Clinical pharmacology

• Physical description and chemical formula
Venofer® (iron sucrose injection, USP) is a brown, sterile, aqueous complex of
polynuclear iron (III) hydroxide in sucrose, containing 20 mg elemental iron per mL.
The sterile solution has an osmolarity of 1250 mOsmol/L. The product does not
contain preservatives.
Molecular Formula: [Na2Fe5O8(OH) · 3(H2O)]n · m(C12H22O11)
Molecular Weight: Approximately 34,000 – 60,000 daltons
Description: Iron sucrose is a brown, aqueous solution
with a pH of 10.5–11.1
• Mechanism of action
Venofer® is used to replenish body iron stores in patients with iron deficiency
anemia in non-dialysis dependent-CKD patients receiving or not receiving an erythropoietin,
and in hemodialysis and peritoneal dialysis dependent-CKD patients
receiving an erythropoietin. Iron is essential to the formation of hemoglobin and to
the function and formation of other heme and nonheme compounds. Untreated
depletion of iron stores leads to iron-deficient erythropoiesis and, in turn, to iron
deficiency anemia. Administration of Venofer® replenishes tissue iron stores, reverses
iron depletion and iron-deficient erythropoiesis, and corrects or prevents iron
deficiency anemia.
Following intravenous administration, Venofer® is dissociated into iron and sucrose
by the reticuloendothelial system, and iron is transferred from the blood to a pool of
iron in the liver and bone marrow. Ferritin, an iron storage protein, binds and
sequesters iron in a nontoxic form, from which iron is easily available. Iron binds to
plasma transferrin, which carries iron within the plasma and the extracellular fluid to
supply the tissues. The transferrin receptor, located in the cell membrane, binds the
transferrin iron complex, which is then internalized in vesicles. Iron is released within
the cell, and the transferrin-receptor complex is returned to the cell membrane.
Transferrin without iron (apotransferrin) is then released to the plasma. The intracellular
iron becomes (mostly) hemoglobin in circulating red blood cells (RBCs).
Transferrin synthesis is increased and ferritin production reduced in iron deficiency.
The converse is true when iron is plentiful.
9
The stability of Venofer® (iron sucrose injection, USP) allows a competitive
exchange of iron between iron sucrose and selective iron-binding proteins such as
transferrin and ferritin. Pharmacokinetic parameters show that the administered iron
disappears very rapidly from the serum, insuring a rapid correction of iron deficiency
anemia.130
• Pharmacokinetics130-135
In healthy adults treated with intravenous doses of Venofer®, its iron component
exhibits first-order kinetics:
– Elimination T1/2 6 hours
– Total clearance 1.2 Liters per hour
– Non–steady–state apparent volume of distribution 10.0 Liters
– Steady–state apparent volume of distribution 7.9 Liters
Since iron disappearance from the serum depends on the need for iron in the iron
stores and iron-utilizing tissues of the body, serum clearance of iron is expected to
be more rapid in iron-deficient patients treated with Venofer® as compared with
healthy individuals.
Distribution
In healthy adults, the iron component of Venofer® appears to distribute mainly in the
blood and to some extent in extravascular fluid.
Metabolism
Iron sucrose is dissociated into iron and sucrose by the reticuloendothelial system.
Elimination
The sucrose component is eliminated mainly by urinary excretion. Some iron is
also eliminated in the urine (approximately 5%).
• Ferrokinetics132
Following a single dose of 100 mg iron, iron uptake in bone marrow, liver, and
spleen is rapid, followed by emergence of injected iron in circulating RBCs. Total
RBC uptake accounts for 68% to 97% of injected iron within 2–4 weeks.
10
• Adverse reactions1
The safety of Venofer® (iron sucrose injection, USP) has been documented in six
randomized clinical trials involving 231 hemodialysis dependent; 139 non-dialysis
dependent; 75 peritoneal dialysis dependent patients; and two post-marketing safety
studies in 1,051 hemodialysis patients for a total of 1,496 patients. Please refer
to the Venofer® product package insert for a complete list of adverse events.
• Hemodialysis Studies11-13
In three clinical safety and efficacy trials (231 patients), several patients experienced
pruritus and one patient experienced a facial rash. No patients experienced
generalized rashes or urticaria. None of these reactions led to treatment discontinuation.
