Nephrol Dial Transplant (2001) 16 wSuppl 7x: 15–19
Flexible dosing schemes for recombinant human
erythropoietin—lessons from our daily practice
Lars Weiss
Centralsjukhuset Hospital, Karlstad, Sweden
Abstract
The availability of recombinant human erythropoietin
(rh-Epo) has revolutionized the treatment of renal
anaemia. Subcutaneous (s.c.) administration of rh-Epo
offers significant advantages over the intravenous (i.v.)
route, and numerous studies have demonstrated its effi-
cacy and tolerability when administered two or three
times weekly. Most of these studies showed a significant
reduction in rh-Epo dosage requirements with s.c.
administration compared with the i.v. route, offering
clear benefits in terms of reduced costs. In addition, s.c.
administration is more convenient and flexible than i.v.
administration, and is recommended by European and
US guidelines. Dosing frequency of rh-Epo is also an
important issue in clinical practice, particularly when
customizing therapy to meet individual patient needs.
A few small-scale studies have shown comparable
efficacy and tolerability of different s.c. dosing
freuencies. Recently, a comprehensive randomized
controlled trial has shown that once weekly s.c. epoetin
beta effectively manages anaemia in haemodialysis
patients, even in patients requiring a high dose. Once
weekly dosing of s.c. epoetin beta adds greater flex-
ibility and an improved capacity to tailor dosing
frequency to patient needs. This reduces clinic time
for patients who do not self-administer and, together
with improved convenience of new formulations
and delivery systems, has the potential to improve
compliance and encourages self-administration.
Keywords: dosing frequency; dosing requirements;
epoetin beta; once weekly; rh-Epo; subcutaneous
Introduction
Recombinant human erythropoietin (rh-Epo, epoetin)
has had a major impact on the health and quality
Correspondence and offprint requests to: Dr Lars Weiss,
Department of Nephrology, Centralsjukhuset Hospital, S-651 85,
Karlstad, Sweden.
# 2001 European Renal Association–European Dialysis and Transplant Association
of life of patients with renal anaemia w1x. Initially,
rh-Epo was administered only via the intravenous (i.v.)
route. Multicentre studies conducted in Europe and
the USA demonstrated that i.v. administration, three
times weekly, was effective and well tolerated in the
treatment of renal anaemia w2,3x.
More recently, numerous studies have confirmed the
efficacy and tolerability of subcutaneous (s.c.) admin-
istration of epoetin when given two or three times
weekly w4 –17x. S.c. administration offers significant
advantages over the i.v. route. In the majority of
studies a significant reduction in rh-Epo dosage was
achieved in patients who received s.c. rh-Epo com-
pared with patients receiving i.v. rh-Epo (see below).
As well as the advantage of reduced dosage require-
ments, and therefore, reduced costs, s.c. administration
is also more convenient and flexible than the i.v. route,
especially for pre-dialysis patients and those on con-
tinuous ambulatory peritoneal dialysis (CAPD). Indeed,
European w18x and US w19x guidelines recommend s.c.,
rather than i.v., administration of rh-Epo.
Dosing frequency is also an important issue both
for healthcare professionals and patients. The addi-
tion of once weekly s.c. epoetin beta to the existing
two and three times weekly options provides greater
flexibility and enhances the ability to tailor dosing
frequency to patient needs w20x. The availability
of once weekly s.c. dosing will also facilitate self-
administration, potentially improving compliance with
therapy and, therefore, patient outcomes.
Advantages of s.c. administration of rh-Epo
Dosage requirements
A reduced dosage requirement is both clinically and
economically desirable and is particularly important
when long-term management is necessary. Several
parallel-group w6–10,13,16x and crossover studies
w4,5,11,12,14,15,17x have assessed whether the route
of administration has an effect on dosage require-
ments. The majority of these studies have shown that,
compared with the i.v. route, a lower s.c. dose is
16 L. Weiss

