum creatinine concentration) and fluid and electrolyte balance (as determined by results of blood chemistry
tests, especially serum potassium, phosphate, and uric acid)
should be monitored in all chronic renal failure patients receiving epoetin alfa. This precaution may be particularly important in patients predisposed to hyperkalemia (e.g., chronic
renal failure patients).24
Compliance with concurrent drug therapy (especially
antihypertensive therapy), dietary restrictions, and dialysis
schedules should be encouraged in chronic renal failure patients receiving epoetin alfa therapy.
Conditions that may diminish or block the effects of
epoetin alfa include states of acute or chronic inflammation,
infection, neoplastic disease or malignancy, underlying
myelodysplastic disorders, marrow suppression from uremia, aluminum overload (possibly by interfering with iron
bioavailability), hyperparathyroidism/osteitis fibrosa cystica,
hypersplenism, acute or chronic blood loss, erythrocyte enMaj Kedokt Indon, Volum: 57, Nomor: 1, Januari 2007

A Review of Pharmacology and Therapeutic Potential in Anemias

zyme abnormalities (e.g., pyruvate kinase deficiency), and/
or folic acid or vitamin B12 deficiency. It is especially important to consider the possibility of diminished response in
patients with an acute or chronic infection or in those undergoing surgery, both states of acute inflammation.25

supplementation (200 mg of oral elemental iron daily, i.e., 900

mg of iron sulfate) should be administered routinely during
the first 4 to 6 weeks of rHuEpo treatment to all patients
except those with increased serum iron and transferrin saturation.7,9

Precautions in Pregnancy, Fertility, and Lactation

Although there are no adequate and controlled studies
to date in humans, epoetin alfa has been shown to be teratogenic in rats when given IV at 5 times the usual human dosage. Epoetin alfa should be used during pregnancy only
when the potential benefits justify the possible risks to the
fetus. A decrease in body weight gain, delayed appearance
of abdominal hair, delayed eyelid opening, delayed ossification, and a decrease in the number of caudal vertebrae in
first-generation fetuses has been observed in animal experiments.26

Anemia of Cancer
It has been shown that rHuEpo at a dose of 100 to 150
IU/kg three times weekly corrects chemotherapy-induced
anemia and reduces transfusion requirements.1

Precautions in Pediatric Patients

Safety and efficacy of epoetin alfa in children have not
been established. However, the drug has been used for the
treatment of anemia (e.g., anemia of chronic renal failure,
anemia of prematurity) in a limited number of children younger
than 12 years of age. Results of studies in patients 2.518
years of age and in premature neonates suggest that the
safety and efficacy of the hormone are similar to those in
adults.27
Precautions in Geriatric Patients
While safety and efficacy of epoetin alfa have not been
established specifically in geriatric patients, a large proportion of patients treated with the drug for anemia associated
with chronic renal failure have been 65 years of age or older.
Although no special precautions are necessary, however,
careful monitoring of blood chemistry and blood pressure
may be necessary.28
Dosage recommendations
Prevention of Anemia
When epoetin alfa is used preoperatively to reduce the
need for allogeneic blood transfusions in anemic patients,
who are scheduled to undergo elective noncardiac,
nonvascular surgery with hemoglobin concentration between
10 to 13 g/dL, the recommended dosage is 300 units/kg given
by subcutaneous injection once daily for 10 days prior to
surgery, on the day of surgery, and for 4 days after surgery.8

Anemia of Prematurity
The dosages of rHuEpo used for the treatment of anemia of prematurity have been in the range of 75 to 1,200 IU/
kg/wk. The optimal dosage is 250 IU/kg subcutaneously three
times weekly, from week 1 to 6 of life. Iron supplementation
(5 mg of oral elemental iron per kilogram daily) should be
given along with rHuEpo.11
Postural Hypotension in Autonomic Neuropathy
Dose of recombinant human EPO for the treatment of
postural hypotension in autonomic neuropathy is 25 IU/kg
s.c. thrice weekly.12
The Anemia of Primary Autonomic Failure
Erythropoietin in low doses (25 to 50 units/kg body
weight, subcutaneously, three times a week) has been used
to treat anemia of primary autonomic failure.14
Conclusion
The use of rHuEPO has undoubtedly altered the traditional management of renal anemia. Its therapeutic benefit
has been explored in other clinical areas also. Treatment with
EPO is expensive and not every patient can benefit from it.
One has to be very judicious in the use of erythropoietin.
Iron supplementation is recommended as rHuEPO therapy
accelerates erythropoiesis causing a functional iron deficiency. In future new developments are likely, which optimize and maximize erythropoiesis, making the management
of anemia more effective.
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Anemia of Renal Failure

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