A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Ferrlecit Pharmacology, Pharmacokinetics, Studies, Metabolism - Sodium ferric gluconate
Ferrlecit Pharmacology, Pharmacokinetics, Studies, Metabolism - Sodium ferric gluconate
CLINICAL PHARMACOLOGY
Ferrlecit® is used to replete the total body content of
iron. Iron is critical for normal hemoglobin synthesis to maintain oxygen transport.
Additionally, iron is necessary for metabolism and synthesis of DNA and various
enzymatic processes.
The total body iron content of an adult ranges from 2 to 4
grams. Approximately 2/3 is in hemoglobin and 1/3 in reticuloendothelial storage
(bone marrow, spleen, liver) and ferritin. The body highly conserves iron (daily
loss of 0.03%) requiring supplementation of about 1 mg/day to replenish losses
in healthy, non-menstruating adults. The etiology of iron deficiency in hemodialysis
patients is varied and can include increased iron utilization (e.g., from erythropoietin
therapy), blood loss (e.g., from fistula, retention in dialyzer, hematologic
testing, menses), decreased dietary intake or absorption, surgery, iron sequestration
due to inflammatory process, and malignancy. The administration of exogenous
erythropoietin increases red blood cell production and iron utilization. The
increased iron utilization and blood losses in the hemodialysis patient may
lead to absolute or functional iron deficiency. Iron deficiency is absolute
when hematologic indicators of iron stores are low. Patients with functional
iron deficiency do not meet laboratory criteria for absolute iron deficiency
but demonstrate an increase in hemoglobin/ hematocrit or a decrease in erythropoietin
dosage with stable hemoglobin /hematocrit when parenteral iron is administered.
Pharmacokinetics
Human pharmacokinetic studies have not been performed with
Ferrlecit®. In vitro experiments have shown that less than 1% of the iron
species within Ferrlecit® Injection can be dialyzed through membranes with
pore sizes corresponding to 12,000 to 14,000 daltons over a period of up to
270 minutes. These studies were conducted with undiluted Ferrlecit®, and
with Ferrlecit® diluted in 0.9% saline or double distilled water.
CLINICAL STUDIES
Two clinical studies were conducted to assess the safety and
efficacy of Ferrlecit®.
Study A
Study A was a three-center, randomized, open-label study of
the safety and efficacy of two doses of Ferrlecit® administered intravenously
to iron-deficient hemodialysis patients. The study included both a dose-response
concurrent control and an historical control. Enrolled patients received a test
dose of Ferrlecit® (25 mg of elemental iron) and were then randomly assigned
to receive Ferrlecit® at cumulative doses of either 500mg (low dose) or
1000mg (high dose) of elemental iron. Ferrlecit® was given to both dose
groups in eight divided doses during sequential dialysis sessions (a period
of 16 to 17 days). At each dialysis session, patients in the low-dose group
received Ferrlecit® 62.5 mg of elemental iron over 30 minutes, and those
in the high-dose group received Ferrlecit® 125mg of elemental iron over
60 minutes. The primary endpoint was the change in hemoglobin from baseline
to the last available observation through Day 40.
Eligibility for this study included chronic hemodialysis patients
with a hemoglobin below 10 g/dl (or hematocrit at or below 30%) and either serum
ferritin below 200 ng/ml or iron saturation below 18%. Exclusion criteria included
significant underlying disease or inflammatory conditions or an erythropoietin
(EPO) requirement of greater than 10,000 units three times per week. Parenteral
iron and red cell transfusion were not allowed for two months before the study.
Oral iron and red cell transfusion were not allowed during the study for Ferrlecit®-treated
patients.
The historical control population consisted of 25 chronic hemodialysis
patients who received only oral iron supplementation for 14 months and did not
receive red cell transfusion. All patients had stable EPO doses and hematocrit
values for at least two months before initiation of oral iron therapy.
The evaluated population consisted of 39 patients in the low-dose
Ferrlecit® group, 44 patients in the high-dose Ferrlecit® group, and
25 historical control patients.
