Ferumoxytol

1 INDICATIONS AND USAGE Ferumoxytol is indicated for the treatment of iron deficiency anemia (IDA) in adult patients: • who have intolerance to oral iron or have had unsatisfactory response to oral iron or • who have chronic kidney disease (CKD). Ferumoxytol is an iron replacement product indicated for the treatment of iron deficiency anemia (IDA) in adult patients: • who have intolerance to oral iron or have had unsatisfactory response to oral iron ( 1 ) or • who have chronic kidney disease (CKD). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose of ferumoxytol injection is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer ferumoxytol as an intravenous infusion in 50 to 200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. Administer while the patient is in a reclined or semi-reclined position. Ferumoxytol injection does not contain antimicrobial preservatives. Discard unused portion. Ferumoxytol injection, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2 to 8 mg elemental iron per mL, should be used immediately but may be stored at controlled room temperature (25°C ± 2°C) for up to 4 hours or refrigerated (2 to 8° C) for up to 48 hours The dosage is expressed in terms of mg of elemental iron, with each mL of ferumoxytol containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second ferumoxytol infusion. The recommended ferumoxytol injection dose may be readministered to patients with persistent or recurrent iron deficiency anemia. For patients receiving hemodialysis, administer ferumoxytol once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each ferumoxytol infusion. Allow at least 30 minutes between administration of ferumoxytol and administration of other medications that could potentially cause serious hypersensitivity reactions and/or hypotension, such as chemotherapeutic agents or monoclonal antibodies. Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. • The recommended dose of ferumoxytol is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. ( 2 ) • Administer ferumoxytol as an intravenous infusion in 50 to 200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. ( 2 )

4 CONTRAINDICATIONS Ferumoxytol is contraindicated in patients with: • Known hypersensitivity to ferumoxytol or any of its components [see Warnings and Precautions ( 5.1 )] . • History of allergic reaction to any intravenous iron product [see Warnings and Precautions ( 5.1 )] . • Known hypersensitivity to ferumoxytol or any of its components. ( 4 ) • History of allergic reaction to any intravenous iron product. ( 4 )

5 WARNINGS AND PRECAUTIONS • Greater risk of anaphylaxis in patients with multiple drug allergies. (5.1) • Hypotension: Ferumoxytol may cause hypotension. Monitor for signs and symptoms of hypotension following each administration of ferumoxytol. (5.2) • Iron Overload: Regularly monitor hematologic responses during ferumoxytol therapy. Do not administer ferumoxytol to patients with iron overload. (5.3) • Magnetic Resonance Imaging Test Interference: Ferumoxytol can alter magnetic resonance imaging (MRI) studies. (5.4) 5.1 Serious Hypersensitivity Reactions Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness have occurred in patients receiving ferumoxytol. Other adverse reactions potentially associated with hypersensitivity have occurred (pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first dose or subsequent doses in patients in whom a previous ferumoxytol dose was tolerated. Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering ferumoxytol to these patients. Only administer ferumoxytol as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after ferumoxytol administration for at least 30 minutes and until clinically stable following completion of each infusion [see Adverse Reactions ( 6.2 ) ]. In a clinical study in patients with IDA, regardless of etiology, hypersensitivity reactions were reported in 0.4% (4/997) of subjects receiving ferumoxytol administered as intravenous infusion over at least 15 minutes. These included one patient with severe hypersensitivity reaction and three patients with moderate hypersensitivity reactions. In clinical studies predominantly in patients with IDA and CKD, serious hypersensitivity reactions were reported in 0.2% (4/1,806) of subjects receiving ferumoxytol (administered as a rapid intravenous injection – prior method of administration no longer approved). Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.5% (63/1,806) of these subjects. In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of ferumoxytol may have more severe outcomes [s ee Boxed Warning , Adverse Reactions ( 6.2 ) and Use in Specific Populations ( 8.5 )]. 5.2 Hypotension Ferumoxytol may cause clinically significant hypotension. In a clinical study with ferumoxytol in patients with IDA, regardless of etiology, moderate hypotension was reported in 0.2% (2/997) of subjects receiving ferumoxytol administered as intravenous infusion over at least 15 minutes. In clinical studies in patients with IDA and CKD, hypotension was reported in 1.9% (35/1,806) of subjects, including three patients with serious hypotensive reactions, who had received ferumoxytol as a rapid intravenous injection (prior method of administration no longer approved). Hypotension has also been reported in the post-marketing experience [see Adverse Reactions ( 6.2 )]. Monitor patients for signs and symptoms of hypotension following each ferumoxytol administration [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.1 )]. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy [see Dosage and Administration ( 2 )]. Do not administer ferumoxytol to patients with iron overload. In the 24 hours following administration of ferumoxytol, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the ferumoxytol complex. 5.4 Magnetic Resonance (MR) Imaging Test Interference Administration of ferumoxytol may transiently affect the diagnostic ability of MR imaging. Conduct anticipated MR imaging studies prior to the administration of ferumoxytol. Alteration of MR imaging studies may persist for up to 3 months following the last ferumoxytol dose. If MR imaging is required within 3 months after ferumoxytol administration, use T1- or proton density-weighted MR pulse sequences to minimize the ferumoxytol effects; MR imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of ferumoxytol. Maximum alteration of vascular MR imaging is anticipated to be evident for 1 to 2 days following ferumoxytol administration [see Clinical Pharmacology ( 12.3 )]. Ferumoxytol will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound or nuclear medicine imaging.

