Monoferric

1 INDICATIONS AND USAGE Monoferric 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 who have non-hemodialysis dependent chronic kidney disease (NDD-CKD) MONOFERRIC is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients: who have intolerance to oral iron or have had unsatisfactory response to oral iron. ( 1 ) who have non-hemodialysis dependent chronic kidney disease. ( 1 )

2 DOSAGE AND ADMINISTRATION For patients weighing 50 kg or more: Administer 1,000 mg of Monoferric as an intravenous infusion. For patients weighing less than 50 kg: Administer Monoferric as 20 mg/kg actual body weight as an intravenous infusion. Repeat Monoferric treatment if iron deficiency anemia reoccurs. ( 2 ) 2.1 Recommended Dosage For patients weighing 50 kg or more: Administer 1,000 mg of Monoferric by intravenous infusion over at least 20 minutes as a single dose. Repeat dose if iron deficiency anemia reoccurs. For patients weighing less than 50 kg: Administer Monoferric as 20 mg/kg actual body weight by intravenous infusion over at least 20 minutes as a single dose. Repeat dose if iron deficiency anemia reoccurs. The dosage of Monoferric is expressed in mg of elemental iron. Each mL of Monoferric contains 100 mg of elemental iron. Only administer Monoferric when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions ( Warnings and Precautions (5.1) ) . 2.2 Preparation and Administration Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. The product contains no preservatives. Each vial of Monoferric is single-dose only. Discard unused portion. Withdraw the appropriate volume of Monoferric and dilute in 100 mL to 500 mL of 0.9% Sodium Chloride Injection, USP. Final diluted concentration should be more than 1 mg iron/mL. Compatibility of Monoferric with other drugs has not been established. Monoferric should not be mixed with or physically added to solutions containing other drugs. Administer the prepared solution via intravenous infusion over at least 20 minutes. Following dilution with 0.9% Sodium Chloride Injection, USP, Monoferric solution may be stored at room temperature for up to 8 hours. Extravasation of Monoferric may cause brown discoloration at the extravasation site which may be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Monoferric administration at that site.

4 CONTRAINDICATIONS Monoferric is contraindicated in patients with a history of serious hypersensitivity to Monoferric or any of its components (see Warnings and Precautions (5.1) , Description (11) ) . Reactions have included shock, clinically significant hypotension, loss of consciousness, and/or collapse. Serious hypersensitivity to Monoferric or any of its components. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Monitor patients for signs and symptoms of hypersensitivity during and after Monoferric administration for at least 30 minutes and until clinically stable following completion of the infusion. ( 5.1 ) Iron Overload: Do not administer Monoferric to patients with iron overload. ( 5.2 ) 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 Monoferric. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Monoferric administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Monoferric when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Monoferric is contraindicated in patients with prior serious hypersensitivity reactions to Monoferric or any of its components ( see Contraindications (4) ). In clinical trials in patients with IDA and CKD, serious or severe hypersensitivity were reported in 0.3% (6/2008) of the Monoferric treated subjects. These included 3 events of hypersensitivity in 3 patients; 2 events of infusion-related reactions in 2 patients and 1 event of asthma in one patient. 5.2 Iron Overload Excessive therapy with parenteral iron can lead to excess iron storage and possibly iatrogenic hemosiderosis or hemochromatosis. Monitor the hematologic response (hemoglobin and hematocrit) and iron parameters (serum ferritin and transferrin saturation) during parenteral iron therapy. Do not administer Monoferric to patients with iron overload (see Overdosage (10) ) .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity Reactions (see Warnings and Precautions (5.1) ) . Iron Overload (see Warnings and Precautions (5.2) ) . Most commonly reported adverse reactions (incidence ≥1%) are rash and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharmacosmos at 1-888-828-0655 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, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. The safety of Monoferric was evaluated in 3008 patients with iron deficiency anemia enrolled in two randomized, actively-controlled trials. Trial 1 enrolled adult patients with iron deficiency anemia with intolerance to oral iron or had an unsatisfactory response to oral iron with a clinical need for repletion of iron stores. Eligible subjects were required to have a baseline hemoglobin of ≤11g/dl, transferrin saturation (TSAT) of less than 20% and serum ferritin level of <100 ng/mL. Trial 2 enrolled adult patients with non-dialysis dependent chronic kidney disease (CKD) with iron deficiency anemia ( see Clinical Studies (14) ). Eligible subjects also had to have serum ferritin ≤100 ng/mL or ≤300 ng/mL if TSAT ≤30%. Trial 1 and Trial 2 In the two randomized, actively-controlled clinical trials, Trial 1 and Trial 2 (see Clinical Studies (14) ) , patients were randomized in a 2:1 ratio to intravenous Monoferric (n = 2008) or intravenous iron sucrose (n = 1000) respectively. Monoferric was administered as a single intravenous infusion of 1000 mg diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 minutes (approximately 50 mg iron/min). Iron sucrose was administered as 200 mg undiluted intravenous injections over approximately 2-5 minutes and repeated according to standard practice or physician choice up to a maximum of five times (1000 mg) within the first two weeks starting at baseline. The data described below reflect exposure to Monoferric in 2008 patients exposed to a 1000 mg single intravenous dose of Monoferric. The mean cumulative intravenous Iron exposure was 984 mg. Trial 1 included 1483 patients with iron deficiency anemia in the safety analysis that had intolerance to oral iron or have had unsatisfactory response to oral iron or with a clinical need for rapid repletion of iron stores. Trial 2 included 1525 patients in the safety analysis who had non-dialysis dependent CKD. The mean (SD) age of the combined study population was 56.4 (18.3) years. The majority of patients were women (75.7%). Adverse reactions were reported in 8.6% (172/2008) of patients treated with Monoferric. Adverse reactions related to treatment and reported by ≥1% of the treated patients in the combined analysis of Trial 1 and 2 are listed in Table 1. Table 1. Adverse Reactions (≥1%) in Patients Receiving Monoferric in Clinical Trials 1 and 2 Monoferric (N = 2008) N (%) Iron sucrose (N = 1000) N (%) Adverse Reaction Nausea 24 (1.2) 11 (1.1) Rash 21 (1) 1 (0.1) Adjudicated serious or severe hypersensitivity reactions were reported in 6/2008 (0.3%) patients in the Monoferric group. Hypophosphatemia (serum phosphate <2.0 mg/dL) was reported in 3.5% of Monoferric-treated patients in Trials 1 & 2. 6.2 Post-marketing Experience 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. The following adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Monoferric: Cardiac disorders: Tachycardia Gastrointestinal disorders: Abdominal pain, nausea and vomiting, constipation, diarrhea General disorders and administration site conditions: Fatigue, pyrexia, chest pain, chills, Fishbane reaction, extravasation, influenza like symptoms, injection site reactions, malaise, pain Immune System disorders: Anaphylactic/anaphylactoid reaction, hypersensitivity Investigations: Hepatic enzymes increased Musculoskeletal and connective tissue disorders: Back pain, muscle spasms, arthralgia, myalgia Nervous system disorders: Dizziness, headache, paresthesia, dysgeusia, seizure, loss of consciousness, syncope Psychiatric disorders: Anxiety Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, bronchospasm Skin and subcutaneous tissue disorders: Erythema, urticaria, discoloration skin, rash, pruritus, skin exfoliation, angioedema, sweating Vascular disorders: Hypertension, hypotension, flushing, phlebitis Extravasation of Monoferric at the injection site that may lead to irritation of the skin and potentially long lasting brown discoloration at the site of injection has also been reported.