required to maintain haemoglobin levels in patients
with renal disease (Tables 1 and 2). In the largest of
these studies w9x, 208 long-term haemodialysis patients
were randomized to receive i.v. (101 patients) or s.c.
(107 patients) rh-Epo for 26 weeks. In this study, the
mean weekly dose required to maintain the target
haematocrit of 30–33% was 27–32% lower in the s.c.
group than in the i.v. group (95.1 vs 140.3 Uukg body
weight, P-0.001), which is consistent with other
parallel-group studies (Table 1).
Greater dosage reductions have been observed in
crossover studies. In one study w12x, patients received
i.v. rh-Epo for 6 months before switching to s.c.
rh-Epo for 10 months, followed by a further 6 months
of i.v. therapy. These investigators reported a 60%
reduction in rh-Epo dosage, and maintained haemo-
globin levels, with s.c. administration. There were no
between-group differences in blood pressure, serum
chemistry or dialysis adequacy.
Dosing frequency
Although the mode of administration has received
considerable attention, the optimal dosing frequency
for rh-Epo has not been as widely studied. Current
European weekly dosing frequencies were recently
published in the European Survey on Anaemia
Management w21x. As part of this survey, the frequency
of administration was recorded in a large number of
patients receiving i.v. (ns 5431) and s.c. (ns 6365)
rh-Epo. The survey reported that the majority of
patients who received i.v. rh-Epo were on a three times
Table 1. S.c. rh-Epo administration allows dosage reduction in
patients with renal anaemia (parallel-group studies)
Duration Patients Dosage
(weeks) (n) reduction (%)
weekly regimen (65.6%) whereas 11.1% and 22.6%
of patients were receiving i.v. rh-Epo once or twice
weekly. In contrast, dosing frequency was more evenly
distributed in patients receiving s.c. rh-Epo. In these
patients, 25.7%, 36.4% and 37.4% received rh-Epo
once, twice or three times a week, respectively
(Figure 1). These data suggest that physicians are
already adopting a flexible approach towards anaemia
management.
A number of small-scale studies (-40 patients)
have shown comparable efficacy and tolerability of
different s.c. rh-Epo dosing frequencies in patients
receiving haemodialysis or peritoneal dialysis w5,22–26x
(Table 3). In most studies there was only a slight
increase in rh-Epo weekly dose in the once weekly
groups. Lui et al. w26x compared the effect of twice
weekly vs once weekly s.c. administration of rh-Epo
in haemodialysis patients. After 12 weeks of treat-
ment with rh-Epo, the mean ("SD) haemoglobin
levels rose from 6.9"0.7 to 8.9"1.3 gudl in the once
weekly group and from 7.2"1.0 to 9.3"1.6 gudl in
the twice weekly group. The mean weekly doses of
rh-Epo used during the study were 127"6 and
115"18 Uukg of body weight for the once weekly
and twice weekly groups, respectively. Treatment
was well tolerated in both treatment groups. Similar
data have been reported in haemodialysis patients
receiving once weekly or three times weekly adminis-
tration w23x. This study showed similar tolerability and
dosage requirements in the once weekly and three
times weekly groups, with both groups maintaining
haemoglobin between 9–12 gudl.
In order to further assess the efficacy and
tolerability of different dosing frequencies, a large,
multicentre, randomized trial was conducted to com-
pare once weekly with two or three times weekly
administration w20x.

De Schoenmakere et al. w6x 52 30 no change

Eidemak et al. w7x 6–14 29 25
Jensen et al. w8x 16 50 no change
Kaufman et al. w9x 26 208 27 32
Muirhead et al. w10x 24 128 25
Schaller et al. w13x 35 90 33
Virot et al. w16x 16 49 25

Table 2. S.c. rh-Epo administration allows dosage reduction in

patients with renal anaemia (crossover studies)

Duration Patients Dosage

(weeks) (n) reduction (%)

