Venofer Mechanism of Action

Pharmacotherapeutic group: Anti-anaemic preparation, iron, parenteral preparation. ATC code: B03 AC.
Pharmacology: Pharmacodynamics: Mechanism of action: Iron sucrose, the active ingredient of Venofer, is composed of a polynuclear iron(III)-hydroxide core surrounded by a large number of non-covalently bound sucrose molecules. The complex has a weight average molecular weight (Mw) of approximately 43 kDa. The polynuclear iron core has a structure similar to that of the core of the physiological iron storage protein ferritin. The complex is designed to provide, in a controlled manner, utilisable iron for the iron transport and storage proteins in the body (i.e., transferrin and ferritin, respectively).
Following intravenous administration, the polynuclear iron core from the complex is taken up predominantly by the reticuloendothelial system in the liver, spleen, and bone marrow. In a second step, the iron is used for the synthesis of Hb, myoglobin and other iron-containing enzymes, or stored primarily in the liver in the form of ferritin.
Clinical efficacy and safety: Nephrology: Dialysis dependent chronic kidney disease: Study LU98001 was a prospective, open-label, single arm study to investigate the efficacy and safety of Venofer in hemodialysis patients with iron deficiency anaemia (Hb concentration >8 and <11.0 g/dl, TSAT <20%, and serum ferritin <300 μg/l) who were receiving rHuEPO therapy. A total of 77 patients [44 (57%) male; mean age 62.5 (range: 24-85 years)] participated in the study and received 100 mg of iron as Venofer administered via the dialysis line for up to 10 sessions over 3 to 4 weeks. A mean total dose of 983.1 ±105.63 mg of iron as Venofer was administered over a mean of 9.8 ±1.06 dialysis sessions. A Hb >11 g/dl was attained in 39/45 (87%; 95% CI 76.5, 96.9) of evaluable patients. Similar results were observed in the ITT population 60/77 (78%; 95% CI 68.5, 87.3). The maximum increase in serum ferritin from 83.6 ±11.69 μg/l to 360.3 ±36.81 μg/l (n=41) was seen at the completion of treatment with Venofer. The maximum increase in TSAT from 17.1 ±1.5% to 27.6 ±2.7% (n=41) was seen at the 5-week follow-up visit.
Non-dialysis dependent chronic kidney disease: Study 1VEN03027 was an open-label, randomised study comparing Venofer and oral ferrous sulfate in adult patients with renal insufficiency and iron deficiency anemia (Hb ≤11.0 g/dl, serum ferritin ≤300 μg/l, and TSAT ≤25%) with or without rHuEPO therapy. Patients were randomized to 1000 mg of iron as Venofer (500 mg infusion over 3.5 to 4 hours on Days 0 and 14, or 200 mg injections administered over 2 to 5 minutes on 5 different occasions from Day 0 to Day 14) or oral ferrous sulfate 325 mg (65 mg iron), 3 times daily for 56 days. A total of 91 patients were included in each treatment group. A statistically significant greater proportion of patients in the Venofer group (35/79; 44.3%) compared to the oral iron group (23/82; 28.0%) had an increase in Hb >1.0 g/dl during the study (p=0.0344). A clinical response (defined as Hb increase ≥1.0 g/dl and serum ferritin increase ≥160 μg/l) was more frequently observed in patients treated with Venofer (31/79; 39.2%) compared to oral iron (1/82; 1.2%); p<0.0001.
Gastroenterology: A randomised, controlled study compared Venofer with oral iron in 91 patients with irritable bowel disease and anaemia (Hb <11.5 g/dl). Patients were randomised to receive either oral ferrous sulfate tablets 200 mg twice daily (n=46) or Venofer (n=45) given as either a single I.V. dose of 200 mg of iron once per week or every second week for 20 weeks. Forty-three patients in the Venofer group completed the study compared to 35 patients in the oral iron group (p=0.0009). At the end of treatment, 66% of patients in the Venofer group had an increase in Hb ≥2.0 g/dl compared to 47% in the oral iron group (p=0.07). In the oral iron group, 41% of patients had anaemia at the end of study compared to 16% in the Venofer group (p=0.007). Forty-two percent of patients in the Venofer group reached their reference Hb (15 g/dl in males and 13 g/dl in females) compared to 22% in the oral iron group (p=0.04).
Post partum: A prospective, randomised, controlled trial in 43 women with postpartum iron deficiency anaemia (Hb <9 g/dl and serum ferritin <15 μg/l at 24-48 hours post-delivery) compared 2 x 200 mg of iron as Venofer given on Days 2 and 4 (n=22) to 200 mg of oral iron as ferrous sulfate given twice daily for 6 weeks (n=21). Significantly higher Hb levels were observed in the Venofer group compared to the oral iron group on Days 5 and 14 (p <0.01). The mean increase in Hb from baseline at Day 5 was 2.5 g/dl in the Venofer group and 0.7 g/dl in the oral iron group. By Day 40 there was no significant difference in Hb levels between the treatment groups. There was a significant increase in serum ferritin in the Venofer group by Day 5 and the serum ferritin remained significantly higher in the Venofer group compared to the oral iron group throughout the study (p<0.01 at Days 5 and 14 and p<0.05 at Day 40).
Pregnancy: In a randomised, open label study 90 women in their third trimester of pregnancy with iron deficiency anaemia (Hb 8 to 10.5 g/dl and serum ferritin <13 μg/l) were randomized to Venofer (n=45) or oral iron polymaltose complex (n=45). The individually calculated total dose of iron as Venofer was administered over 5 days with a maximum single dose of 200 mg given as an infusion and a maximum daily dose of 400 mg iron. The oral iron group received 100 mg iron as tablets thrice daily until delivery. The change in Hb from baseline was significantly greater in the Venofer group compared to the oral iron group at day 28 and at delivery (p<0.01). At delivery the number of patients reaching Hb target was 43 (95.6%) and 28 (62.2%) in the Venofer and oral iron groups, respectively (p<0.001). Serum ferritin values increased significantly over time in both the Venofer (p<0.05) and oral iron (p<0.05) groups.
Pharmacokinetics: Distribution: The ferrokinetics of iron sucrose labelled with 52Fe and 59Fe were assessed in 6 patients with anaemia and chronic renal failure. In the first 6-8 hours, 52Fe was taken up by the liver, spleen and bone marrow. The radioactive uptake by the macrophage-rich spleen is considered to be representative of the reticuloendothelial iron uptake.
Following intravenous injection of a single 100 mg iron dose of iron sucrose in healthy volunteers, maximum total serum iron concentrations were attained 10 minutes after injection and had an average concentration of 538 μmol/l. The volume of distribution of the central compartment corresponded well to the volume of plasma (approximately 3 litres).
Biotransformation: Upon injection, sucrose largely dissociates and the polynuclear iron core is mainly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow. At 4 weeks after administration, red cell iron utilization ranged from 59 to 97%.
Elimination: The iron sucrose complex has a weight average molecular weight (Mw) of approximately 43 kDa, which is sufficiently large to prevent renal elimination. Renal elimination of iron, occurring in the first 4 hours after injection of a Venofer dose of 100 mg iron, corresponded to less than 5% of the dose. After 24 hours, the total serum iron concentration was reduced to the pre-dose level. Renal elimination of sucrose was about 75% of the administered dose.
Toxicology: Preclinical safety data: Nonclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and toxicity to reproduction and development.