No serious or life-threatening anaphylactoid reaction was observed in the
three clinical efficacy trials11-13.
Adverse reactions, whether or not related to Venofer® administration, reported by
>5% of the 231 treated patients in the above three hemodialysis studies are as follows:
hypotension, muscle cramps, nausea, headache, graft complications, vomiting,
dizziness, hypertension, chest pain, and diarrhea. Some of these symptoms
may be seen in hemodialysis patients not receiving intravenous iron.
• Non-Dialysis Dependent Chronic Kidney Disease Studies92,125
Adverse reactions, whether or not related to Venofer® administration, reported by
>5% of treated patients from a total of 139 patients in two clinical studies are as follows:
taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness,
hypertension, vomiting, arthralgia, back pain, headache, extremity pain, and
injection site burning.
• Peritoneal Dialysis Dependent - Chronic Kidney Disease Study1,124
Adverse reactions, whether or not related to Venofer® administration, reported by >
5% of treated patients from a total of 121 patients (75 Venofer® treated patients) are
as follows: diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis,
peripheral edema and nausea.
• Post Marketing Safety Studies
In the two post-marketing safety studies, 665 patients received multiple doses of
Venofer®, and 386 patients received a single dose of Venofer®. In the multiple dose
study, only serious adverse events and drug related non-serious events were
reported. Adverse events reported in >1% of 1,051 patients were congestive heart
failure (CHF), sepsis and taste disturbance.23,24.
11
• Important Safety Information
Venofer® (iron sucrose injection, USP) is contraindicated in patients with new evidence
of iron overload, in patients with known hypersensitivity to Venofer® or any of
its inactive components, and in patients with anemia not caused by iron deficiency.
Hypersensitivity reactions have been reported with IV iron products. Hypotension
has been reported frequently in hemodialysis dependent-CKD patients receiving IV
iron, and, has also been reported in non-dialysis dependent and peritoneal dialysis
dependent-CKD patients receiving IV iron. Hypotension following administration of
Venofer® may be related to rate of administration and total dose delivered.
In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the
most frequent adverse events (>5%), whether or not related to Venofer® administration,
were hypotension, cramps/leg cramps, nausea, headache, graft complications,
vomiting, dizziness, hypertension, chest pain and diarrhea. In post-marketing safety
studies in hemodialysis dependent-CKD patients (N=1051), the most frequent
adverse events reported (>1%) were congestive heart failure, sepsis and taste perversion.
In multi-dose efficacy studies in non-dialysis dependent-CKD patients
(N=91), the most frequent adverse events (>5%) whether or not related to Venofer®
administration, were taste disturbance, peripheral edema, diarrhea, constipation,
nausea, dizziness, and hypertension. In the study of peritoneal dialysis dependent-
CKD patients (N=75), the most frequent adverse events, whether or not related to
Venofer®, reported by >5% of these patients were diarrhea, peritoneal infection,
vomiting, hypertension, pharyngitis, peripheral edema and nausea.
• Drug interactions
As with all parenteral iron preparations, Venofer® should not be administered concomitantly
with oral iron preparations since the absorption of oral iron may be
reduced. In patients previously receiving oral iron therapy, administration of
Venofer® should prompt discontinuation of oral iron agents.1
Pregnancy Category B:
Teratology studies have been performed in rats and have revealed no evidence
of impaired fertility or harm to the fetus due to Venofer® (iron sucrose injection,
USP). There are, however, no adequate and well controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
12
Pediatric Use:
Safety and effectiveness of Venofer® (iron sucrose injection, USP) in pediatric
patients have not been established1. In a country where Venofer® is available for
use in children, at a single site, five premature infants (weight less than 1,250g)
developed necrotizing enterocolitis and two of the five expired during or following a
period when they received Venofer®, several other medications and erythropoietin.
Necrotizing enterocolitis may be a complication of prematurity in very low birth
weight infants. No causal relationship to Venofer® or any other drugs could be
established.
Geriatric Use:
The clinical efficacy studies of Venofer® did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Of the 1,051 patients in two post-marketing safety studies of Venofer®
40% were age 65 or older. No overall differences in safety were observed between
these subjects and younger subjects. Other reported clinical experience has not
identified differences in response between elderly and younger patients. However,
greater sensitivity of some older individuals cannot be ruled out.1