Albitar et al. w4x 26 16 53

Besarab et al. w5x 15 29 34 – 43
Paganini et al. w11x 24 72 26
Parker et al. w12x 40 44 60
Steffensen et al. w14x 12 12 47
Taylor et al. w15x 8 16 4
Zehnder and Blumberg w17x 36 6 43–59 Fig. 1. Dosing frequencies for i.v. j and s.c. h rh-Epo administra-
tion (adapted from Jacobs et al. w21x).
Flexible dosing schemes for rh-Epo 17
Table 3. Studies comparing dosing frequency and dosage of s.c. rh-Epo in patients receiving haemodialysis and peritoneal dialysis

Dialysis Patients (n) Dosing frequency and dosage

population
Doses Dosage Doses Dosage
per week (IUukguweek) per week (IUukguweek)

Besarab et al. w5x HD 29 3 105 1 115

Brahm w22x PD 22 7 68 2 87
Canaud et al. w23x HD 36 3 111 1 123
Frifelt et al. w24x PD 33 3 66 1 77
Lago et al. w25x HD 30 3 n.a. 1 n.a.
Lui et al. w26x HD 20 2 115 1 127

HD, haemodialysis; PD, peritoneal dialysis; n.a., not available.

Multicentre study of once weekly administration Table 4. Mean ("SD) haemoglobin level (gudl) at baseline (week 0)
of s.c. epoetin beta and weeks 6, 16, and 24 (Weiss et al. w20x)

