features of darbepoetin alfa in the nephrology setting

Features of darbepoetin alfa in the nephrology setting

Module 2 – Achieving and maintaining the Hb target with darbepoetin alfa

In patients not on dialysis

EU label for all ESAs

Hb target: 10–12 g/dl Avoid sustained Hb >12 g/dl

Treatment of symptomatic anaemia

Restrictive dose titration

Lowest epoetin dose should be used

Uniform EU label applies to all ESAs

Hb = haemoglobin

Aranesp SPC Feb 2012, Mircera SPC Nov 2011, NeoRecormon SPC Aug 2011, Epoetin alfa Hexal SPC Apr 2011, Silapo SPC Jun 2011, Eporatio SPC Sep 2010available at: http://www.ema.europa.euEprex SPC Oct 2011, available at http://www.medicines.org.uk/emc/medicine/889/SPC

http://www.ema.europa.eu/

http://www.medicines.org.uk/emc/medicine/889/SPC

1Agarwal et al. J Intern Med 2006;260:577–85. 2Carrera et al. Nephrol Dial Transplant 2006;21:2846–50. 3Locatelli et al. Kidney Int 2001;60:741–7. 4Eprex® (epoetin alfa) SPC Oct 2011, available at http://www.medicines.org.uk/emc/medicine/889/SPC .5NeoRecormon® (epoetin beta) SPC Aug 2011, available at: http://www.ema.europa.eu.6Omontys (peginesatide) Prescribing Information March 2012, available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 7Aranesp® (darbepoetin alfa) SPC Feb 2012 , available at: http://www.ema.europa.eu .8Mircera® (methoxy polyethylene glycol-epoetin beta) SPC Nov 2011, available at: http://www.ema.europa.eu.

The half-life of darbepoetin alfa is long enough to allow extended dosing1,2 but is short enough for customized control of Hb levels3

Epoetinalfa

Epoetinbeta

Peginesatideacetate

Darbepoetinalfa

peg-EPO0

20

40

60

80

100

120

140

160

24 13-28

73

25-53

139

Hal

f-li

fe (

ho

urs

)

4 5 6,* 7

8

*Peginesatide acetate is currently not approved in the EU

http://www.medicines.org.uk/emc/medicine/889/SPC


http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm



The half-life of the darbepoetin alfa molecule has the flexibility to regain and maintain Hb control

Long enough

Convenience

Long enough for extended dosing

Short enough for customised control

Short enough for customized control

Short enough

Concern

Extended dosing of darbepoetin alfa in CKD patients not on dialysis

Experience with:• Q2W dosing• QM dosing• Needle-stick injury prevention

CKD = chronic kidney disease. QW = weekly. Q2W = every other week. QM = once monthly

Darbepoetin alfa prescribing information:Correction Phase: HD patients - QW dosing; CKD patients not on dialysis – QW or Q2W SC dosingMaintenance Phase: HD patients - QW or Q2W dosing; CKD patients not on dialysis – QW, Q2W or QM SC dosing

Every other week (Q2W) dosing of darbepoetin alfa was effective in CKD patients not on dialysis

Reference Study description* Treatment period

Hb study target

rangePrimary

end point

Suranyi et al.Am J Nephrol 2003;23:106–11

N = 76EPO naive → Q2W DA

24 weeks 11–13 g/dlPatients achieving

Hb 11–13 g/dl

Toto et al.Am J Nephrol 2004;24:453–60

N = 608EPO naive → Q2W DA

24 weeks 11–13 g/dlDose of DA,

when Hb ≥11 g/dl

Hertel et al.Am J Nephrol 2006;26:149–56

N = 524QW rHuEPO → Q2W DA

52 weeks ≤ 12 g/dlMean Hb during

week 20–32

Galle et al.Nephrol Dial Transplant2012;27:2303-11

N = 4278Epoetin a, epoetin b, DA

QW, DA other→ DA Q2W / QM SC

12 months >11

achievement of Hb level >11 g/dl,

absolute Hb level 12 months post-

initiation

*Open-label studies

DA = darbepoetin alfa. rHuEPO = recombinant human erythropoietin

High response rate with Q2W dosing of darbepoetin alfa

• Hb response was achieved in 97% of patients (N = 61) completing 24 weeks of treatment

Suranyi et al. Am J Nephrol 2003;23:106–11

Pat

ien

ts (

%)

97%

3%0

20

40

60

80

100Patients within Hb study target range (11–13 g/dl)

Patients outside Hb study target range

Patients were judged to have achieved a Hb response when they reached the Hb target range (11.0–13.0 g/dl).