8.1 Pregnancy Risk Summary There are no available data on Monoferric use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Published studies on the use of intravenous iron products in pregnant women have not reported an association with adverse developmental outcomes. However, these studies cannot establish or exclude the absence of any drug-related risk during pregnancy because the studies were not designed to assess for the risk of major birth defects ( see Data ) . 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 ) . Iron complexes have been reported to be teratogenic and embryocidal in non-iron depleted pregnant animals. The findings in animals may be due to iron overload and may not be applicable to patients with iron deficiency. Animal reproduction studies of ferric derisomaltose administered to rats and rabbits during the period of organogenesis caused adverse developmental outcomes including structural abnormalities and embryo-fetal mortality at doses approximately 0.09 and 0.4 times the maximum recommended human dose (MRHD) of 1000 mg, respectively, based on body surface area ( 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 Untreated iron deficiency anemia (IDA) in pregnancy is associated with adverse maternal outcomes such as post-partum anemia. Adverse pregnancy outcomes associated with IDA includes 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 Monoferric) which may cause fetal bradycardia, especially during the second and third trimester. Data Animal Data Iron complexes have been reported to be teratogenic and embryocidal in non-anemic pregnant animals at single doses above 125 mg iron/kg body weight. The highest recommended dose in human clinical use is 20 mg iron/kg body weight. In a combined fertility and embryo-fetal development study in rats, ferric derisomaltose was administered intravenously to female rats 14 days prior to cohabitation and through gestation day (GD) 17 at doses of 3, 11, and 32 mg Fe/kg/day. The doses of 11 and 32 mg Fe/kg/day (approximately 0.1 and 0.3 times the MRHD of 1000 mg, based on body surface area (BSA)) resulted in an increase in the incidence of skeletal developmental delays. Ferric derisomaltose was administered intravenously to pregnant rabbits during organogenesis, from GD7 to GD20, at doses of 11, 25 and 43 mg Fe/kg/day. The dose of 43 mg Fe/kg/day (approximately 0.8 times the MRHD of 1000 mg, based on BSA) resulted in increased maternal mortality, abortion, and premature delivery, and increased postimplantation loss. Adverse developmental findings at this dose included fetal mortality, reduced fetal weights, and fetal developmental variations and malformations (including domed head, cleft palate, microglossia, hydrocephaly, small brain). Fetal malformations and reduced fetal weights were also noted in the 25 mg Fe/kg/day group (approximately 0.5 times the MRHD based on BSA).