Ferinject Mechanism of Action

Anti-anemia.
Pharmacotherapeutic group: Iron trivalent, parenteral preparation. ATC code: B03AC.
Pharmacology: Pharmacodynamics: Ferric carboxymaltose (Ferinject) dispersion for injection/infusion is a colloidal solution of the iron complex ferric carboxymaltose.
The complex is designed to provide, in a controlled way, utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).
Red cell utilisation of ⁵⁹Fe from radio-labelled Ferric carboxymaltose (Ferinject) ranged from 91% to 99% in subjects with iron deficiency (ID) and 61% to 84% in subjects with renal anaemia at 24 days post-dose.
Ferric carboxymaltose (Ferinject) treatment results in an increase in reticulocyte count, serum ferritin levels and TSAT levels to within normal ranges.
Clinical efficacy and safety: The efficacy and safety of Ferric carboxymaltose (Ferinject) has been studied in different therapeutic areas necessitating intravenous iron to correct iron deficiency. The main studies are described in more detail as follows.
Cardiology: Chronic heart failure: Study CONFIRM-HF was a double-blind, randomised, 2-arm study comparing Ferric carboxymaltose (Ferinject) (n=150) vs. placebo (n=151) in subjects with chronic heart failure (CHF) and ID for a treatment period of 52 weeks. At Day 1 and Week 6 (correction phase), subjects received either Ferric carboxymaltose (Ferinject) according to a simplified dosing grid using baseline Hb and body weight at screening (see Dosage & Administration), placebo or no dose. At Weeks 12, 24, and 36 (maintenance phase) subjects received Ferric carboxymaltose (Ferinject) (500 mg iron) or placebo if serum ferritin was <100 ng/mL or 100-300 ng/mL with TSAT <20%. The treatment benefit of Ferric carboxymaltose (Ferinject) vs. placebo was demonstrated with the primary efficacy endpoint, the change in the 6-minute walk test (6MWT) from baseline to Week 24 (33±11 metres, p=0.002). This effect was sustained throughout the study to Week 52 (36±11 metres p<0.001).
Study EFFECT-HF was an open-label (with blinded endpoint evaluation), randomised, 2-arm study comparing Ferinject (n=86) vs. standard of care (n=86) in subjects with chronic heart failure and ID for a treatment period of 24 weeks. At Day 1 and Week 6 (correction phase), subjects received either Ferinject according to a simplified dosing grid using baseline Hb and body weight at screening (see Dosage & Administration) or standard of care. At Week 12, (maintenance phase) subjects received Ferinject (500 mg iron) or standard of care if serum ferritin <100 ng/ml or 100 to 300 ng/ml and TSAT <20%. The treatment benefit of Ferinject vs. standard of care was demonstrated with the primary efficacy endpoint, the change in weight-adjusted peak VO₂ from baseline to Week 24 (LS Mean 1.04 ±0.44, p=0.02).
Nephrology: Haemodialysis-dependent chronic kidney disease: Study VIT-IV-CL-015 was an open-label, randomised parallel group study comparing Ferric carboxymaltose (Ferinject) (n=97) to iron sucrose (n=86) in subjects with ID anaemia undergoing haemodialysis. Subjects received Ferric carboxymaltose (Ferinject) or iron sucrose 2-3 times per week in single doses of 200 mg iron directly into the dialyser until the individually calculated cumulative iron dose was reached (mean cumulative dose of iron as Ferric carboxymaltose (Ferinject): 1,700 mg). The primary efficacy endpoint was the percentage of subjects reaching an increase in Hb of ≥1.0 g/dL at 4 weeks after baseline. At 4 weeks after baseline, 44.1% responded to treatment with Ferric carboxymaltose (Ferinject) (i.e. Hb increase of ≥1.0 g/dL) compared to 35.3% for iron sucrose (p=0.2254).
Non-dialysis-dependent chronic kidney disease: Study 1VIT04004 was an open-label, randomised active-control study, evaluating the safety and efficacy of Ferric carboxymaltose (Ferinject) (n=147) vs. oral iron (n=103). Subjects in the Ferric carboxymaltose (Ferinject) group received 1,000 mg of iron at baseline and 500 mg of iron at days 14 and 28, if TSAT was <30% and serum ferritin was <500 ng/mL at the respective visit. Subjects in the oral iron arm received 65 mg iron TID as ferrous sulphate from baseline to day 56. Subjects were followed-up until day 56. The primary efficacy endpoint was the percentage of subjects achieving an increase in Hb of ≥1.0 g/dL anytime between baseline and end of study or time of intervention. This was achieved by 60.54% of subjects receiving Ferric carboxymaltose (Ferinject) vs. 34.7% of subjects in the oral iron group (p<0.001). Mean haemoglobin change to day 56/end of study was 1.0 g/dL in the Ferric carboxymaltose (Ferinject) group and 0.7 g/dL in the oral iron group (p=0.034, 95% CI: 0.0, 0.7).
