Ferinject Mechanism of Action

Pharmacotherapeutic group: Iron trivalent, parenteral preparation. ATC Code: B03AC.
Pharmacology: Pharmacodynamics: Mechanism of action: Ferinject solution for injection/infusion is a colloidal solution of ferric carboxymaltose. It contains iron in a stable ferric state as a non-dextran iron complex consisting of a polynuclear iron-hydroxide core with a carbohydrate ligand. Because of the high stability of the complex, there is only a very small amount of weakly-bound iron (also called labile or free iron). The structure of the core of ferric carboxymaltose is similar to that of ferritin, the physiological iron storage protein. 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). Positron Emission Tomography (PET) showed that red cell utilisation of ⁵⁹Fe from radio-labelled ferric carboxymaltose ranged from 91% to 99% in subjects with iron deficiency and 61% to 84% in subjects with renal anaemia at 24 days post-dose. Ferinject treatment led to a clear increase in reticulocyte count indicating the increased saturation of erythrocyte precursor cells as iron becomes available. Serum ferritin levels and TSAT levels increasing to the normal range confirmed replenishment of the iron stores.
Clinical studies have shown that the haematological response and the filling of the iron stores is faster after intravenous administration of ferric carboxymaltose than with orally administered comparators.
Clinical efficacy and safety: Clinical efficacy studies have been conducted in numerous aetiologies that are representative of underlying diseases that may lead to iron deficiency, i.e., diseases with increased inflammatory status that may impair iron absorption, as well as indications with large losses of iron that cannot be compensated via dietary or oral iron. A brief summary of the key studies has been provided as follows.
Cardiology: Chronic heart failure: Study CONFIRM-HF was a double-blind, randomised, 2-arm study comparing Ferinject (n=150) vs. placebo (n=151) in subjects with chronic heart failure and ID for a treatment period of 52 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), placebo or no dose. At Weeks 12, 24, and 36 (maintenance phase) subjects received 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 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: Four Phase 3 studies have been conducted in nephrology.
Haemodialysis-dependent chronic kidney disease: In a study of haemodialysis patients (VIT-IV-CL-015), the primary response rate, defined as an increase in Hb of at least 1 g/dL at 4 weeks after baseline, was 46.4% in the ferric carboxymaltose group and 37.2% in the Venofer group.
Non-dialysis-dependent chronic kidney disease: In a pre-dialysis chronic kidney disease population (1VIT04004), 1 to 3 doses of ferric carboxymaltose (over 2 to 4 weeks) was shown more effective than 8 weeks of three times daily (TID) oral iron therapy across all primary and secondary ranked efficacy endpoints, and a statistically significant (p<0.001) greater proportion of subjects in the ferric carboxymaltose group (60.4%) compared to the ferrous sulphate group (34.7%) achieved an increase in Hb ≥1 g/dL. In a 44-week long-term extension to this study (1VIT05005), the efficacy of ongoing maintenance dosing with ferric carboxymaltose was demonstrated with primary endpoint (defined as Hb ≥11.0 g/dL, ferritin 100-800 ng/mL, and TSAT 30-50% on the same visit) achieved by 51.4% of patients overall. In another study including over 400 pre-dialysis patients (1VIT07018), the safety and efficacy of a single bolus injection (≤1,000 mg iron) of ferric carboxymaltose was compared to 30 days of standard medical care. The mean increases from baseline to end of study for Hb (0.54 g/dL), ferritin (294.28 ng/mL), and TSAT (10.01%) in the ferric carboxymaltose group were statistically significantly (p≤0.009) greater than those observed in the standard medical care group (0.31 g/dL, 109.72 ng/mL, and 4.87%, respectively).
Gastroenterology: Inflammatory bowel disease: In a population with inflammatory bowel disease the correction of iron deficiency anaemia via administration of ferric carboxymaltose was observed. In VIT-IV-CL-008, short treatment with ferric carboxymaltose (1 to 2 weeks) was shown to be non-inferior to 12 weeks of twice daily (BID) oral iron therapy: the mean increase in Hb from baseline to Week 12 was 3.83 g/dL in the ferric carboxymaltose group and 3.75 g/dL oral iron group. In the FER-IBD 07-COR study, a simplified dosing schedule (based on Hb and body weight) for ferric carboxymaltose was significantly more effective in improving anaemia by Week 12 compared to Venofer administered per Ganzoni formula. The percentage of responders achieving a Hb increase ≥2 g/dL at Week 12 was 66.06% in the ferric carboxymaltose group and 54.14% in the Venofer group (p=0.008), and 83.77% of ferric carboxymaltose patients (versus 75.91% Venofer) achieved a Hb increase ≥2 g/dL or had Hb within World Health Organisation defined normal limits at Week 12 (p=0.019).
Women's health: Post partum: In gynaecology, 3 studies in post-partum patients and 1 study in patients with heavy uterine bleeding, 1 to 3 doses of ferric carboxymaltose were compared to oral ferrous sulphate 3 times daily for 6 weeks (1VIT06011, 1VIT03001, 1VIT04002/04003) or twice daily for 12 weeks (VIT-IV-CL-009). In post-partum study 1VIT06011, the proportion of patients achieving a Hb level >12 g/dL was statistically significantly (p<0.0001) greater in the ferric carboxymaltose group (91.4%) compared to the ferrous sulphate group (66.7%). In the latter 2 post-partum studies, non-inferiority of ferric carboxymaltose compared to oral iron was demonstrated for the primary Hb endpoints: In study 1VIT03001, the proportion of subjects achieving an increase in Hb levels of ≥2.0 g/dL was 96.4% in the ferric carboxymaltose group and 94.1% in the ferrous sulphate group. In study (VIT-IV-CL-009), the mean change in Hb from baseline to Week 12 was 3.37 g/dL in the ferric carboxymaltose group and 3.29 g/dL in the oral iron group. In the heavy uterine bleeding study 1VIT04002/04003) the proportion of patients who achieved an increase in Hb of ≥2.0 g/dL was statistically significantly (p<0.001) greater in the ferric carboxymaltose group (82.0%) compared with the oral ferrous sulphate group (61.8%).
In another study including over 2,000 patients with either heavy uterine bleeding or post-partum iron deficiency anaemia (1VIT07017), the safety and efficacy of a single bolus injection (≤1,000 mg iron) of ferric carboxymaltose was compared to standard medical care. A statistically significantly greater proportion of subjects in the ferric carboxymaltose group (68.1%) achieved an Hb value >12 g/dL compared to subjects in the standard medical care group (50.7%) who received oral iron.
Pregnancy: Intravenous iron medicines should not be used during pregnancy unless clearly necessary. Treatment with 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 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 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 Ferinject treated women and those treated with oral iron (11.4% 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.
Pharmacokinetics: Distribution: Using positron emission tomography (PET) it was demonstrated that ⁵⁹Fe and ⁵²Fe from 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 Ferinject of 100 to 1000 mg of iron in iron deficient patients, maximum total serum iron levels of 37 μg/ml up to 333 μg/ml after 15 minutes to 1.21 hours respectively are obtained. 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.
Toxicology: Pre-clinical safety data: Pre-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and genotoxicity. Pre-clinical studies indicate that iron released from Ferinject does cross the placental barrier and is excreted in milk in limited, controlled amounts. In reproductive toxicology studies using iron replete rabbits 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 Ferinject. No evidence of allergic or immunotoxic potential has been observed. A controlled in-vivo test demonstrated no cross-reactivity of Ferinject with anti-dextran antibodies. No local irritation or intolerance was observed after intravenous administration.