The mean baseline hemoglobin and hematocrit were similar between
treatment and historical control patients: 9.8 g/dl and 29% and 9.6 g/dl and
29% in low- and high-dose Ferrlecit® treated patients, respectively, and
9.4 g/dl and 29% in historical control patients. Baseline serum iron saturation
was 20% in the low-dose group, 16% in the high-dose group, and 14% in the historical
control. Baseline serum ferritin was 106 ng/ml in the low-dose group, 88 ng/ml
in the high-dose group, and 606 ng/ml in the historical control.
Patients in the high-dose Ferrlecit® group achieved significantly
higher increases in hemoglobin and hematocrit than either patients in the low-dose
Ferrlecit® group or patients in the historical control group (oral iron).
Patients in the low-dose Ferrlecit® group did not achieve significantly
higher increases in hemoglobin and hematocrit than patients receiving oral iron.
See Table 1.
TABLE 1 : Hemoglobin, Hematocrit, and Iron Studies
|
Study A
|
Mean Change from Baseline to Two Weeks After Cessation
of Therapy
|
|
Ferrlecit ® 1000 mg IV (N=44)
|
Ferrlecit ® 500 mg IV (N=39)
|
Historical Control-Oral Iron (N=25)
|
|
|
|
Hemoglobin
|
1.1 g/dl*
|
0.3 g/dl
|
0.4 g/dl
|
|
Hematocrit
|
3.6%*
|
1.4%
|
0.8%
|
|
Iron Saturation
|
8.5%
|
2.8%
|
6.1%
|
|
Serum Ferritin
|
199 ng/ml
|
132 ng/ml
|
NA
|
*p<0.01 versus both the 500mg group and the historical control
group
Study B
Study B was a single-center, non-randomized, open-label, historically-controlled,
study of the safety and efficacy of variable, cumulative doses of intravenous
Ferrlecit® in iron-deficient hemodialysis patients. Ferrlecit® administration
was identical to Study A. The primary efficacy variable was the change in hemoglobin
from baseline to the last available observation through Day 50.
Inclusion and exclusion criteria were identical to those of
Study A as was the historical control population. Sixty-three patients were
evaluated in this study: 38 in the Ferrlecit® treated group and 25 in the
historical control group.
Ferrlecit® treated patients were considered to have completed
the study per protocol if they received at least eight Ferrlecit® doses
of either 62.5mg or 125mg of elemental iron. A total of 14 patients (37%) completed
the study per protocol. Twelve (32%) Ferrlecit® treated patients received
less than eight doses, and 12 (32%) patients had incomplete information on the
sequence of dosing. Not all patients received Ferrlecit® at consecutive
dialysis sessions and many received oral iron during the study.
|
Cumulative Ferrlecit® Dose (mg of elemental iron)
|
62.5
|
250
|
375
|
562.5
|
625
|
750
|
1000
|
1125
|
1187.5
|
|
Patients (#)
|
1
|
1
|
2
|
1
|
10
|
4
|
12
|
6
|
1
|
Baseline hemoglobin and hematocrit values were similar between
the treatment and control groups, and were 9.1g/dl and 27.3% respectively, for
Ferrlecit® treated patients. Serum iron studies were also similar between
treatment and control groups, with the exception of serum ferritin, which was
606 ng/ml for historical control patients, compared to 77 ng/ml for Ferrlecit®
treated patients.
In this patient population, only the Ferrlecit® treated
group achieved significant increase in hemoglobin and hematocrit from baseline.
This increase was significantly greater than that seen in the historical oral
iron treatment group. See Table 2.
TABLE 2 : Hemoglobin, Hematocrit, and Iron Studies
|
Mean Change from Baseline to One Month After Treatment
|
| |
Ferrlecit® (N=38)
|
Oral Iron (N=25)
|
| |
change
|
change
|
|
Hemoglobin (g/dl)
|
1.3a,b
|
0.4
|
|
Hematocrit (%)
|
3.8a,b
|
0.2
|
|
Iron Saturation (%)
|
6.7b
|
1.7
|
|
Serum Ferritin(ng/ml)
|
73b
|
-145
|
a - p<0.05 on group comparison by the ANCOVA method b -
p<0.001 from baseline by the paired t-test method
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