Gastroenterology: Inflammatory bowel disease: Study VIT-IV-CL-008 was a randomised, open-label study which compared the efficacy of Ferric carboxymaltose (Ferinject) vs. oral ferrous sulphate in reducing ID anaemia in subjects with inflammatory bowel disease (IBD). Subjects received either Ferric carboxymaltose (Ferinject) (n=111) in single doses of up to 1,000 mg iron once per week until the individually calculated iron dose (per Ganzoni formula) was reached (mean cumulative iron dose: 1,490 mg), or 100 mg iron BID as ferrous sulphate (n=49) for 12 weeks. Subjects receiving Ferric carboxymaltose (Ferinject) showed a mean increase in Hb from baseline to Week 12 of 3.83 g/dL, which was non-inferior to 12 weeks of twice daily therapy with ferrous sulphate (3.75 g/dL, p=0.8016).
Study FER-IBD-07-COR was a randomised, open-label study comparing the efficacy of Ferric carboxymaltose (Ferinject) vs. iron sucrose in subjects with remitting or mild IBD. Subjects receiving Ferric carboxymaltose (Ferinject) were dosed according to a simplified dosing grid using baseline Hb and body weight (see Dosage & Administration) in single doses up to 1,000 mg iron, whereas subjects receiving iron sucrose were dosed according to individually calculated iron doses using the Ganzoni formula in doses of 200 mg iron until the cumulative iron dose was reached. Subjects were followed-up for 12 weeks. 65.8% of subjects receiving Ferric carboxymaltose (Ferinject) (n=240; mean cumulative iron dose: 1,414 mg) vs. 53.6% receiving iron sucrose (n=235; mean cumulative dose 1,207 mg; p=0.004) had responded at Week 12 (defined as Hb increase ≥2 g/dL). 83.8% of Ferric carboxymaltose (Ferinject)-treated subjects vs. 75.9% of iron sucrose-treated subjects achieved a Hb increase ≥2 g/dL or had Hb within normal limits at Week 12 (p=0.019).
Women's health: Postpartum: Study VIT-IV-CL-009 was a randomised open-label non-inferiority study comparing the efficacy of Ferric carboxymaltose (Ferinject) (n=227) vs. ferrous sulphate (n=117) in women suffering from post-partum anaemia. Subjects received either Ferric carboxymaltose (Ferinject) in single doses of up to 1,000 mg iron until their individually calculated cumulative iron dose (per Ganzoni formula) was reached, or 100 mg of iron as oral ferrous sulphate BID for 12 weeks. Subjects were followed-up for 12 weeks. The mean change in Hb from baseline to Week 12 was 3.37 g/dL in the Ferric carboxymaltose (Ferinject) group (n=179; mean cumulative iron dose: 1,347 mg) vs. 3.29 g/dL in the ferrous sulphate group (n=89), showing non-inferiority between the treatments.
Pregnancy: Intravenous iron medicines should not be used during pregnancy unless clearly necessary. Treatment with Ferric carboxymaltose (Ferinject) should be confined to the second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus, see Use in Pregnancy & Lactation.
Limited safety data in pregnant women are available from study FER-ASAP-2009-01, a randomised, open-label study comparing Ferric carboxymaltose (Ferinject) (n=121) vs. oral ferrous sulphate (n=115) in pregnant women in the second and third trimester with ID anaemia for a treatment period of 12 weeks. Subjects received Ferric carboxymaltose (Ferinject) in cumulative doses of 1,000 mg or 1,500 mg of iron (mean cumulative dose: 1,029 mg iron) based on Hb and body weight at screening, or 100 mg of oral iron BID for 12 weeks. The incidence of treatment-related adverse events was similar between Ferric carboxymaltose (Ferinject) treated women and those treated with oral iron (11.4% Ferric carboxymaltose (Ferinject) group; 15.3% oral iron group). The most commonly reported treatment-related adverse events were nausea, upper abdominal pain and headache. Newborn Apgar scores as well as newborn iron parameters were similar between treatment groups.
Paediatric population: Adolescents aged 14 years or older were included in 4 studies performed in adults. In addition, paediatric studies were performed in children and adolescents aged 1 to 17 years with iron deficiency anaemia. The most common aetiologies for iron deficiency anaemia were gastrointestinal diseases (e.g. inflammatory bowel disease, Helicobacter pylori gastritis, coeliacic disease) and heavy uterine bleeding.
