Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD) Receiving Erythropoetin
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Venofer treatment and 24 in the historical control group)
with iron deficiency anemia. Eligibility criteria for Venofer treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level
between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years.
Of the 77 patients, 44 (57%) were male and 33 (43%) were female. Venofer 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion.
The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Venofer, who were off intravenous iron for at least 2 weeks and
who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group
was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.
Venofer treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population.
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the
historical control population (-27.6 ± 9.5 ng/mL).Transferrin saturation increased at endpoint of study from baseline in the
Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).
Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) with Iron Dextran Intolerance
Study B was a multicenter, open label study of Venofer in 23 patients with iron deficiency and HDD-CKD who had been discontinued from iron dextran due
to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging
from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female. All 23 enrolled patients were
evaluated for efficacy.
Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.
Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin
saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the
patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study,
68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral iron. Exclusion
criteria were similar to those in studies A and B. Venofer was administered in doses of 100 mg during sequential dialysis sessions until
a pre-determined (calculated) total dose of iron was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study
entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the
same erythropoietin dose for the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin
(1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the
observation period and these values remained increased at week 4 of the observation period.
Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral iron versus Venofer in patients with
NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients
with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral iron (325 mg
ferrous sulfate three times daily for 56 days); or Venofer (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions
on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Venofer group was 61.6 years (range
25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral iron group.
A statistically significantly greater proportion of Venofer subjects (35/79; 44.3%) compared to oral iron subjects (23/82; 28%)
had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).
Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous
iron to patients with PDD-CKD receiving an erythropoietin alone without iron supplementation. Patients with PDD-CKD, stable erythropoietin
for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no iron or Venofer (300 mg in
250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated
patients in the Venofer / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients
in the erythropoietin alone group.
Patients in the Venofer / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin
value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated
with Venofer / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects
who received erythropoietin only (33.3%).
Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older
with Chronic Kidney Disease
Study F was a randomized, open-label, dose-ranging study for iron maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis dependent
CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Venofer (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was
13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients
underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33%
and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Venofer once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received
Venofer once every 4 weeks for 3 doses.
Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between
10.5 g/dL and 14.0 g/dL during the 12- week treatment period was 58.7%, 46.7%, and 45.0% in the Venofer 0.5 mg/kg, 1.0 mg/kg,
and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
Venofer® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease.
IMPORTANT SAFETY INFORMATION
Venofer® is contraindicated in patients with known hypersensitivity to Venofer.
WARNINGS AND PRECAUTIONS
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal,
have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of
consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer
immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least
30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and
therapies are immediately available for the treatment of serious hypersensitivity reactions.
Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion.
Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer.
Hypotension following administration of Venofer may be related to rate of administration and/or total dose delivered.
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis.
All adult and pediatric patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit,
serum ferritin and transferrin saturation). Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation (TSAT)
values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing.
The most common adverse reactions (≥2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness, hypotension,
pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain and peripheral edema. Additional adverse reactions
include infusion site pain or burning, graft complications, and nasopharyngitis, sinusitis, upper respiratory tract infections and pharyngitis.
In pediatric patients, more than 50% of the patients experienced at least one treatment-emergent reaction. The most common adverse reactions (≥2%)
were headache, respiratory tract viral infection, peritonitis, vomiting, pyrexia, dizziness, cough, renal transplant, nausea, arteriovenous fistula
thrombosis, hypotension and hypertension.
In post-marketing safety studies of Venofer in 1,051 patients with HDD-CKD, adverse reactions reported by > 1% were cardiac failure congestive, sepsis and dysgeusia.
Because adverse reactions from post-marketing experience are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure. In addition to potential serious hypersensitivity reactions, the following adverse
reactions have been identified during post-approval use of Venofer® (iron sucrose injection, USP): bronchospasm, dyspnea, convulsions, light-headedness, confusion,
angioedema, swelling of the joints, hyperhidrosis, bradycardia and chromaturia.
Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia,
abdominal and muscle pain, edema and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Venofer injection.
Reactions have occurred following the first dose or subsequent doses of Venofer. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
To report adverse events, please contact American Regent at 1-800-734-9236.
You may also contact the FDA at www.fda.gov/medwatch or 1-800-FDA-1088.
Please see Full Prescribing Information