Iron Sucrose

Venofer is indicated for the treatment of iron deficiency anemia (IDA) in patients with chronic kidney disease (CKD). Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia (IDA) in patients with chronic kidney disease (CKD). ( 1 )

Injection: 50 mg/2.5 mL, 100 mg/5 mL, or 200 mg/10 mL (20 mg/mL) in single-dose vials. (3) Injection: 50 mg/2.5 mL, 100 mg/5 mL, or 200 mg/10 mL (20 mg/mL) in single-dose vials.

Known hypersensitivity to Venofer. Known hypersensitivity to Venofer ( 4 )

Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. ( 5.1 ) Hypotension: May cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration. ( 5.2 ) Iron Overload: Regularly monitor hematologic responses during therapy. Do not administer to patients with iron overload. ( 5.3 )

5.1 Hypersensitivity Reactions 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 [see Adverse Reactions ( 6.1 and 6.2 )].

5.2 Hypotension 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 the rate of administration and/or total dose administered [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.2 )].

5.3 Iron Overload 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 [see Dosage and Administration ( 2 ) and Overdosage ( 10 )].

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Hypotension [see Warnings and Precautions ( 5.2 )] Iron Overload [see Warnings and Precautions ( 5.3 )] Adult patients: The most common adverse reactions (≥2%) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. ( 6.1 ) Pediatric patients: The most common adverse reactions (≥2%) are headache, respiratory tract viral infection, peritonitis, vomiting, pyrexia, dizziness, cough, nausea, arteriovenous fistula thrombosis, hypotension, and hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. Adverse Reactions in Adults Patients with CKD The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks. Table 1. Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator * EPO=Erythropoietin Body System/Adverse Reactions HDD-CKD NDD-CKD PDD-CKD Venofer Venofer Oral Iron Venofer EPO* Only (N=231) (N=139) (N=139) (N=75) (N=46) % % % % % Subjects with any adverse reaction 78.8 76.3 73.4 72.0

65.2 Ear and Labyrinth Disorders Ear Pain 0 2.2 0.7 0 0 Eye Disorders Conjunctivitis 0.4 0 0 2.7 0 Gastrointestinal Disorders Abdominal pain 3.5 1.4 2.9 4.0

6.5 Diarrhea 5.2 7.2 10.1 8.0

4.3 Dysgeusia 0.9 7.9 0 0 0 Nausea 14.7 8.6 12.2 5.3

4.3 Vomiting 9.1 5.0 8.6 8.0

2.2 General Disorders and Administration Site Conditions Asthenia 2.2 0.7 2.2 2.7 0 Chest pain 6.1 1.4 0 2.7 0 Feeling abnormal 3.0 0 0 0 0 Infusion site pain or burning 0 5.8 0 0 0 Injection site extravasation 0 2.2 0 0 0 Peripheral edema 2.6 7.2 5.0 5.3

10.9 Pyrexia 3.0 0.7 0.7 1.3 0 Infections and Infestations Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis 2.6 2.2 4.3 16.0

4.3 Injury, Poisoning and Procedural Complications Graft complication 9.5 1.4 0 0 0 Metabolism and Nutrition Disorders Fluid overload 3.0 1.4 0.7 1.3 0 Gout 0 2.9 1.4 0 0 Hyperglycemia 0 2.9 0 0

2.2 Hypoglycemia 0.4 0.7 0.7 4.0 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 3.5 1.4 2.2 4.0

4.3 Back pain 2.2 2.2 3.6 1.3

4.3 Muscle cramp 29.4 0.7 0.7 2.7 0 Myalgia 0 3.6 0 1.3 0 Pain in extremity 5.6 4.3 0 2.7

6.5 Nervous System Disorders Dizziness 6.5 6.5 1.4 1.3

4.3 Headache 12.6 2.9 0.7 4.0 0 Respiratory, Thoracic and Mediastinal Disorders Cough 3.0 2.2 0.7 1.3 0 Dyspnea 3.5 5.8 1.4 1.3

2.2 Nasal congestion 0 1.4 2.2 1.3 0 Skin and Subcutaneous Tissue Disorders Pruritus 3.9 2.2 4.3 2.7 0 Vascular Disorders Hypertension 6.5 6.5 4.3 8.0