7 DRUG INTERACTIONS Drug-drug interaction studies with ferumoxytol were not conducted. Ferumoxytol may reduce the absorption of concomitantly administered oral iron preparations.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] • Hypotension [see Warnings and Precautions ( 5.2 )] • Iron Overload [see Warnings and Precautions ( 5.3 )] • Magnetic Resonance (MR) Imaging Test Interference [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (≥ 2%) are diarrhea, headache, nausea, dizziness, hypotension, constipation, and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS with ferumoxytol injection, contact Sandoz Inc., at 1-800-525-8747, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies, 3,968 subjects were exposed to ferumoxytol. Of these subjects 31% were male and the median age was 54 years (range of 18 to 96 years). The data described below reflect exposure to ferumoxytol in 997 patients exposed to a 1.02 g course of ferumoxytol administered as two 510 mg intravenous (IV) doses: 992 subjects (99.5%) received at least 1 complete dose of ferumoxytol and 946 subjects (94.9%) received 2 complete doses. The mean cumulative IV Iron exposure was 993.80 ±119.085 mg. The safety of ferumoxytol was studied in a randomized, multicenter, double-blind clinical trial in patients with IDA (IDA Trial 3), [see Clinical Studies (14.1)]. In this trial, patients were randomized to two intravenous infusions of 510 mg (1.02 g) of ferumoxytol (n=997), or two intravenous infusions of 750 mg (1.500 g) of ferric carboxymaltose (FCM) (n=1000). Both intravenous irons were infused over a period of at least 15 minutes. Most patients received their second infusion of ferumoxytol and FCM 7(+1) days after Dose 1. The mean (SD) age of the study population (N=1997) was 55.2 (17.16) years. The majority of patients were female (76.1%), white (71.4%) and non-Hispanic (81.8%). The mean (SD) hemoglobin at baseline for all patients was 10.4 (1.5) g/dl. Serious adverse events were reported in 3.6% (71/1997) of ferumoxytol-and FCM-treated patients. The most common (≥2 subjects) serious AEs reported in ferumoxytol-treated patients were syncope, gastroenteritis, seizure, pneumonia, hemorrhagic anemia, and acute kidney injury. In FCM-treated patients the most common (≥2 subjects) serious AEs were syncope, cardiac failure congestive, angina pectoris, and atrial fibrillation. Adverse reactions related to ferumoxytol and reported by ≥ 1% of ferumoxytol-treated patients in IDA Trial 3 are listed in Table 1 . Table 1: Adverse Reactions to Ferumoxytol Reported in ≥1% of IDA Patients in IDA Trial 3 Adverse Reactions Ferumoxytol 2 x 510 mg (N = 997) % Ferric Carboxymaltose 2 x 750 mg (N = 1000) % Headache 3.4 3.1 Nausea 1.8 3.4 Dizziness 1.5 1.6 Fatigue 1.5 1.2 Diarrhea 1 0.8 Back Pain 1 0.4 In IDA Trial 3, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 ferumoxytol-treated patients included arthralgia (0.3%), dyspnea (0.3%), flushing (0.2%), chest discomfort (0.2%), chest pain (0.2%), nausea (0.2%), back pain (0.2%), dizziness (0.2%) and headache (0.2%). Across two clinical trials in patients with IDA (IDA Trial 1 and 2), [see Clinical Studies ( 14.1 )], patients were randomized to: two injections (rapid intravenous injection -prior method of administration no longer approved) of 510 mg of ferumoxytol (n=1,014), placebo (n=200), or five injections/infusions of 200 mg of iron sucrose (n=199). Most patients received their second ferumoxytol injection 3 to 8 days after the first injection. Adverse reactions related to ferumoxytol and reported by ≥ 1% of ferumoxytol-treated