Iron Sucrose

1 INDICATIONS AND USAGE Iron Sucrose Injection is indicated for the treatment of iron deficiency anemia (IDA) in patients with chronic kidney disease (CKD). Iron Sucrose Injection is an iron replacement product indicated for the treatment of iron deficiency anemia (IDA) in patients with chronic kidney disease (CKD).

2 DOSAGE AND ADMINISTRATION Population Dose Adult Patients Hemodialysis Dependent- Chronic Kidney Disease (HDD-CKD) ( 2.2 ) 100 mg slow intravenous injection or infusion Non-Dialysis Dependent- Chronic Kidney Disease (NDD-CKD) ( 2.3 ) 200 mg slow intravenous injection or infusion Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) ( 2.4 ) 300 mg or 400 mg intravenous infusion Pediatric patients HDD-CKD ( 2.5 ), PDD- CKD or NDD-CKD ( 2.6 ) 0.5 mg/kg slow intravenous injection or infusion 2.1 Mode of Administration Administer Iron Sucrose Injection only intravenously by slow injection or by infusion. The dosage of Iron Sucrose Injection is expressed in mg of elemental iron. Each mL contains 20 mg of elemental iron. 2.2 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Administer Iron Sucrose Injection 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session [ see How Supplied/Storage and Handling ( 16.2 ) ] . Administer Iron Sucrose Injection early during the dialysis session (generally within the first hour). The usual total treatment course of Iron Sucrose Injection is 1000 mg. Iron Sucrose Injection treatment may be repeated if iron deficiency reoccurs. 2.3 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Administer Iron Sucrose Injection 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Iron Sucrose Injection, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14 [ see How Supplied/Storage and Handling ( 16.2 ) ] . Iron Sucrose Injection treatment may be repeated if iron deficiency reoccurs. 2.4 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Administer Iron Sucrose Injection in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Iron Sucrose Injection in a maximum of 250 mL of 0.9% NaCl [ see How Supplied/Storage and Handling ( 16.2 ) ] . Iron Sucrose Injection treatment may be repeated if iron deficiency reoccurs. 2.5 Pediatric Patients (2 Years of Age and Older) with HDD-CKD for Iron Maintenance Treatment. For iron maintenance treatment: Administer Iron Sucrose Injection at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 0.9% NaCl at a concentration of 1 to 2 mg/mL and administered over 5 to 60 minutes. Do not dilute to concentrations below 1 mg/mL [ see How Supplied/Storage and Handling ( 16.2 ) ] . Iron Sucrose Injection treatment may be repeated if necessary. The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established. 2.6 Pediatric Patients (2 Years of Age and Older) with NDD-CKD or PDD-CKD who are on Erythropoietin Therapy for Iron Maintenance Treatment For iron maintenance treatment: Administer Iron Sucrose Injection at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 0.9% NaCl at a concentration of 1 to 2 mg/mL and administered over 5 to 60 minutes. Do not dilute to concentrations below 1 mg/mL [ see How Supplied/Storage and Handling ( 16.2 ) ] . Iron Sucrose Injection treatment may be repeated if necessary. The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Iron Sucrose Injection administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Iron Sucrose Injection 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 Iron Sucrose Injection. 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 Iron Sucrose Injection immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Iron Sucrose Injection administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Iron Sucrose Injection 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 Iron Sucrose Injection may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Iron Sucrose Injection. Hypotension following administration of Iron Sucrose Injection 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 Iron Sucrose Injection require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Iron Sucrose Injection 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 ) ] .

4 CONTRAINDICATIONS Known hypersensitivity to Iron Sucrose Injection • Known hypersensitivity to Iron Sucrose Injection ( 4 )

7 DRUG INTERACTIONS Iron Sucrose Injection 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 risk 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 Iron Sucrose Injection) 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 Iron Sucrose Injection in pregnant women have not reported an association of Iron Sucrose Injection 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 Iron Sucrose Injection and any potential adverse effects on the breastfed child from Iron Sucrose Injection 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 Iron Sucrose Injection. 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).

6 ADVERSE REACTIONS 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 Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 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 Adult Patients with CKD The frequency of adverse reactions associated with the use of Iron Sucrose Injection 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 Iron Sucrose Injection 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 Iron Sucrose Injection Exceeds the Rate for Comparator * EPO=Erythropoietin Body System/Adverse Reactions HDD-CKD NDD-CKD PDD-CKD Iron Sucrose Injection Iron Sucores Injection Oral Iron Iron Sucorse Injection 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 t…