6.5 Hypotension 39.4 2.2 0.7 2.7

2.2 One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients were treated with Venofer there were no occurrences of adverse reactions that precluded further use of Venofer [see Warning and Precautions ( 5 )]. Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older) In a randomized, open-label, dose-ranging trial for iron maintenance treatment with Venofer in pediatric patients with CKD on stable erythropoietin therapy [see Clinical Studies ( 14.7 )] , at least one adverse reaction was experienced by 57% (27/47) of the patients receiving Venofer 0.5 mg/kg, 53% (25/47) of the patients receiving Venofer 1 mg/kg, and 55% (26/47) of the patients receiving Venofer 2 mg/kg. A total of 5 (11%) subjects in the Venofer 0.5 mg/kg group, 10 (21%) patients in the Venofer 1 mg/kg group, and 10 (21%) patients in the Venofer 2 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common adverse reactions (>2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Venofer. Because these reactions 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 the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by >1% were cardiac failure congestive, sepsis and dysgeusia. Immune system disorders: anaphylactic-type reactions, angioedema Psychiatric disorders: confusion Nervous system disorders: convulsions, collapse, light-headedness, loss-of-consciousness Cardiovascular System : bradycardia, shock, acute myocardial ischemia with or without myocardial infarction or with in-stent thrombosis in the context of a hypersensitivity reaction Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnea Musculoskeletal and connective tissue disorders: back pain, swelling of the joints Renal and urinary disorders: chromaturia General disorders and administration site conditions: hyperhidrosis 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. Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms. Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

Venofer may reduce the absorption of concomitantly administered oral iron preparations.

8.1 Pregnancy Risk Summary Published studies on intravenous iron sucrose treatment after the first trimester of pregnancy have not shown adverse maternal or fetal outcomes (see Data) . Available reports of intravenous iron sucrose use in pregnant women during the first trimester are insufficient to assess the risk of major birth defects and miscarriage. There are risks to the mother and fetus associated with untreated IDA in pregnancy as well as risks to the fetus associated with maternal severe hypersensitivity reactions (see Clinical Considerations) . Animal reproduction studies of iron sucrose administered to rats and rabbits during the period of organogenesis at elemental iron doses equivalent to the maximum recommended human dose based on body surface area revealed no evidence of harm to the fetus (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Iron deficiency anemia during pregnancy should be treated. Untreated IDA in pregnancy is associated with adverse maternal outcomes such as post-partum anemia. Adverse pregnancy outcomes associated with IDA include increased risk for preterm delivery and low birth weight. Fetal/Neonatal adverse reactions Severe adverse reactions including circulatory failure (severe hypotension, shock including in the context of anaphylactic reaction) may occur in pregnant women with parenteral iron products (such as Venofer) which may cause fetal bradycardia, especially during the second and third trimester. Data Human Data Published data from randomized controlled studies and prospective observational studies on the use of Venofer in pregnant women have not reported an association of Venofer and adverse developmental outcomes. However, these studies did not include women exposed during the first trimester of pregnancy and were not designed to assess the risk of major birth defects. Maternal adverse events reported in these studies are similar to those reported during clinical trials in adult males and non-pregnant females [see Adverse Reactions (6.1)] . Animal Data Iron sucrose was administered intravenously to rats and rabbits during the period of organogenesis at elemental iron doses up to 13 mg/kg/day (0.25 times or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus.

8.2 Lactation Risk Summary Iron sucrose is present in human milk, and available published reports following exposure to 100-300 mg intravenous iron sucrose have not reported adverse reactions in breastfed infants (see Data) . There are no data on the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for Venofer and any potential adverse effects on the breastfed child from Venofer or from the underlying maternal condition. Data A published study showed no difference in iron concentration in the colostrum of 10 iron deficient breastfeeding women who were 2 to 3 days postpartum and received a single dose of 100 mg of intravenous iron sucrose compared to 5 breastfeeding women who received no iron. These results may underestimate the amount of iron in breastmilk following the standard dose of Venofer. A published report of 78 breastfeeding women who received 300 mg of intravenous iron sucrose over 3 days (infant age not reported) did not report on the safety of iron sucrose in breastfed infants; however adverse reactions in breastfed infants were not reported. Clinical Considerations Monitor breastfed infants for gastrointestinal toxicity (constipation, diarrhea).

8.4 Pediatric Use Safety and effectiveness of Venofer for iron replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established. Safety and effectiveness of Venofer for iron maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Venofer at doses of 0.5 mg/kg, 1 mg/kg, and 2 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing [see Clinical Studies ( 14.7 )]. Venofer has not been studied in patients younger than 2 years of age. 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 died 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.

8.5 Geriatric Use Of the 1,051 patients in two post-marketing safety studies of Venofer, 40% were 65 years and older. No overall differences in safety or effectiveness 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. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Venofer is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous administration, Venofer is dissociated into iron and sucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.