MONOFERRIC Solution for injection Ref.[10064] Active ingredients:

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)).

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)).

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 ≤200 μg/L 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:

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.

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

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

Skin and subcutaneous tissue disorders: Erythema, urticaria, discoloration skin, rash, pruritus, 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.

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, macroglossia, 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).

Risk Summary

The available data on the use of Monoferric in lactating women demonstrate that iron is present in breast milk. However, the data do not inform the potential exposure of iron for the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Monoferric in addition to any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Monitor breastfed children for gastrointestinal toxicity (constipation, diarrhea).

Safety and effectiveness have not been established in pediatric patients.

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.