• At time of response the mean (SD) DA dose was 63.5 ± 16.9 μg/Q2W (N = 463*)

Mea

n H

b c

on

cen

trat

ion

(g

/dl)

Q2W

do

se o

f D

A (

µg

)

Study week1 3 7 11 13 17 21 23

9

10

11

12

13

14

191595

50

40

60

80

90

70

DA doseHb

30

20

Toto et al. Am J Nephrol 2004;24:453–60

Q2W darbepoetin alfa effectively corrected anaemia and maintained stable Hb levels

*Patients who completed 24 weeks of DA treatment

Hb response was defined as a Hb range of between 11.0 and 13.0 g/dl for up to 24 weeks

Baseline(n = 524)

Evaluation period(n = 407)

0

2

4

6

8

10

12

14

0

10

20

30

40

50

11.2 11.4

49.7 48.9

Hb Dose

Mea

n H

b

con

cen

trat

ion

(g

/dl)

Mea

n D

A d

os

e (µ

g/w

k)

(n = 523) (n = 428)

Hertel et al. Am J Nephrol 2006;26:149–56

Q2W dosing of darbepoetin alfa remained steady over time

Q2W/QM darbepoetin alfa effectively corrected anaemia and maintained stable Hb levels in ESA-prior as well as ESA-naive patients not on dialysis

Full Analysis Set (n=2085)

Hb DA dose

Me

an

Hb

co

nc

. (9

5%

CI)

, g

/dL

Ge

om

etr

ic M

ea

n W

ee

kly

Do

se

(9

5%

CI)

, µ

g/w

k

Months Before/After Initiation

10.0

10.5

11.0

11.5

12.0

12.5

10

15

20

25

-6 -5 -4 -3 -2 -1 P I 1 2 3 4 5 6 7 8 9 10 11 12

Full Analysis Set (n=2193)

10.0

10.5

11.0

11.5

12.0

12.5

10

15

20

25

-6 -5 -4 -3 -2 -1 P I 1 2 3 4 5 6 7 8 9 10 11 12 Ge

om

etr

ic M

ea

n W

ee

kly

Do

se

(9

5%

CI)

, µ

g/w

k

Me

an

Hb

co

nc

. (9

5%

CI)

, g

/dL

Months Before/After Initiation

Hb DA dose

Galle et al. Nephrol Dial Transplant 2012;27:2303-11.

Q2W = bi-weekly. QM = monthly. ESA = erythropoiesis stimulating agent. DA = darbepoetin alfa.P = immediately prior to initiation. I = at initiation.

ESA-prior patients ESA-naive patients

ESA dose

Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysis

Reference Study description* Treatment and evaluation period

Hb study target (g/dl)

Primary endpoint

Ling et al.Clin Nephrol 2005;63:327–34

N = 97Q2W DA → QM DA 29 weeks 10-12

proportion of patients maintaining Hb study target range

Agarwal et al.J Intern Med 2006;260:577–85

N = 152Q2W DA → QM DA 33 weeks 11-13

proportion of patientswith Hb ≥ 11 g/dl during the

evaluation period

Disney et al.Nephrology 2007;12:95–101

N = 66Q2W DA → QM DA 33 weeks 10-13

proportion of patients maintainingmean Hb ≥ 10 g/dl during the

evaluation period

Galle et al.Nephrol Dial Transplant2012;27:2303-2311

N = 4278Epoetin a, epoetin b,

DA QW, DA other→ DA Q2W / QM SC

12 months >11achievement of Hb level >11 g/dl,

absolute Hb level 12 months post-initiation

Hoggard et al.Curr Med Res Opin2006;22:2023-30

N = 442QW/Q2W Epoetin α →

QM DA28 weeks 10-12

Patient preference at week 21 for QM DA versus previous QW

Epoetin α

*Open-label studies

Ling et al. Clin Nephrol 2005;63:327–34

Patients could be safely and effectively switched from Q2W to QM dosing of darbepoetin alfa