patients in these trials were similar to those seen in Trial 3. In Trials 1 and 2, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 ferumoxytol-treated patients included hypersensitivity (0.6%), hypotension (0.3%), and rash (0.2%). In addition, a total of 634 subjects enrolled in and completed participation in a Phase 3 open label extension study. Of these, 337 subjects met IDA treatment criteria and received ferumoxytol. Adverse reactions following this repeat ferumoxytol dosing were generally similar in type and frequency to those observed after the first two intravenous injections. Across three randomized clinical trials in patients with IDA and CKD (CKD Trials 1, 2, and 3), [see Clinical Studies ( 14.2 )], a total of 605 patients were exposed to two injections of 510 mg of ferumoxytol and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second ferumoxytol injection 3 to 8 days after the first injection. Adverse reactions related to ferumoxytol and reported by ≥ 1% of ferumoxytol-treated patients in the CKD randomized clinical trials are listed in Table 2 . Diarrhea (4%), constipation (2.1%) and hypertension (1%) have also been reported in ferumoxytol-treated patients. Table 2: Adverse Reactions to Ferumoxytol Reported in ≥1% of Patients with IDA and CKD Trials 1, 2 and 3 Adverse Reactions Ferumoxytol 2 x 510 mg (n = 605) % Oral Iron (n = 280) % Nausea 3.1 7.5 Dizziness 2.6 1.8 Hypotension 2.5 0.4 Peripheral Edema 2 3.2 Headache 1.8 2.1 Edema 1.5 1.4 Vomiting 1.5 5 Abdominal Pain 1.3 1.4 Chest Pain 1.3 0.7 Cough 1.3 1.4 Pruritus 1.2 0.4 Pyrexia 1 0.7 Back Pain 1 0 Muscle Spasms 1 1.4 Dyspnea 1 1.1 Rash 1 0.4 In these clinical trials in patients with IDA and CKD, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 ferumoxytol-treated patients included hypotension (0.4%), chest pain (0.3%), and dizziness (0.3%). Following completion of the controlled phase of the trials, 69 patients received two additional 510 mg intravenous injections of ferumoxytol (for a total cumulative dose of 2.04 g). Adverse reactions following this repeat ferumoxytol dosing were similar in character and frequency to those observed following the first two intravenous injections. 6.2 Postmarketing Experience Because adverse 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. The following serious adverse reactions have been reported from the post-marketing experience with ferumoxytol: fatal, life-threatening, and serious anaphylactic-type reactions, acute myocardial ischemia with or without myocardial infarction or with in-stent thrombosis in the context of a hypersensitivity reaction, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of ferumoxytol. Reactions have occurred following the first dose or subsequent doses of ferumoxytol.

8.1 Pregnancy Risk Summary Limited available data with ferumoxytol use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with untreated iron deficiency anemia (IDA) in pregnancy as well as risks to the fetus associated with maternal severe hypersensitivity reactions ( see Clinical Considerations ). In animal studies, administration of ferumoxytol to pregnant rabbits during organogenesis caused adverse developmental outcomes including fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Untreated iron deficiency anemia (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 ferumoxytol) which may cause fetal bradycardia, especially during the second and third trimester. Data Animal Data Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and soft tissue fetal malformations and decreased fetal weights.