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.

Mechanism of Action²
Venofer^® is used to replenish body iron stores in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) patients receiving or not receiving erythropoietin and in Hemodialysis Dependent (HDD-CKD) and Peritoneal Dialysis Dependent (PDD-CKD) - Chronic Kidney Disease 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.

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:

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
The safety of Venofer^® (iron sucrose injection, USP) has been documented in six randomized clinical trials involving 231 hemodialysis dependent - CKD patients, 75 peritoneal dialysis dependent - CKD patients, and 139 non-dialysis dependent - CKD 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.¹

Hemodialysis Studies^8-10
In three clinical efficacy trials (231 patients), several patients experienced pruritis 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 trials.

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.

Peritoneal Dialysis Dependent Chronic Kidney Disease Study¹¹
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.

Non-Dialysis Dependent Chronic Kidney Disease Studies^12-13
Adverse reactions, whether or not related to Venofer^® administration, reported by ≥ 5% of Venofer^® 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.

Post Marketing Safety Studies^14,15
In the two post-marketing safety studies, 665 hemodialysis patients received multiple doses of Venofer^®, and 386 hemodialysis 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 perversion.


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.  In a country where Venofer^® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) 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.¹

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 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 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.  


Please see Full Prescribing Information .



References

1. Venofer® [package insert]. Shirley, NY: American Regent, Inc.; 2007.
2. Danielson BG, Salmonson T, Derendorf H, et al. Pharmacokinetics of iron [III]-hydroxide complex after a single dose in healthy volunteers. Arzn-Forsch/Drug Res. 1996;46:615-621.
3. Beshara S, Lundqvist H, Sundin J, et al. Kinetic analysis of 52Fe labelled iron (III) hydroxide sucrose complex following bolus administration using positron emission tomography. Brit J Haematology. 1999;104:288-295.
4. Beshara S, Lundqvist H, Sundin J, et al. Pharmacokinetic analysis and red cell utilization of 52Fe/59Fe labelled iron (III) hydroxide sucrose complex following intravenous administration using positron emission tomography. Clinical study report, 1997 and data on file: American Regent, Inc., Shirley, NY.
5. Krzysko K, Bokowski W, Wichlinski LM. Pharmacokinetics of serum iron in humans. Zbl Pharm. 1984;123:598-599.
6. Anatkov A, Gekova K. The use of large intravenous doses of iron in the treatment of iron-deficiency anemia. Problems of Hematology and Blood Transfusions in Medicine and Physioculture. 1970;13:295-298.
7. Major A, Mathez-Loic F, Rohling R, et al. The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin. Brit J Haematology. 1997;98:292-294.
8. Van Zyl-Smit R, Moosa MR, Potgieter CD, Viljoen HG, Naicker S. A multicentre study to investigate the tolerance, safety and efficacy of intravenous iron sucrose in hemodialysis patients with anemia. Clinical study report, 1997 and data on file: American Regent, Inc., Shirley, NY. Abstract in Kidney International 1999; 55: 2130.
9. Charytan C, Levin N, Al-Saloum M, et al. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia: North American clinical trial. 1999 Am J Kidney Dis 2001; 37(2): 300-307.
10. Van Wyck DB, Cavallo G, Spinowitz BS, et al. Safety and efficacy of iron sucrose in patients sensitive to iron dextran: North American clinical trial. Am J Kidney Dis 2000; 36: 88-97.
11. Singh H, Reed J, Noble S.  Effect of iron therapy in peritoneal dialysis patients receiving erythropoiesis stimulating agents for anemia:  a randomized, controlled trial. (in press)
12. Charytan C, Quinibi W, Bailie W. Comparison of Intravenous Iron Sucrose to Oral Iron in the Treatment of Anemic Patients with Chronic Kidney Disease Not on Dialysis. Nephron Clinical Practice. 2005, Vol.100, c55-c62.
13. Van Wyck et al. A randomized controlled trial comparing IV iron sucrose to oral iron in anemic patients with non-dialysis dependent CKD. Kidney Int. 2005;68:2846-2856
14. Aronoff GR, Bennett WM, Blumenthal S, Charytan C, Pennell JP, Reed J, Rothstein M, Strom J, Wolf A, VanWyck D, Yee J. Iron sucrose in hemodialysis patients: Safety and efficacy of iron replacement and maintenance therapy. Kidney Int. 2004; 66:1193-1198
15. Rothstein M, Carvello A, Charytan C, Collins D. A randomized study to assess the safety and tolerability of 200 and 100mg of Venofer administered to hemodialysis patients. Data on File: American Regent, Inc. Shirley, NY [IVEN01015]