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

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

Cardiac Electrophysiology

Electrocardiogram (ECG) monitoring for QT prolongation was performed in a sub-study in 35 patients randomized to Monoferric in Trial 1. No large mean increase in QTc (i.e. >20 ms) interval was detected at the 1000 mg single dose of Monoferric.

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.

Distribution

Circulating iron is removed from the plasma by cells of the reticuloendothelial system. The iron is bound to the available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, to the transport molecule transferrin.

Elimination

After a single 1000 mg Monoferric dose, the mean (CV%) half-life of serum total iron is 27 (13.3%) hr.

Excretion

Due to the size of the complex, Monoferric is not excreted via the kidneys. Small quantities of iron are excreted in urine and feces.

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.

The safety and efficacy of Monoferric for treatment of iron deficiency anemia (IDA) were evaluated in two randomized, open-label, actively-controlled clinical trials performed in a total of 3050 patients with IDA of different etiology. Trial 1 included patients with IDA who had intolerance to oral iron or who had had unsatisfactory response to oral iron or for whom there was a clinical need for rapid repletion of iron stores. Trial 2 included patients with IDA who had non-dialysis dependent chronic kidney disease (NDD-CKD). In these two 8-Week trials, patients were randomized 2:1 to treatment with Monoferric or iron sucrose. Monoferric was intravenously administered as a single dose of 1000 mg.

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).

Table 2. Change in Hemoglobin Endpoints in Trial 1:

* Least square mean
^† The estimate is from a mixed model for repeated measures with treatment, week, treatment-by-week and stratum as fixed effects and baseline Hb and baseline-by-week as covariates.

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).

Table 3. Change in Hemoglobin Endpoints in Trial 2:

* Least square mean
^† The estimate is from a mixed model for repeated measures with treatment, week, treatment-by-week and stratum as fixed effects and baseline Hb and baseline-by-week as covariates.