Ferumoxytol

12.1 Mechanism of Action Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.

1 INDICATIONS AND USAGE Feraheme 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). Feraheme 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 Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Feraheme as an intravenous infusion in 50-200 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. Feraheme does not contain antimicrobial preservatives. Discard unused portion. Feraheme, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 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 (2-8° C) for up to 48 hours. The dosage is expressed in terms of mg of elemental iron, with each mL of Feraheme containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Feraheme infusion. The recommended Feraheme dose may be readministered to patients with persistent or recurrent iron deficiency anemia. For patients receiving hemodialysis, administer Feraheme 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 Feraheme infusion. Allow at least 30 minutes between administration of Feraheme 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 Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. ( 2 ) • Administer Feraheme as an intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes ( 2 )

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 Feraheme, contact AMAG Pharmaceuticals, Inc. at 1-877-411-2510, 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 Feraheme. 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 Feraheme 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 Feraheme 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 Feraheme (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 Feraheme 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 Feraheme-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 Feraheme and reported by ≥1% of Feraheme-treated patients in IDA Trial 3 are listed in Table 1 . Table 1: Adverse Reactions to Feraheme Reported in ≥1% of IDA Patients in IDA Trial 3 Adverse Reactions Feraheme 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 Feraheme-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 Feraheme (n=1,014), placebo (n=200), or five injections/infusions of 200 mg of iron sucrose (n=199). Most patients received their second Feraheme injection 3 to 8 days after the first injection. Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-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 Feraheme-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 Feraheme. Adverse reactions following this repeat Feraheme 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 Feraheme and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second Feraheme injection 3 to 8 days after the first injection. Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-treated patients in the CKD randomized clin

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