• Baseline versus evaluation period:• Mean Hb level remained

stable (11.1 ± 0.6 g/dl versus 11.1 ± 0.7)

• DA monthly dose was similar (88.7 ± 49.9 µg versus 86.6 ± 78.8 µg)

Patients achieving Hb target0

10

20

30

40

50

60

70

80

90

100

85%

N = 86

Pat

ien

ts (

%)

• Hb concentration was maintained within the target range in 85% (95% CI = 78% – 93%) of patients who completed the study period of 29 weeks

Switch from Q2W to QM darbepoetin alfa allowed stable Hb levels and steady dose

• 76% (95% CI: 68%; 83%) of patients achieved mean Hb ≥11 g/dl during evaluation(n = 150*)

Agarwal et al. J Intern Med 2006;260:577–85

*Patients who received at least one dose of DA

9

10

11

12

13

14

BL 1Study week

Hb

(g

/dl)

5 9 13 17 21 25 29 33

Mean (SE)

0

50

150

250

Study month

Dar

bep

oe

tin

alf

a (m

g/m

on

th)

1 2 3 4 5 6 7 8

Median (95% CI)

200

100

Q2W dosing of darbepoetin alfa could be safely and effectively extended to the QM regimen

• 83% of patients had mean Hb ≥10 g/dl during the evaluation (n=66*)• QM DA treatment was safe and well-tolerated

Disney et al. Nephrology 2007;12:95–101

*Patients who received at least one dose of DA

Study week

Dar

bep

oe

tin

alf

a d

ose

(m

g/m

on

th)

0

25

50

75

100

125

150

Hb

(g

/dl)

14

13

12

11

10

0

BL 5 9 13 17 21 25 291 33

HbDose

70% of CKD patients not on dialysis achieved Hb level>11 g/dl with extended (Q2W/QM) darbepoetin alfa dosing

Galle et al. Nephrol Dial Transplant 2012;27:2303-2311

% p

atie

nts

wit

h H

b >

11 g

/dL

Initiation Months 10 to 120

10

20

30

40

50

60

70

80

71 70

19

72

ESA priorESA naïve

Hb target was achieved with QM darbepoetin alfa in the majority of CKD patients not on dialysis

1Agarwal et al. J Intern Med 2006;260:577–852Disney et al. Nephrology 2007;12:95–1013Ling et al. Clin Nephrol 2005;63:327–344Galle et al. Nephrol Dial Transplant 2012;27:2303-2311

11-13 g/dL 10-13 g/dL 10-12 g/dL >11 g/dL0%

20%

40%

60%

80%

100%

76%1 83%2 85%3

70-72%4

Patients achieving Hb target

% o

f p

atie

nts

Hb study target range

96% of patients preferred QM darbepoetin alfa

Hoggard et al. Curr Med Res Opin 2006;22:2023–30

• Mean Hb level remained stable between baseline (11.4 g/dl) and the end of the study (11.2 g/dl)

0%

20%

40%

60%

80%

100%

Did not prefer DA QM

Preferred DA QM

Pat

ien

t re

spo

ns

e (%

)

N = 319

Correcting anaemia by darbepoetin alfa QM in CKD patients not on dialysis: Design of a randomisedphase III study (20060163)

Darbepoetin alfa Q2W

Darbepoetin alfa QM

• ≥ 18 years of age• Clinically stable• eGFR 15-59 mL/min/1.73 m2 • Hb < 10 g/dL at two

consecutive measurements• Adequate iron stores

(TSAT≥15%)

Evaluation weeks 29-33Titration weeks 1 -28

• 1:1 randomisation• Double-blind to dose and dosing interval• Target Hb = 10.0 – 12.0 g/dL and ≥ 1.0 g/dL above baseline• Initiation dose: 0.75 µg/kg Q2W or 1.5 µg/kg QM• Non-inferiority margin: -0.5 g/dL

