Mechanism Of Action
Venofer is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous
administration, Venofer is dissociated into iron and sucrose and the iron is transported as a complex
with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells is
incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, Venofer is dissociated into iron and sucrose. In 22 patients
undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy
treated with iron sucrose containing 100 mg of iron, three times weekly for three weeks, significant
increases in serum iron and serum ferritin and significant decreases in total iron binding capacity
occurred four weeks from the initiation of iron sucrose treatment.
In healthy adults administered intravenous doses of Venofer, its iron component exhibited first order
kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume
of distribution of 7.9 L. The iron component appeared to distribute mainly in blood and to some extent
in extravascular fluid. A study evaluating Venofer containing 100 mg of iron labeled with 52Fe/59Fe in
patients with iron deficiency showed that a significant amount of the administered iron is distributed to
the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trapping
Following intravenous administration of Venofer, iron sucrose is dissociated into iron and sucrose. The
sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single
intravenous dose of Venofer containing 1,510 mg of sucrose and 100 mg of iron in 12 healthy adults (9
female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in
24 h. Some iron was also eliminated in the urine. Neither transferrin nor transferrin receptor levels
changed immediately after the dose administration. In this study and another study evaluating a single
intravenous dose of iron sucrose containing 500 to 700 mg of iron in 26 patients with anemia on
erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the iron was
eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics
of Venofer have not been studied.
Pharmacokinetics In Pediatric Patients
In a single-dose PK study of Venofer, patients with NDD-CDK ages 12 to 16 (N=11) received
intravenous bolus doses of Venofer at 7 mg/kg (maximum 200 mg) administered over 5 minutes.
Following single dose Venofer, the half-life of total serum iron was 8 hours. The mean Cmax and AUC
values were 8545 μg/dL and 31305 hr•μg/dL, respectively, which were 1.42- and 1.67-fold higher than
dose adjusted adult Cmax and AUC values.
Venofer is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux
dialysis membranes. In in vitro studies, the amount of iron sucrose in the dialysate fluid was below the
levels of detection of the assay (less than 2 parts per million).
Clinical Studies Overview
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients
were conducted to assess the safety and efficacy of Venofer.
Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD
(77 patients with Venofer treatment and 24 in the historical control group) with iron deficiency anemia.
Eligibility criteria for Venofer treatment included patients undergoing chronic hemodialysis, receiving
erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum
ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years.
Of the 77 patients, 44 (57%) were male and 33 (43%) were female.
Venofer 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow
infusion. The historical control population consisted of 24 patients with similar ferritin levels as
patients treated with Venofer, who were off intravenous iron for at least 2 weeks and who had received
erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry.
The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80
years. Patient age and serum ferritin level were similar between treatment and historical control
Patients in the Venofer treated population showed a greater increase in hemoglobin and hematocrit than
did patients in the historical control population. See Table 2.
Table 2. Changes from Baseline in Hemoglobin and Hematocrit
||End of treatment
||2 week follow-up
||5 week follow-up
||1.0 ± 0.12**
||0.0 ± 0.21
||1.3 ± 0.14**
||-0.6 ± 0.24
||1.2 ± 0.17*
||-0.1 ± 0.23
||3.1 ± 0.37**
||-0.3 ± 0.65
||3.6 ± 0.44**
||-1.2 ± 0.76
||3.3 ± 0.54
||0.2 ± 0.86
|**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and
erythropoietin dose as covariates.
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3
± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin
saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ±
1.6%) compared to this historical control population (-5.1 ± 4.3%).
Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Study B was a multicenter, open label study of Venofer in 23 patients with iron deficiency and HDDCKD
who had been discontinued from iron dextran due to intolerance. Eligibility criteria were
otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages
ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13
(56%) were female.
All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL),
hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%)
were observed from baseline to end of treatment.
Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients
with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL,
who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients
enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated
for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the
patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A
and B. Venofer was administered in doses of 100 mg during sequential dialysis sessions until a predetermined
(calculated) total dose of iron was administered. A 50 mg dose (2.5 mL) was given to
patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving
erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for
the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in
mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin
saturation (14%) were observed at week 2 of the observation period and these values remained
increased at week 4 of the observation period.
Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy
of oral iron versus Venofer in patients with NDD-CKD with or without erythropoietin therapy.
Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with
NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were
randomized to receive oral iron (325 mg ferrous sulfate three times daily for 56 days); or Venofer
(either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day
14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Venofer group
was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral
A statistically significantly greater proportion of Venofer subjects (35/79; 44.3%) compared to oral iron
subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at any time during the study (p = 0.03).
Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving
an erythropoietin and intravenous iron to patients with PDD-CKD receiving an erythropoietin alone
without iron supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin
of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no iron or
Venofer (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9%
NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Venofer /
erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46
patients in the erythropoietin alone group.
Patients in the Venofer / erythropoietin group had statistically significantly greater mean change from
baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin
alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Venofer / erythropoietin (59.1
%) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects
who received erythropoietin only (33.3%).
Study F: Iron Maintenance Treatment Dosing In Pediatric Patients Ages 2 Years And Older
With Chronic Kidney Disease
Study F was a randomized, open-label, dose-ranging study for iron maintenance treatment in pediatric
patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The
study randomized patients to one of three doses of Venofer (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The
mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three
groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and
25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12
g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD
received Venofer once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received
Venofer once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin
dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL
during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Venofer 0.5 mg/kg, 1.0
mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.