Since Venofer® (iron sucrose injection, USP) was first approved in Switzerland in
1950, a large body of evidence in the form of study reports and publications has
been produced that demonstrates the safety and efficacy of intravenous iron
sucrose. The evaluation of clinical safety and efficacy of Venofer® is based on
results from more than 100 studies3-124 involving more than 7,000 subjects. More
than 5,000 patients were treated with Venofer®. These studies demonstrate the
effectiveness of Venofer® in the treatment of iron deficiency anemia, alone and in
combination with an erythropoietin. The incidence of serious adverse reactions is
low. Based on use in an estimated 4.6 million patients that received Venofer®
worldwide between 1992 and August 2005, only 108 hypersensitivity reactions have
been reported, including serious or life threatening reactions2. Venofer® is well tolerated
in the vast majority of patients, including those with a history of hypersensitivity
reactions to iron dextran and other parenteral iron preparations. Venofer® is easy
to administer either as a slow injection or as an infusion. A test dose is not required,
however, some physicians used a test dose at their discretion in two U.S. pivotal trials
in HDD-CKD patients.
Review of selected clinical trials in Chronic Kidney Disease
Study A Hemodialysis Patients (Charytan et al,12 Van Wyck et al136)
Study A was a multicenter, open-label, historically controlled study in 101
hemodialysis patients (77 patients with Venofer® treatment and 24 in the historical
control group) with iron deficiency anemia. Eligibility for Venofer® treatment
included patients undergoing chronic hemodialysis three times weekly,
receiving erythropoietin, hemoglobin concentration greater than 8.0 and less
than 11.0 g/dL for at least two consecutive weeks, transferrin saturation <
20%, and serum ferritin < 300 ng/mL. The erythropoietin dose was to be
held constant throughout the study. The protocol did not require administration
of a test dose; however, some patients received a test dose at the physician’s
discretion. Exclusion criteria included significant underlying disease,
asthma, active inflammatory disease, or serious bacterial or viral infection.
Venofer® 5 mL (one vial) containing 100 mg of elemental iron was administered
through the dialysis line at each dialysis session either as a slow injection
or a saline-diluted slow infusion for a total of 10 dialysis sessions with a
cumulative dose of 1000 mg elemental iron. A maximum of 3 vials of
Venofer® was administered per week. No additional iron preparations were
allowed until after the day 57 evaluation. The mean change in hemoglobin
from baseline to day 24 (end of treatment), day 36, and day 57 was
assessed.
• Four of the 77 patients (5%) had six adverse events believed to be
related to Venofer®, including diarrhea (2 patients), abdominal pain,
nausea, constipation, and taste perversion.
• No hypersensitivity reactions were seen, including in any of 10 patients
who had shown previous intolerance/allergy to iron dextran injection, USP.
The historical control population consisted of 24 patients similar to patients
treated with Venofer® (iron sucrose injection, USP) 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.51 Patient age and serum ferritin level were similar between treatment
and historical control patients. The mean baseline hemoglobin and hematocrit
were higher, and the erythropoietin dose was lower in the historical control
population than in the Venofer®-treated population.
• Patients in the Venofer®-treated population showed a statistically
significantly greater increase in hemoglobin and hematocrit than
did patients in the historical control population.
– At the 2-week follow-up, patients in the Venofer®-treated population
showed a significantly (p<0.01) greater increase in hemoglobin
(1.3 g/dL) and hematocrit (3.6%) than did patients in the historical
control population (Hb, -0.6 g/dL, Hct, -1.2%).
– At the 5-week follow-up, Venofer®-treated patients showed a
significantly (p<0.05) greater increase in hemoglobin (1.2 g/dL)
than did patients in the historical control group (-0.1 g/dL).
– At the end of treatment, patients in the Venofer® -treated population
showed a significantly (p<0.01) greater increase in hemoglobin
(1.0 g/dL) and hematocrit (3.1%) than did patients in the historical
control group (Hb, -0.5 g/dL, Hct, -0.8%).
• Serum ferritin increased significantly (p=0.001) at endpoint of study from
baseline in the Venofer®-treated population (165.3 ng/mL) compared with
the historical control population (-27.6 ng/mL). Transferrin saturation also
increased significantly (p=0.0016) at endpoint of study from baseline in the
Venofer® treated population (8.8%) compared with the historical control
population (-5.1%).