Primary Objective: To determine whether the efficacy of once monthly (QM) dosing of darbepoetin alfa is non-inferior to that of once every 2 week (Q2W) dosing for the correction of anemia in subjects with CKD not on dialysis

N ~ 334

(90% power, 5% significance level)

Primary Endpoint: Hb change between baseline and the evaluation period (weeks 29-33)

Other Endpoints:

- achieving both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL- the time to achieve both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL- Darbepoetin alfa doses over the duration of the study- Safety data

Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at: http://www.abstracts2view.com/era/

http://www.abstracts2view.com/era/

Baseline characteristics were not different in the QM and Q2W groups (I/II)

Darbepoetin alfa

Q2W

(N = 175)QM

(N = 180)Total

(N = 355)

Female – n(%) 107 (61.1) 104 (57.8) 211 (59.4)

Race – n (%) 134 (94.4) 138 (89.6) 272 (91.9)

White / Caucasian 166 (94.9) 163 (90.6) 329 (92.7)

Black / African American 0 1 (0.6) 1 (0.3)

Other 9 (5.1) 16 (8.9) 25 (7.0)

Age (years) – mean (SD) 68.4 (14.1) 66.3 (15.2) 67.3 (14.7)

Range, years 20 – 90 19 – 92 19 - 92

Weight (kg) - mean (SD) 77.2 (18.6) 75.2 (16.9) 76.2 (17.8)

Range, kg 39 – 142 38 – 125 38 - 142

Primary aetiology of CKD – n (%)

Diabetes mellitus 69 (39.4) 79 (43.9) 148 (41.7)

Hypertension 44 (25.1) 41 (22.8) 85 (23.9)

Glomerulonephritis 7 (4.0) 13 (7.2) 20 (5.6)

Urological disease 6 (3.4) 4 (2.2) 10 (2.8)

Polycystic kidney disease 3 (1.7) 3 (1.7) 6 (1.7)

Other / unknown 46 (26.3) 40 (22.2) 86 (24.2)



Baseline characteristics were not different in the QM and Q2W groups (II/II)

Darbepoetin alfa

Q2W

(N = 175)QM

(N = 180)Total

(N = 355)

Medical history – n (%)

Cardiovascular disease 167 (95.4) 172 (95.6) 339 (95.5)

Endocrine or metabolic disease 127 (72.6) 131 (72.8) 258 (72.7)

Hb concentration, g/dL – mean (SD) 9.13 (0.61) 9.11 (0.70) 9.12 (0.65)

Range, g/dL 6.2 – 9.9 5.2 – 9.9 5.2 – 9.9

Hb category – n (%)

<8.0 g/dL 8 (4.6) 14 (7.8) 22 (6.2)

≥8.0 to <9.0 g/dL 43 (24.6) 36 (20.0) 79 (22.3)

≥9.0 to <9.5 g/dL 69 (39.4) 72 (40.0) 141 (39.7)

≥9.5 to <10.0 g/dL 55 (31.4) 58 (32.2) 113 (31.8)

eGFR, mL/min/1.73 m2 – mean (SD) 25.9 (9.1) 28.3 (11.1) 27.1 (10.2)

Range, mL/min/1.73 m2 13 – 59 13 – 66 13 - 66

TSAT, % – mean (SD) 27.8 (14.2) 28.9 (13.6) 28.4 (13.9)

Range, % 4 – 94 15 – 97 4 - 97



Series1-0.5

0

0.5

1

1.5

2

2.5Q2W (N = 142)

QM (N = 154)

Treatment difference(QM-Q2W)

Darbepoetin alfa QM dosing was non-inferior to Q2W dosing in correcting CKD anaemia

Change in haemoglobin from baseline to evaluation

Hb

, g

/dL

(95

% C

I)

ANCOVA model adjusted for baseline Hb

Non-inferiority margin

Primary efficacy analysis set Darbepoetin alfa

Q2W (N = 142) QM (N = 154)Treatment difference

(QM-Q2W)Adjusted mean change (SE) in Hb, g/dL 2.16 (0.09) 1.97 (0.08) -0.19 (0.12)95% CI 1.98, 2.33 1.80, 2.14 -0.43, 0.05

Patients achieving a Hb level ≥ 10.0 g/dL and an increase from baseline ≥ 1.0 g/dL