In a prospective pharmacokinetic/pharmacodynamic phase 2 study (1VIT13036), 35 children at a median age of 9.8 years (range: 1.5-17.5 years) were treated in 2 consecutive dose cohorts with single doses of Ferinject 7.5 mg iron/kg body weight (n = 16) or Ferinject 15 mg iron/kg body weight (n = 19), at a maximum dose of 750 mg iron. Hb, ferritin and TSAT increased dose-dependently. On day 35 after injection, the mean (SD) increase in Hb was 1.9 (1.38) g/dL with Ferinject 7.5 mg iron/kg and 2.8 (1.15) g/dL with Ferinject 15 mg iron/kg. See Adverse Reactions.
In a prospective, open-label, parallel-group phase 3 study (1VIT17044), efficacy and safety of Ferinject were compared with oral iron therapy. 40 children at a median age of 14.5 years (range:1 to 17 years) were treated with 2 doses of Ferinject 15 mg iron/kg body weight at a 7-day interval (maximum single dose 750 mg) and 39 children at a median age of 14.0 years (range: 1 to 17 years) with oral ferrous sulphate for 28 days. A similar increase in Hb was observed after both treatment with Ferinject and treatment with oral iron sulphate. The increase in Hb from baseline to day 35 (LS Mean [95%CI]) was 2.22 [1.69, 2.75] g/dL after Ferinject and 1.92 [1.43, 2.41] g/dL after oral iron sulphate. In total, 87.5% of patients in the intravenous iron group achieved a Hb increase >1 g/dL at EOS. The increase in ferritin and TSAT, used as a measure for the replenishment of iron stores, was higher after Ferinject therapy compared to oral iron sulphate therapy, with an increase in ferritin from baseline to day 35 (LS Mean [95%CI]) of 132.1 [105.44, 158.76] ng/mL after Ferinject and 11.0 [-15.62, 37.65] ng/mL after oral iron sulphate. The corresponding increase in TSAT was 24.3 [19.19, 29.41]% and 8.7 [3.70, 13.63]%, respectively. See Adverse Reactions.
Ferritin monitoring after replacement therapy: There is limited data from study VIT-IV-CL-008 which demonstrates that ferritin levels decrease rapidly 2-4 weeks following replacement and more slowly thereafter. The mean ferritin levels did not drop to levels where retreatment might be considered during the 12 weeks of study follow up. Thus, the available data does not clearly indicate an optimal time for ferritin retesting although assessing ferritin levels earlier than 4 weeks after replacement therapy appears premature. Thus, it is recommended that further re-assessment of ferritin should be made by the clinician based on the individual patient's condition.
Pharmacokinetics: Distribution: Positron emission tomography demonstrated that ⁵⁹Fe and ⁵²Fe from Ferric carboxymaltose (Ferinject) was rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the liver and spleen.
After administration of a single dose of Ferric carboxymaltose (Ferinject) of 100 to 1,000 mg of iron in ID subjects, maximum total serum iron levels of 37 μg/mL up to 333 μg/mL are obtained after 15 minutes to 1.21 hours respectively. The volume of the central compartment corresponds well to the volume of the plasma (approximately 3 litres).
Elimination: The iron injected or infused was rapidly cleared from the plasma, the terminal half-life ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.
Paediatric population: The pharmacokinetic properties of Ferinject at a dose of 15 mg iron/kg were similar to those for adult patients with iron deficiency. Serum iron increased proportionally to the dose after a single dose of 7.5 mg iron/kg or 15 mg iron/kg. After a single dose of Ferinject of 15 mg iron/kg body weight (maximum 750 mg), average maximum total serum iron values of 310 μg/mL were measured after 1.12 hours. The terminal half-life was 9.8 hours, and the distribution volume estimated by the population pharmacokinetic analysis was 0.42 to 3.14 l. Based on model-based simulations, the paediatrics subjects tended to have lower systemic exposure (lower AUC0-72h) compared to the adults (median per age group: 3,340 μg×h/mL (1 to 2 years), 4,110 μg×h/mL (3 to 12 years), 4,740 μg×h/mL (13 to 17 years), 8,864 μg×h/mL (adults)).
Toxicology: Preclinical safety data: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and genotoxicity. Preclinical studies indicate that iron released from Ferric carboxymaltose (Ferinject) does cross the placental barrier and is excreted in milk in limited, controlled amounts. In reproductive toxicology studies using iron replete rabbits Ferric carboxymaltose (Ferinject) was associated with minor skeletal abnormalities in the fetus. In a fertility study in rats, there were no effects on fertility for either male or female animals. No long-term studies in animals have been performed to evaluate the carcinogenic potential of Ferric carboxymaltose (Ferinject). No evidence of allergic or immunotoxic potential has been observed. A controlled in-vivo test demonstrated no cross-reactivity of Ferric carboxymaltose (Ferinject) with anti-dextran antibodies. No local irritation or intolerance was observed after intravenous administration.