The authors concluded that doses of 100 mg Venofer® (iron sucrose injection, USP)
given IV in 10 consecutive dialysis sessions for a total dose of 1,000 mg were effective
and safe in hemodialysis patients with iron deficiency anemia receiving supplemental
erythropoietin therapy and can be administered without a test dose.
Study B Hemodialysis Patients (Van Wyck et al13)
The safety and efficacy of Venofer® in hemodialysis patients who had
experienced intolerance to iron dextran were also examined in a singlearm,
two-period, open-label, multicenter study by Van Wyck et al. Sixteen
patients with Hb < 11g/dL and a history of mild reactions and 7 patients with
a history of severe anaphylactoid reactions to iron dextran were included.
Following an observation period, patients received 100 mg Venofer® either
by intravenous injection or infusion for 10 consecutive dialysis sessions over
3-4 weeks. A test dose was not required; however, some patients received a
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test dose at the physician’s discretion. Since the study was primarily a safety
study, efficacy assessments were limited to changes from baseline to day 24
(end of treatment evaluation).
• There were no serious hypersensitivity reactions, no serious adverse
drug reactions, and no patients discontinued from the study
due to adverse drug reactions.
• Three mild adverse events considered related or possibly related
to iron sucrose were reported in 2 patients:
– Taste perversion (metallic taste, 1 patient twice)
– Pruritus (1 patient)
• Concomitant use of ACE inhibitors was present in 12 of 23
patients (52%).
• Mean hemoglobin increased from 10.4 g/dL to 11.5 g/dL
at day 24 (p<0.05, increase 11.0%).
• Mean hematocrit increased from 32.8% to 36.4% at day
24 (p<0.05, increase of 11.0%).
• MCV, MCHC, serum iron, TSAT, and serum ferritin also
increased significantly, and total iron binding capacity (TIBC)
decreased significantly.
The authors concluded that Venofer® (iron sucrose injection, USP) is safe and
effective in the management of anemia in hemodialysis patients receiving
supplemental erythropoietin sensitive to iron dextran and can be administered without
a test dose by IV push or infusion.
Study C Hemodialysis Patients (Van Zyl-Smit et al11)
A safety and efficacy study of Venofer® or the combination of Venofer® and
erythropoietin was performed in an open, single-arm, two-period, multicenter
study by Van Zyl-Smit et al in South Africa. One hundred thirty-one patients
were enrolled. All suffered from hemodialysis-associated anemia, were
undergoing maintenance hemodialysis (2 to 3 sessions per week), had an
Hb < 10.0 g/dL, serum transferrin saturation < 20%, and serum ferritin < 200
ng/mL. A first dose of 50 mg of Venofer® was administered at the first
hemodialysis session, followed by doses of 100 mg of iron during dialysis
3 times weekly until an individually calculated dose, based upon baseline
hemoglobin, and body weight, was administered. Patients were then followed
for an additional 4 weeks, in a no-treatment observation period.
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The modified intent-to-treat population consisted of 130 patients. Mean
hematologic and iron parameters at baseline and following treatment with
Venofer® (iron sucrose injection, USP) are given below:
• Mean hemoglobin increased from 7.2 g/dL to 9.0 g/dL at
observation week two and 9.2 g/dL at observation week four
(p<0.0001, maximum increase of 28%).
• Mean hematocrit increased from 22.5% to 27.9% at observation
week two and 28.5% at observation week four (p<0.0001,
maximum increase of 27%).
• Mean serum ferritin increased from 65.1 ng/mL to 512.7 ng/mL at
observation week two and 440.2 ng/mL at observation week four
(p<0.0001, maximum increase of 687%).
• Mean serum transferrin saturation increased from 11.4% to
27.7% at observation week two and 27.6% at observation
week four (p<0.0001, maximum increase of 143%).
Adverse events (> 1%) that were reported to be possibly related to Venofer®
were hypotension (13%), nausea (3%), increased liver function test (2%),
pneumonia (2%), and vomiting (2%). Hypotension was also associated with
hemodialysis itself and occurred with similar frequency during the treatment
period and during the observation period when no iron was given.
The authors concluded that Venofer® was safe and effective in the treatment of
patients with hemodialysis-associated anemia.