At any time, n (%) 139 (97.9) 151 (98.1) 290 (98.0)95% CI 95.5, 100 95.9, 100 96.4, 99.6During the evaluation period, n (%) 131 (92.3) 142 (92.2) 273 (92.2)95% CI 87.9, 96.7 88.0, 96.4 89.2, 95.3



Hb achieved over time was similar in the QM and Q2W groups

Base-line

3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 335

6

7

8

9

10

11

12

QM (N = 154) Q2W (N = 142)

Mea

n H

b,

95%

CI

(g/d

L)

Study week

Baseline Hb is the mean of week -2 and -1 screening valuesHb within 90 days of a transfusion are excluded.

Number of subjects

Q2W (n): 142 141 142 140 140 139 140 139 138 139 137 138 139 138 137 140 136QM (n): 154 153 152 152 153 151 149 150 150 148 146 148 151 150 151 152 149



Comparable proportion of patients achieved a Hb level ≥10 g/dL and a Hb increase ≥1 g/dL from baseline to the evaluation period


Pro

port

ion

of p

atie

nts

(%)

120

80

40

0Q2W

(n = 142)QM

(n = 154)

20

100

60

Tim

e to

firs

t ach

ieve

men

t to

Hb

leve

l ≥10

g/d

Lan

d a

Hb

incr

ease

≥1

g/dL

from

bas

elin

e (

wee

k)

12

8

4

0Q2W

(n = 142)QM

(n = 154)

2

10

6

97.9 98.15

5


Greater darbepoetin alfa weekly doses were used in the QM group than in the Q2W group


Wei

ght

-adj

uste

d w

eekl

y D

A d

ose

(µg/

kg/w

eek)

0.4

0.3

0.2

0

1

Time (months)

3 5 7 9 11 13 15 17 21 23 25 27 29 31

0.1 Q2W (n = 154)

QM (n = 142)

19

Number of subjects at risk:

Q2W:

QM: 154 154 153 153 154 154 151 153 153 150 154 153 154 151 153153

142 141 142 141 141 139 142 141 140 140 141 142 139 137 139142

Data are presented as geometric mean ± 95% confidence interval.


Similar safety outcomes were reported with Q2W and QM dosing regimens

Darbepoetin alfa

Full Analysis Set

Q2W(N = 175)

n (%)

QM(N = 180)

n (%)

Total(N = 355)

n (%)

All treatment emergent adverse events 129 (73.7) 126 (70.0) 255 (71.8)

Serious adverse events 52 (29.7) 54 (30.0) 106 (29.9)

Leading to discontinuation of investigational product 10 (5.7) 7 (3.9) 17 (4.8)

Serious 7 (4.0) 4 (2.2) 11 (3.1)

Non-serious 4 (2.3) 3 (1.7) 7 (2.0)

Leading to discontinuation from study 7 (4.0) 2 (1.1) 9 (2.5)

Serious 6 (3.4) 1 (0.6) 7 (2.0)

Non-serious 1 (0.6) 1 (0.6) 2 (0.6)

Fatal adverse events 7 (4.0) 5 (2.8) 12 (3.4)

Events of interest 81 (46.3) 76 (42.2) 157 (44.2)



SureClick™ improved self-administration, perceived competence and satisfaction in non-dialysed CKD patients

Bonafont et al. Nefrologia 2013;33:214-22.

p<0.001 24% increase

Baseline(n = 132)

Last visit(n = 126)

0

10

20

30

40

50

60

70

80

47.7

74.2

Self-administration

% o

f p

atie

nts

Baseline(n = 132)

Last visit(n = 126)

0

4

8

12

16

20

24

28

32

36

25.5

31.6

Satisfaction

Sco

re (

scal

e o

f 0

-36)

Baseline(n = 132)

Last visit(n =126)

1

2

3

4

5

6

7

4.3

5.6

Perceived compe-tence

Sco

re

(sca

le o

f 1

-7)

30% increasep<0.0001

p<0.0001

Security and convenience with needle-stick prevention

Needle-stick injuries affect more than 3 million health-care workers every year, putting them at serious risk of acquiring a blood-borne pathogen1

