Key Learnings in Iron Deficiency Anemia and Venofer^® (iron sucrose injection, USP)

Normal Iron Physiology
Iron is essential for many vital functions in the human body. While virtually all cells require iron, too much iron can be detrimental to cells and tissues. Most of the body's iron supply is found in red blood cells (RBCs), myoglobin, and respiratory enzymes within cells, and it is classified as functional iron. The remainder of the body's iron is stored in reticuloendothelial cells as ferritin and hemosiderin. The iron that is bound to transferrin is the source of iron for developing erythroid cells in the bone marrow.

The amount of iron absorbed varies—it depends on the amount ingested, its form (heme versus nonheme), the presence of iron absorption enhancers and inhibitors, and current iron requirements of the body. Plasma iron levels can be affected rapidly and profoundly when the demand for RBC production increases. The rate of iron mobilization from storage will not support RBC production more than 3 times greater than normal. If additional iron is needed, iron deficiency develops; hemoglobin (Hb) and tissue iron stores fall.

Approximately 0.8% of RBCs turn over each day. Most of the iron (95%) in adult men required to produce new RBCs comes from the destruction of senescent RBCs through what is essentially a highly effective recycling process.

Iron Deficiency
Significant long-term blood loss from any cause will deplete iron stores, thereby increasing iron needs beyond what can be absorbed from the diet. Anemia is any condition in which the blood contains quantities of RBCs and Hb that are below normal ranges.

Specialized cells in the kidney produce erythropoietin, which is a protein that enhances erythropoiesis. Iron supply and epoetin stimulation of erythroid cells must be balanced. If the supply of iron is inadequate to meet erythroid cell demands, blood levels of Hb and RBCs decrease. This condition is called iron deficiency anemia. In patients with chronic kidney disease, anemia develops principally as a result of inadequate production of erythropoietin. In addition, blood loss related to hemodialysis occurs mainly due to blood retention in the dialyzer and blood lines, frequent blood sampling, and blood loss associated with venous access. Anemia in patients with end-stage renal disease (ESRD) is associated with a deficient production of erythropoietin.

In 1989, epoetin became available to treat ESRD-associated anemia and has improved the quality of life in patients with ESRD by increasing their energy and exercise tolerance, reducing fatigue, increasing appetite, and reducing the need for blood transfusions.

Epoetin treatment can lead to functional iron deficiency:

• Administration of epoetin leads to dramatic increases in RBC production
• Administration of epoetin also increases iron uptake by erythroid cells. Reticuloendothelial cells are unable to release stores of iron fast enough to accommodate the stepped-up RBC production. Despite adequate levels of stored iron, insufficient iron is available for the RBC production stimulated by epoetin
• These circumstances lead to the development of iron deficiency erythropoiesis. The RBCs produced are small and have a low Hb content and a high concentration of protoporphyrin. Another consequence of functional iron deficiency is a poor response to epoetin therapy

The 2 tests most commonly used to diagnose iron deficiency are serum ferritin and transferrin saturation (TSAT). Target iron levels established by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) are TSAT ≥20% and serum ferritin ≥100 ng/mL. The target Hb level is 11 to 12 g/dL, and the target hematocrit (HCT) level is 33% to 36%.

Kidney Function and Chronic Kidney Disease
The kidneys represent the main organs of excretion in the body, removing wastes and extra water from the blood, which would otherwise build up in the body and cause damage.  There are approximately 1 million nephrons in each kidney. Nephrons perform the functions of filtration, reabsorption, and secretion.  The most common diseases affecting kidney function are diabetes and hypertension.

Dial ysis is a form of renal replacement therapy.  This process cleans and filters the blood, removing harmful wastes and excess salt and fluids by passing blood across a semipermeable membrane.

Treatment for ESRD is expensive, but the federal government helps pay for the majority of the cost.

Management of Iron Deficiency Anemia in Patients With Chronic Kidney

An Hb level >10 g/dL and/or an HCT level >30% are associated with increased survival of patients undergoing dialysis, decreased cardiac complications, improved quality of life, and increased exercise capacity. Iron supplementation may improve the response to epoetin therapy and/or decrease the dose required to achieve Hb/HCT target levels. Monitoring iron status and administering supplemental iron as needed during treatment is necessary to provide sufficient iron to meet the demands of increased RBC production. After the target Hb/HCT levels are attained, long-term maintenance therapy is required to maintain a safe, stable iron level.

Despite the widespread use of epoetin, anemia continues to be observed in many patients with ESRD. Many of these patients with ESRD are also iron deficient. However, several FDA-approved products are available, including oral and IV iron preparations. Noncompliance with oral iron therapy should be considered. Factors contributing to this noncompliance include gastrointestinal side effects, inconvenience (must be taken 3 to 4 times daily), and nonreimbursed costs. More than 25% of patients taking three to four 325-mg oral iron tablets daily experience gastrointestinal distress. The NKF-K/DOQI guidelines recommend a trial of oral iron but also note that oral iron is frequently ineffective in attaining target Hb/HCT levels in hemodialysis patients with iron deficiency.

Venofer^® for Safety, Speed, and Versatility
Venofer^® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in non-dialysis dependent - chronic kidney disease (NDD-CKD) patients receiving or not receiving an erythropoietin and in hemodialysis dependent (HDD-CKD) and peritoneal dialysis dependent (PDD-CKD) chronic kidney disease patients receiving an erythropoietin. Venofer^® treatment results in significant increases (p<.05) in^1,2:

• Hb
• HCT
• TSAT
• Serum ferritin
• Mean corpuscular volume (MCV)
• Mean corpuscular hemoglobin (MCH)
• Serum iron

Venofer^® treatment also results in a significant decrease (p<.05) in total iron-binding capacity. Even patients with severe reactions to iron dextran and other IV irons have been shown to respond safely to Venofer^®.^1,2

Venofer^®, the number one prescribed IV iron, supports treatment safety and versatility with all of these features:

• Over 50 years of worldwide clinical experience
• Safety and efficacy confirmed in US clinical trials in hemodialysis and peritoneal dialysis dependent - CKD patients and non-dialysis dependent - CKD patients^1-4
• No test dose required
• No bolded or black box warnings
• Recommended Dose:
  • NDD-CKD - Administration of total cumulative dose (1,000 mg)
    • 200 mg slow IV injection over 2 - 5 minutes within a 14 day period*
  • HDD-CKD - Administration of total cumulative dose (1,000 mg) over consecutive hemodialysis sessions
    • 100 mg slow IV injection over 2 - 5 minutes,or
    • 100 mg in 100 mL 0.9% NaCl as an IV infusion over at least 15 minutes
  • PDD-CKD - Administration of a total cumulative dose (1,000 mg) in 3 divided doses within a 28 day period
    • 2 infusions of 300 mg each (diluted in 250 mL of 0.9% NaCl) over 1.5 hours on days 1 and 14 followed by:
    • 1 infusion of 400 mg (diluted in 250 mL of 0.9% NaCl) over 2.5 hours 14 days later
• Dextran free
• Preservative free
• Available in convenient single-dose vials
• Nondialyzable⁴
  
• A reimbursement hotline (800-282-7712) and Patient Assistance Program

* There is limited experience with administration of an infusion of 500 mg of Venofer in 250 mL 0.9% NaCl over 3.5-4 hours;  hypotension occurred in 2 of 30 patients treated.

 



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. Data on file. American Regent, Inc, Shirley, NY.
2. 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.
3. 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. Am J Kidney Dis. 2001;37:300-307.
4. Venofer^® [package insert]. Shirley, NY: American Regent, Inc; 2007.