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Study D - Non-Dialysis Dependent CKD Patients (VanWyck et al)123
The safety and efficacy of Venofer® (iron sucrose injection, USP) in non-dialysis CKD
patients was examined in a randomized, open-label multicenter, active-controlled
study by Van Wyck et al. 182 patients were treated with oral iron (N=91) or Venofer®
(N=91) with or without an erythropoietin. Erythropoietin therapy was stable for 8
weeks prior to randomization. Patients with an average baseline Hg <11 g/dL, TSAT
< 25%, and ferritin < 300 ng/mL were randomized to receive either oral iron (325 mg
ferrous sulfate TID for 56 days) or Venofer® (200 mg IV over 2-5 minutes 5 times within
14 days or 500 mg IV infusion over 3.5-4 hours on Day 1 and Day 14). Sixty-one
patients received 280 doses of 200 mg iron sucrose, and 30 patients received 58
doses of iron sucrose 500 mg.
• A statistically greater proportion of Venofer® treated patients (44.3%) compared
to oral iron patients (28%) had a clinically significant response as
defined as an increase in hemoglobin > 1 g/dL at any time during the study.
(p=0.03)
• The mean increase in hemoglobin at Day 42 was greater in the Venofer®
treated patients (0.7 g/dL) compared to oral iron patients (0.4g/dL)
(p=0.0298)
• A greater proportion of Venofer® treated patients (39.2%) compared to oral
iron patients (1.2%) had a clinically significant response defined as an
increase in hemoglobin > 1 g/dL, and ferritin > 160 ng/mL at any time during
the study.(p<0.0001)
• Patients in the oral iron group, but not the Venofer® group, showed a statistically
significant rise in serum creatinine at study day 56/end of study (0.2
mg/dL, p<0.0013)
• Non-compliance was more common in the oral iron treatment group.
• No serious adverse drug events were seen in patients administered Venofer®
200 mg IV over 2-5 minutes, but drug related hypotension, including one
event considered serious, occurred in 2 females weighing less than 65 kg
after 500 mg doses were given over 4 hours.
• Among non-serious ADEs reported, GI complaints were seen most frequently
in both treatment groups, but the nature of GI complaints differed between
groups. Transient taste disturbance was the most prominent GI complaint
associated with Venofer® administration. Constipation, diarrhea, nausea,
vomiting and dyspepsia were associated with oral iron therapy. Headache,
myalgia, and hypotension were also associated with Venofer® administration.
The authors concluded that Venofer® administration of 1000 mg in divided
doses is superior to oral iron therapy in the management of NDD-CKD patients
with anemia and low iron indices. Venofer® therapy was safe, well tolerated and
more effective than oral iron treatment.
Study E - Peritoneal Dialysis Dependent CKD Patients (Singh et al)1,124
The safety and efficacy of Venofer® (iron sucrose injection, USP) in peritoneal dialysis
dependent-CKD patients receiving an erythropoietin was examined in a multicenter,
randomized, controlled trial by Singh et al. 126 patients were treated with an erythropoietin
and Venofer® (N=75), or an erythropoietin alone without iron supplementation.
Erythropoietic therapy was unchanged for 8 weeks prior to randomization and during
the study period. Patients with Hg < 11.5 g/dL, TSAT < 25 %, and ferritin < 500
ng/mL were randomized to receive either no iron (n=46) or Venofer® (300 mg diluted
in 250 mL 0.9% NaCl over 1.5 hours on Days 1 and 15 and 400 mg diluted in 250 mL
0.9% NaCl over 2.5 hours on Day 29) (n=75).
• Patients in the Venofer®/erythropoietin group had a greater mean hemoglobin
change from baseline to the highest hemoglobin value (1.3 g/dL)
(p<0.01)
• A greater proportion of patients treated with Venofer®/erythropoietin (59.1%)
had an increase in hemoglobin of > 1 g/dL at any time during the study
compared to patients who received erythropoietin alone (33.3%) (p < 0.05)
• There were no serious adverse events after Venofer® administration at
either dose level. 8 patients experienced at least 1 non-serious adverse
event thought to be related to study drug with GI complaints seen most frequently.
The authors concluded that Venofer® is an effective adjunct to erythropoietic
therapy in anemic patients with PDD-CKD. Administration of Venofer® as an
IV infusion of 300 mg over 1.5 hours or 400 mg over 2.5 hours is well tolerated
and provides a practical approach to correcting iron deficiency anemia
and replenishing iron stores.
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