Using needle-stick prevention devices has been shown to reduce needle-stick injuries by 83%2

SureClick™ improves self-administration, perceived competence and satisfaction in non-dialysed CKD patients3

1Prüss-Ustün et al. Am J Ind Med. 2005;48:482–902http://www.thebody.com/content/art5949.html3Bonafont et al. Nefrologia 2010;30(Suppl1):55

Module 2 –Achieving and maintaining the Hb target with darbepoetin alfa

In patients on haemodialysis

Extended dosing of darbepoetin alfa was effective in CKD patients on haemodialysis

Reference Study descriptionTreatment + evaluation

period


Primaryend point

Tolman et al.J Am Soc Nephrol 2005;16:1463–70

N = 162TIW EB

→ QW DA / QW EB9 months 11–12

Study drug doseat 9 months

Mann et al.Clin Nephrol 2007;67:140–8

N = 5520 (pooled)QW EA / EB→ Q2W DA

24 weeks 10–13 Change in Hb between baseline and evaluation

Carrera et al.Nephrol Dial Transplant 2006;21:2846–50

N = 105QW DA IV

→ Q2W DA IV12 months 11–13

Change in Hb between the switch from QW to

Q2W DA

Rottembourg et al.Clin Nephrol2011;75(3):242-50

N = 6104Epoetin a, b, DA, no

ESA → Q2W DA12 months

11–13*10–12+

Hb concentration 12 months after initiation of

DA Q2W

BIW = twice a week. CKD = chronic kidney disease. EB = epoetin beta. Hb = haemoglobin. QW = once a week. Q2W = every other week. TIW = three times a week. IV = intravenous.*Before 2008+After 2008

20% dose decrease after switching from SC epoetin beta TIW to SC DA QW

• Epoetin beta SC doses increased by 24% after switching from TIW to QW dosing

µg/kg/wk IU/kg/wk

Mea

n H

b c

on

cen

trat

ion

(g

/dl,

95%

CI)

Tolman et al. J Am Soc Nephrol 2005;16:1463–70

1.2

1.0

0.8

0.6

0.4

Mea

n w

eek

ly t

reat

men

t d

ose

240

200

160

120

80

0.0

9.0

10.0

11.0

12.0

13.0

0 1 2 3 4 5 6 7 8 9

Months

Hb

Dose

Epoetin beta (EB) Darbepoetin alfa

N=81

SC = subcutaneous

Q2W darbepoetin alfa treatment maintained Hb values with no change in the mean dose

• Hb values and darbepoetin alfa dosages remained stable over time, independent of the route of administration

Mann et al. Clin Nephrol 2007;67:140–8

Study week

Mea

n b

loo

d H

b v

alu

e (

g/d

l) (

±SD

)

Mea

n w

eek

ly d

osa

ge

(μg

/kg

/wk)

(±S

D)

6

7

8

9

10

11

12

13

14

-2 0 2 4 6 8 10 12 14 16 18 20 22 240

0.4

0.8

1.2

1.6

2.0

Hb

Dose

Hb-IV Hb-SC

Dose-IV Dose-SC

N = 1088*

* Patients who received at least one dose of DAIV = intravenous

Mean Hb concentration and DA dose remained stable after switch to Q2W DA

Carrera et al. Nephrol Dial Transplant 2006;21:2846–50

• The median weekly dose of DA was 30 µg at baseline, at the end of treatment period 1 (TP1), and at the end of treatment period 2 (TP2)

Baseline End of TP1 (QW)(n = 90)

End of TP2 (Q2W)(n = 80)

0

2

4

6

8

10

12

1411.75 11.79 11.7

Mea

n H

b (

d/d

L)

Months before / after Conversion

Mea

n H

b (

g/d

L)

Hb Dose

Wee

kly

do

se

(µg

/wk)

9.0

9.5

10.0

10.5

11.0

11.5

12.0

12.5

13.0

-6 -5 -4 -3 -2 -1 P C 1 2 3 4 5 6 7 8 9 10 11 12

5

10

15

20

25

30

35

40

45

n= 3500 4029 4363 4522 4589 4632 - 5195 4610 4756 4622 4591 4531 4430 4300 4381 4271 4131 4132 3822

n= 4182 4450 4630 4802 4923 5007 5000 5318 5314 5281 5231 5165 5071 4991 4881 4797 4710 4604 4488 4365

Adapted from: Rottembourg et al. Clin Nephrol 2011;75:242–50.

