Clinical Pharmacology¹

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 Action²
Venofer^® is used to replenish body iron stores in patients with iron deficiency on chronic hemodialysis who are receiving 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.

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.²

Pharmacokinetics^2-7
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 Venofer^® iron component 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%).

Dialyzability
Results of an in vitro study found that Venofer^® was not significantly removed by either high-efficiency or high-flux dialyzers.

Ferrokinetics⁴
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 to 4 weeks.

Adverse Reactions
Exposure to Venofer^® (iron sucrose injection, USP) has been documented in 231 hemodialysis patients in 3 efficacy studies and in 1051 hemodialysis patients in 2 postmarketing safety studies. The following adverse events, whether or not related to Venofer^® administration, reported by >5% of treated patients from a total of 231 patients in 3 efficacy studies, are as follows: hypotension (36%), cramps/leg cramps (23%), nausea, headache, vomiting, and diarrhea. Adverse events, whether or not related to Venofer^® (iron sucrose injection, USP) administration, reported by >1% of treated patients are as follows: headache, fever, pain, asthenia, unwell, malaise, accidental injury, hypotension, chest pain, hypertension, hypervolemia, nausea, vomiting, abdominal pain, elevated liver enzymes, dizziness, cramps/leg cramps, musculoskeletal pain, dyspnea, pneumonia, cough, pruritus, and application site reaction. Some of these symptoms may be seen in patients with chronic renal failure or on hemodialysis not receiving IV iron.

In the 3 efficacy studies (231 patients) and 2 postmarketing safety studies (1051 patients), several patients experienced mild to moderate hypersensitivity reactions, presenting with wheezing, dyspnea, hypotension, rashes, and pruritus. No serious or life-threatening hypersensitivity reactions associated with Venofer^® administration were observed in these studies.

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.⁸

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.

Pediatric Use:
Safety and effectiveness of Venofer^® in pediatric patients have not been established.

Geriatric Use:
Pivotal trials of Venofer^® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 1051 patients in 2 postmarketing safety studies of Venofer^®, 40% were 65 years or older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.¹

IMPORTANT SAFETY INFORMATION
Venofer^® (iron sucrose injection, USP) is contraindicated in patients with 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 injectable iron products. Hypotension has been reported frequently in patients receiving intravenous iron. Hypotension following administration of Venofer^® may be related to rate of administration and total dose delivered. In multidose efficacy studies (N=231), the most frequent adverse events, whether or not related to Venofer^® administration, were hypotension, cramps/leg cramps, nausea, headache, vomiting, and diarrhea. In postmarketing safety studies (N=1051), the most frequent adverse events reported (>1%) were congestive heart failure, sepsis, and taste perversion.
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