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.

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)) .

6.1 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%.

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

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Of the 3934 patients in clinical studies of Monoferric, 29% were 65 years and over, while 13% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients 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.

12.1 Mechanism of Action

Ferric derisomaltose is a complex of iron (III) hydroxide and derisomaltose, an iron carbohydrate oligosaccharide that releases iron. Iron binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.

12.2 Pharmacodynamics

Serum ferritin peaks approximately 7 days after an intravenous dose of Monoferric and slowly returns to stable levels after about 4 weeks.

12.3 Pharmacokinetics

The pharmacokinetics of total iron (derisomaltose-bound plus transferrin-bound iron) were evaluated in adult patients with IDA.

After a single dose of Monoferric, maximum concentration (C max) and area under the concentration time curve (AUC) of serum total iron increased approximately proportionally over the 100 to 1000 mg dose range. After a 1000 mg single dose, the C max and AUC inf of total iron (geometric mean and CV%) of serum total iron were 408 (10.5) μg/mL and 17730 (22.1) μg.h /mL.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted.

Iron oligosaccharide, an earlier formulation of ferric derisomaltose, was not genotoxic in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberrations test and an in vivo mouse micronucleus assay.

In a combined fertility and embryo-fetal development study in rats, ferric derisomaltose was administered intravenously to male rats 28 days prior to mating and through cohabitation and to female rats 14 days prior to cohabitation and through GD 17. Doses administered were 2, 6, or 19 mg Fe/kg/day in males and 3, 11, or 32 mg Fe/kg/day in females. There was no effect on male or female fertility in rats at up to 19 mg Fe/kg/day (approximately 0.2 times the MRHD of 1000 mg, based on BSA) in males and up to 32 mg Fe/kg/day (approximately 0.3 times the MRHD of 1000 mg based on BSA) in females.

Iron Deficiency Anemia in Patients Who Had Intolerance to Oral Iron or Who Had Unsatisfactory Response to Oral Iron

In Trial 1 (NCT02940886) 1512 adult patients with IDA caused by different etiologies, who had documented intolerance or lack of response to oral iron or screening hemoglobin (Hb) measurement sufficiently low to require repletion of iron stores were randomized in a 2:1 ratio to treatment with Monoferric or iron sucrose. Adult patients aged ≥18 years with baseline Hb ≤11 g/dL, TSAT <20 %, and s-ferritin <100 ng/mL were eligible for enrollment. The median age of patients was 44 years (range 18-91) and 89 % were women.

The efficacy of Monoferric was established based upon the change in Hb from baseline to week 8. Non-inferiority was demonstrated for change in Hb from baseline to Week 8 (Table 2).

Iron Deficiency Anemia in Patients with Non-Hemodialysis Dependent Chronic Kidney Disease (NDD-CKD)

Trial 2 (NCT02940860) was a randomized controlled trial in 1538 patients with NDD-CKD who were randomized in a 2:1 ratio to treatment with Monoferric or iron sucrose respectively. Adult patients aged ≥18 years with Hb ≤11 g/dL, s-ferritin ≤100 ng/mL (or ≤300 ng/mL if TSAT ≤30%), chronic renal impairment with eGFR between 15-59 mL/min, and either no ESAs or ESAs at a stable dose (+/-20 %) for 4 weeks before randomization were eligible for enrollment. The median age of patients was 69 years (range 25-97), 63% were female.

The efficacy of Monoferric was established based upon the demonstration of non-inferiority for change in hemoglobin from baseline to Week 8 (Table 3).

16.1 How Supplied

Monoferric injection is a sterile, dark brown, non-transparent aqueous solution supplied in cartons as single-dose vials (10 mL, 5 mL or 1 mL) in the following configurations:

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). See the USP controlled room temperature.

Do not freeze.

When added to an infusion bag containing 0.9% Sodium Chloride Injection, USP, Monoferric solution may be stored for up to 8 hours at room temperature.

Prior History of Allergies to Parenteral Iron Products

Question patients regarding any prior history of reactions to parenteral iron products (see Warnings and Precautions (5.1)) .

Hypersensitivity Reactions

Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Monoferric administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems (see Warnings and Precautions (5.1)) .