Hb = haemoglobin. DA = darbepoetin alfa. HD = haemodialysis. P = Prior to Conversion, C = At Conversion.200: 1 conversion ratio

Hb and weekly ESA dose remained stable after switch to darbepoetin alfa Q2W in HD patients

Months before / after Conversion

Hb Dose

Wee

kly

d

ose

(µ

g/w

k)

Mea

n H

b (

g/d

L)

9.0

9.5

10.0

10.5

11.0

11.5

12.0

12.5

13.0

-6 -5 -4 -3 -2 -1 P C 1 2 3 4 5 6 7 8 9 10 11 12

5

10

15

20

25

30

35

40

45

n= 362 441 489 529 520 504 - 702 541 530 542 520 511 510 492 506 489 471 481 426

n= 487 534 567 604 646 655 654 741 741 738 730 721 711 700 692 676 660 644 631 612

Hb = haemoglobin. DA = darbepoetin alfa. PD = peritoneal dialysis. P = Prior to Conversion, C = At Conversion.200: 1 conversion ratio

Adapted from: Rottembourg et al. Clin Nephrol 2011;75:242–50.

Hb remained stable and weekly ESA dose decreased after switch to darbepoetin alfa Q2W in PD patients

Module 2 –Achieving and maintaining the Hb target with darbepoetin alfa

In paediatric patients with chronic renal failure

Reference Study description* Treatment period


Primaryend point

André et al.Pediatr Nephrol 2007;22:708–14

N = 39 (11–18 yrs)

• ESA naive QW DA**

• BIW/TIW rHuEPO QW DA***

• QW rHuEPO Q2W DA***

6 months 11–13(g/dl)

Mean dose of DA to achieve and maintain Hb levels of 11–13 g/dl

Warady et al.Pediatr Nephrol 2006;21:1144–52

N = 124 (1–18 yrs)• BIW/TIW rHuEPO BIW/TIW

rHuEPO• BIW/TIW rHuEPO QW DA• QW rHuEPO Q2W DA

28 weeks 10–12.5 (g/dl)

Comparing the efficacy of DA with that of rHuEpo

Darbepoetin alfa was studied in paediatric patients with chronic renal failure (CRF)

BIW = twice a week. DA = darbepoetin alfa. ESA, = erythropoiesis-stimulating agents. Hb = haemoglobin. QW = once a week. Q2W = every other week. rHuEPO = recombinant human erythropoietin. TIW = three times a week Dose conversion ratio: 100 (200) IU rHuEPO 0.42 (1) µg DADA doses were determined based on the cumulative rHuEpo dose during the previous 1-week or 2-week periods

* Open label studies** Not on dialysis *** 79.3% on dialysis

In paediatric CRF patients switched to DA, the Hb level increased by month 3 and stabilised by month 6

André et al. Pediatr Nephrol 2007;22:708–14

*Patients between 11 and 18 years of ageCRF = Chronic Renal Failure

Do

se (

µg

/kg

/wee

k)

Hb (g/dl) DA dose (µg/kg/week)

Naive patients* (n = 10)

0.5

1.0

1.5

MonthsD

ose

(µ

g/k

g/w

eek)

08

10

12

14

Hb

(g

/dl)

0 1 2 3 4 5 6

Mean and SD

Switched patients* (n = 29)

0

0.5

1.0

1.5

8

10

12

14

Hb

(g

/dl)

0 1 2 3 4 5 6

Months

Mean and SD

In paediatric CKD patients switched to DA, Hb concentrations remained stable

Warady et al. Pediatr Nephrol 2006;21:1144–52

∆Hb: Mean change (SE)

∆Hb (rHuEPO): −0.16 (0.31) g/dl

∆Hb (DA): 0.15 (0.23) g/dl

Study week

Mea

n H

b (

g/d

l)