This comprehensive, randomized controlled trial, Weeks Treatment regimen

conducted at 15 Swedish dialysis centres, compared
the efficacy and tolerability of once weekly s.c. epoetin Once weekly Two or three times
(n s 88) weekly (n s 30)
beta with the same total dose administered two or
three times weekly in 158 patients receiving chronic
haemodialysis w20x. 0 11.4"0.6 11.2"0.6
6 11.1"1.0 11.3"1.1
Patients with a stable haemoglobin level of 16 11.1"1.1 11.3"0.9
10.0–12.5 gudl, optimal iron status and a dialysis dose 24 11.1"1.2 11.2"1.2
KtuV )1.0 during an 8-week pre-study period were
entered into the study. Patients were randomized to Once weekly group vs two or three times weekly group, weeks 0–24,
receive either once weekly s.c. epoetin beta or their statistically non-significant.
original two or three times weekly regimen (control) in
a 3 : 1 ratio for 24 weeks. During the pre-study period
the weekly dosage requirement of epoetin beta was Table 5. Mean ("SD) epoetin beta dose (IUukg body weight) at
determined and fixed. Six weeks after randomization, baseline (week 0) and weeks 6, 16, and 24 (Weiss et al. w20x)
a 20% increase in epoetin beta was allowed if serum
haemoglobin was -10 gudl and had decreased )1 gudl Weeks Treatment regimen
from the last two pre-randomization haemoglobin
levels. Dosage was decreased by 20% if a haemoglobin Once weekly Two or three times
(n s 88) weekly (n s 30)
level )13 gudl was recorded and had increased by
)1.0 gudl compared with the pre-randomization mean
value. Any subsequent dosage adjustments were made 0 102"71 109"49
6 107"70 112"54
every fourth week. 16 103"68 109"57
The primary efficacy variable was the proportion of 24 106"74 115"58
patients who maintained a stable haemoglobin level
without requiring an increase in total weekly dose. Once weekly group vs two or three times weekly group, weeks 0–24,
Secondary outcome variables were mean haemoglobin statistically non-significant.
level and epoetin beta dose. Tolerability was assessed
by general and local tolerance to epoetin beta, blood
pressure, adverse events and withdrawal from the study.
times weekly indicates that once weekly s.c. treatment
This study found that an equal proportion (73%) of
was effective and well tolerated even in patients who
patients in the two groups maintained stable haemo-
were initially receiving a high dose of rh-Epo (approx-
globin levels without an increase in epoetin beta dosage
imately 10 000 IUuweek). In this subgroup, both
during the 24-week study period. There were no statis-
epoetin beta dose and haemoglobin levels remained
tically significant between-group differences in mean
constant for the duration of the study (Figure 2).
haemoglobin levels or epoetin dosage at randomiza-
tion or study completion (Tables 4 and 5). In addition,
s.c. epoetin beta was well tolerated in both treatment
groups and there were no reports of pain at the site of Conclusions
injection.
Subsequent subgroup analysis of all patients who Studies have consistently shown that a reduction in
before randomization were receiving injections three rh-Epo dosage can be achieved with s.c. administration.
18
Fig. 2. Epoetin beta dosage post-dialysis in patients originally
receiving three times weekly administration (adapted from Weiss
et al. w20x). j Active group, once weekly; h control group, three
times weekly.
Indeed, current guidelines recommend administration
of rh-Epo via the s.c. route. S.c. administration of
epoetin beta is effective, well tolerated, convenient and
flexible, and can be performed once, twice or three
times weekly. In addition, there is evidence that once
weekly epoetin beta is effective and well tolerated
even in haemodialysis patients with high dosage
requirements.
The proven efficacy of once weekly dosage with
epoetin beta adds greater flexibility and improves
capacity to tailor dosing frequency to patient needs.
Reduction in clinic time for patients who do not
self-administer is an added benefit and means that
physicians and nurses are able to utilize their time
more efficiently. The reduction in clinic time for
patients and the potential for a reduced number of
injections may also provide benefit in terms of quality
of life. The capacity to tailor dosage and dosing
frequency, as well as haemoglobin target levels (see
Macdougall w27x), will potentially be enhanced by
recent advances in epoetin beta delivery systems spe-
cifically designed to facilitate individualized therapy.
These offer the potential for enhanced convenience
and flexibility, and may encourage self-administration
and compliance with therapy.
References
1. Winearls CG. Recombinant human erythropoietin: 10 years
of clinical experience. Nephrol Dial Transplant 1998; 10
wSuppl 2x: 3–8
2. Bommer J, Kugel M, Schoeppe W et al. Dose-related effects
of recombinant human erythropoietin on erythropoiesis. Results
of a multicenter trial in patients with end-stage renal disease.