12.0

11.5

11.0

10.5

5 10 15 20 25 End of studyBaseline

n = 59

n = 27

Hb change between baseline and evaluation period

Incidence of injection site pain was similar with rHuEPO and darbepoetin alfa

Warady et al. Pediatr Nephrol 2006;21:1144–52

Darbepoetin alfa(n = 81)

rHuEPO(n = 42)

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

11.1 11.9

Inci

den

t o

f In

ject

ion

pai

n (

%)

Label extension for darbepoetin alfa –Paediatric patients with chronic renal failure

Hb target: 10–12 g/dl Avoid sustained Hb >12 g/dl

Treatment of symptomatic anaemia

Restrictive dose titration

Lowest darbepoetin dose should be used

For patients aged between 11 and 18 yearsTreatment of patients younger than 1 year of age has not been studied

Aranesp SPC Feb 2012, available at: http://www.ema.europa.eu


Paediatric patients with chronic renal failure – Correction phase

If Hb >12 g/dl, consider dose reduction. If Hb continues to increase, reduce dose by ~25%. If after dose reduction Hb continues to increase, withhold

dose temporarily. Re-initiate with ~25% lower dose.

Hb increases <1 g/dlin four weeks dose: Dose increase ~25%

Hb increases >2 g/dl in four weeks dose:

Dose reduction ~25%

Hb not to exceed12 g/dl

Paediatric patients with chronic renal failure ≥11 yearsInitial dose: 0.45 μg/kg SC/IV QW

Patients not on dialysis: 0.75 μg/kg SC Q2W



Paediatric patients with chronic renal failure – Maintenance phase

Paediatric patients ≥ 11 years

Patients on dialysis:•QW / Q2W darbepoetin alfa•Q2W dose should be equivalent to

twice the previous QW dose

Patients not on dialysis: •Q2W QM darbepoetin alfa*•QM dose should be equivalent to

twice the previous Q2W dose

rHuEPO BIW/TIW darbepoetin alfa QW** rHuEPO QW darbepoetin alfa Q2W** Hb should be monitored every 1 or 2 weeks Same route of administration should be used

*Once the Hb target has been achieved**Dose of darbepoetin alfa (μg/week & μg/2 weeks) can be determined by dividing the total weekly dose of r-

HuEPO (IU/week) by 240



Summary: Patients achieved and maintained Hb targets with darbepoetin alfa

Patients not on dialysis• Q2W dosing of darbepoetin alfa successfully achieves Hb targets in ESA-

naive patients and effectively maintained it when patients were switched from rHuEPO to Q2W DA1-4

• QM DA is safe and effective in CKD patients by maintaining the target Hb levels in over 70–85% of the patients with a stable dose requirement4-7

• Use of SureclickTM improves convenience and satisfaction for patients and offers benefits to the health-care professionals by reducing the risk of needle-stick injuries8-10

Patients on haemodialysis• Switch from rHuEPO (TIW/BW/QW) to less frequent dosing with SC or IV

darbepoetin alfa (QW/Q2W) is effective in maintaining Hb levels11-14

Children are able to maintain target Hb levels at extended dosing intervals while receiving darbepoetin alfa15-16

1Suranyi et al. Am J Nephrol 2003;23:106–11. 2Toto et al. Am J Nephrol 2004;24:453–60. 3Hertel et al. Am J Nephrol 2006;26:149–56.4Galle et al. Nephrol Dial Transplant 2012;27:2303-2311. 5Agarwal et al. J Intern Med 2006;260:577–85. 6Disney et al. Nephrology 2007;12:95–101.7Ling et al. Clin Nephrol 2005;63:327–34. 8http://www.thebody.com/content/art5949.html. 9Hoggard et al. Curr Med Res Opin 2006;22:2023–30.10Bonafont et al. Nefrologia 2010;30(Suppl1):55. 11Tolman et al. J Am Soc Nephrol 2005;16:1463–70. 12Mann et al. Clin Nephrol 2007;67:140–8. 13Carrera et al. Nephrol Dial Transplant 2006;21:2846–50. 14Rottembourg et al. Clin Nephrol 2011;75(3):242–50.15André et al. Pediatr Nephrol 2007;22:708–14. 16Warady et al. Pediatr Nephrol 2006;21:1144–52.

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