Contrib Nephrol 1988; 66: 85–93
L. Weiss
3. Eschbach JW, Abdulhadi MH, Browne JK et al. Recombinant
human erythropoietin in anemia patients with end-stage renal
disease. Ann Intern Med 1989; 111: 992–1000
4. Albitar S, Meulders Q, Hammond H et al. Subcutaneous
versus intravenous administration of erythropoietin improves its
efficiency for the treatment of anaemia in haemodialysis patients.
Nephrol Dial Transplant 1995; 10 wSuppl 6x: 40–43
5. Besarab A, Flaharty KK, Erslev AJ et al. Clinical pharmacology
and economics of recombinant human erythropoietin in end-
stage renal disease: the case for subcutaneous administration.
J Am Soc Nephrol 1992; 2: 1405–1416
6. De Schoenmakere G, Lameire N, Dhondt A et al. The
haematopoietic effect of recombinant human erythropoietin
in haemodialysis is independent of the mode of administration
(i.v. or s.c.). Nephrol Dial Transplant 1998; 13: 1770–1775
7. Eidemak I, Friedberg MO, Ladefoged SD et al. Intravenous vs
subcutaneous administration of recombinant human erythro-
poietin in patients on haemodialysis and CAPD. Nephrol Dial
Transplant 1992; 7: 526–529
8. Jensen JD, Madsen JK, Jensen LW. Comparison of dose
requirement, serum erythropoietin and blood pressure follow-
ing intravenous and subcutaneous erythropoietin treatment
of dialysis patients: IV and SC erythropoietin. Eur J Clin
Pharmacol 1996; 50: 171–177
9. Kaufman JS, Reda DJ, Fye CL et al. Subcutaneous compared
with intravenous epoetin in patients receiving hemodialysis.
N Engl J Med 1998; 339: 578–583
10. Muirhead N, Churchill DN, Goldstein M et al. Comparison of
subcutaneous and intravenous recombinant human erythro-
poietin for anemia in hemodialysis patients with significant
comorbid disease. Am J Nephrol 1992; 12: 303–310
11. Paganini E, Eschbach JW, Lazarus JM et al. Intravenous versus
subcutaneous dosing of epoetin alfa in hemodialysis patients.
Am J Kidney Dis 1995; 26: 331–340
12. Parker KP, Mitch WE, Stivelman JC et al. Safety and efficacy of
low-dose subcutaneous erythropoietin in hemodialysis patients.
J Am Soc Nephrol 1997; 8: 288–293
13. Schaller R, Sperschneider H, Thieler H et al. Differences in
intravenous and subcutaneous application of recombinant
human erythropoietin: a multicentre trial. Artif Organs 1994;
18: 552–558
14. Steffensen G, Aunsholt NA, Ahlbom G. Comparative crossover
study of intravenously and subcutaneously administered recom-
binant human erythropoietin in hemodialysis patients. Blood
Purif 1992; 10: 241–247
15. Taylor JE, Belch JJF, Fleming LW et al. Erythropoietin response
and route of administration. Clin Nephrol 1994; 41: 297–302
16. Virot JS, Janin G, Guillaumie J et al. Must erythropoietin be
injected by subcutaneous route for every hemodialyzed patient?
Am J Kidney Dis 1996; 28: 400–408
17. Zehnder C, Blumberg A. Recombinant human erythropoietin
in anemic patients on maintenance hemodialysis: comparison
between intravenous and subcutaneous administration. Nephron
1991; 57: 485–486
18. Working Party for European Best Practice Guidelines for the
Management of Anaemia in Patients with Chronic Renal
Failure. European best practice guidelines for the management
of anaemia in patients with chronic renal failure. Nephrol Dial
Transplant 1999; 14 wSuppl 5x: 1–50
19. NKF-KuDOQI Clinical Practice Guidelines: update 2000. Am J
Kidney Dis 2001; 37 wSuppl 1x: S5–S238
20. Weiss LG, Clyne N, Fihlho J-D et al. The efficacy of once
weekly compared with two or three times weekly subcutaneous
epoetin b: results from a randomized controlled multicentre trial.
Nephrol Dial Transplant 2000; 15: 2014–2019
21. Jacobs C, Hörl WH, Macdougall IC et al. European Best
Practice Guidelines 9–13: anaemia management. Nephrol Dial
Transplant 2000; 15 wSuppl 4x: 33–42
22. Brahm M. Subcutaneous treatment with recombinant human
erythropoietin: the influence of injection frequency and skin-fold
thickness. Scand J Urol Nephrol 1998; 33: 192–196
23. Canaud B, Bennhold I, Delons S et al. What is the optimum
frequency of administration of r-HuEpo for correcting anemia in
hemodialysis patients? Dial Transplant 1995; 24: 306–329
Flexible dosing schemes for rh-Epo
24. Frifelt JJ, Tvedegaard E, Bruun K et al. Efficacy of recombinant
human erythropoietin administered subcutaneously to CAPD
patients once weekly. Perit Dial Int 1996; 16: 594–598
25. Lago M, Perez-Garcia R, Garcia de Vinuesa MS et al.
Efficiency of once-weekly subcutaneous administration of
recombinant human erythropoietin versus three times a
week administration in hemodialysis patients. Nephron 1996;
72: 723–724
19
26. Lui SF, Wong KC, Li PK, Lai KN. Once weekly versus twice
weekly subcutaneous administration of recombinant human
erythropoietin in haemodialysis patients. Am J Nephrol 1992;
12: 55–60
27. Macdougall IC. Individualizing target haemoglobin concentra-
tions—tailoring treatment for renal anaemia. Neprol Dial
Transplant 2001; 16 wSuppl 7x: 9–14