Download PDF
Arzneimittelforschung 2010; 60(6): 373-385
DOI: 10.1055/s-0031-1296302
Ferric Carboxymaltose
Editio Cantor Verlag Aulendorf (Germany)

Pharmacodynamics and safety of ferric carboxymaltose: a multiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder

Peter Geisser
1   Vifor (International) Inc., St. Gallen, Switzerland
,
Vitaly Rumyantsev
2   Central Scientific Institute of Gastroenterology of Moscow Health Committee, Moscow, Russia
› Author Affiliations
Further Information

Publication History

Publication Date:
21 December 2011 (online)

    Permissions and Reprints

Abstract

This multiple-dose Phase I/II study provided pharmacodynamics and pharmacokinetics data on the therapeutic benefit of ferric carboxymaltose (FCM, Ferinject®) and evaluated the safety and tolerability of this intravenous (i. v.) iron preparation. Two doses of iron as FCM were given as i.v. infusion over 15 min, 500 mg iron given once weekly for up to 4 weeks (Cohort 1) or 1000 mg iron weekly for 2 weeks (Cohort 2), in patients with a total requirement ≥ 1000 mg iron (total cumulative maximum dose ≤ 2000 mg iron). Adults with moderate to severe, stable iron-deficiency anaemia (IDA) (haemoglobin [Hb] ≤11.0 g/dl, serum ferritin <100 µg/l, transferrin saturation [TSAT] <16%) due to a gastrointestinal (GI) disorder were included. Pharmacodynamics variables: proportion of patients achieving values within the reference range for Hb (men: 14.0–18.0 g/dl, women: 12.0–16.0 g/dl), serum ferritin (20–500 µg/1), TSAT (16–45%) and proportion of patients with an increase in Hb of at least 2.0 g/dl. Pharmacokinetics variables: total serum iron levels at time of maximum serum iron concentration during the fast elimination phase and at trough time-points. Safety assessments: the incidence of adverse events (AEs) and changes in vital signs, physical examinations, and clinical laboratory parameters. In Cohorts 1 and 2, 14/20 (70%) versus 19/26 (73%) of patients completed the study. Individual calculated iron deficits were 1000–2100 mg. The mean cumulative dose of FCM in Cohorts 1 and 2 was 1800 mg and 1563 mg iron, respectively. At baseline, patients in both cohorts had similar Hb levels (mean 8.7 g/dl in both cohorts). More than 97% of patients demonstrated a clinically meaningful increase in Hb levels (≥ 1.0 g/dl) during the study. By the week 4 follow-up visit, an increase of at least 2.0 g/dl was achieved by 15/20 (75%) and by 19/26 (73.1%) patients in Cohorts 1 and 2, respectively, and the mean increase in Hb was 3.2 g/dl in Cohort 1 and 3.3 g/dl in Cohort 2. By day 28, 3/6 (50%) patients in Cohort 1 had achieved normal Hb levels, and by the 4-week post-treatment follow-up visit 7/19 patients (37%) in Cohort 1 and 12/25 (48%) in Cohort 2 had reached Hb levels within the reference range. Serum ferritin levels increased rapidly at the start of treatment and remained in the reference range throughout the study; increases were greater in Cohort 2. Mean baseline TSAT values were similar in both cohorts (24.2% in Cohort 1, 20.7% in Cohort 2), and were within the reference range at the week 4 follow-up visit for 41.0 and 39.1% of the patients in Cohorts 1 and 2, respectively. The incidence of AEs occurring after the first administration of FCM (treatment-emergent AEs, TEAE) was generally low and similar in Cohorts 1 (11/20 [55.0%]) and 2 (13/26 [50.0%]). Most TEAEs were mild; only 2/20 patients (10.0%) in Cohort 1 and 3/26 (11.5%) in Cohort 2 had TEAEs of moderate intensity. There were no AEs of severe intensity, serious AEs, or deaths. Most AEs were considered by the investigator to be unrelated or unlikely to be related to the study medication. Since accumulation of serum iron was not observed, a dosing interval of 3–4 days (500 mg iron) or 1 week (1000 mg iron) was demonstrated to be adequate. The increase in serum ferritin and TSAT at the 4-week follow-up visit is indicative of a repletion of the iron stores. The results suggest that doses up to 1000 mg i. v. iron administered as FCM over 15 min are well tolerated and effective in the treatment of patients with IDA due to a GI disorder.

Key words

Anaemia - Crohn’s disease - Ferinject® - Ferric carboxymaltose - Inflammatory bowel disease - Intravenous iron - Iron deficiency
 

  • References

  • 1 Umbreit J. Iron deficiency: a concise review. Am J Hematol. 2005; 78 (3) 225-31
    CrossrefPubMedGoogle Scholar
  • 2 World Health Organization Iron deficiency anaemia. Assessment, prevention, and control. A guide for programme managers. Report No. Document WHO/NHD/1.3 Geneva: World Health Organization; 2001
    Google Scholar
  • 3 Cavill I, Auerbach M, Bailie GR, Barrett-Lee P, Beguin Y, Kaltwasser P et al. Iron and the anaemia of chronic disease: a review and strategic recommendations. Curr Med Res Opin. 2006; 22 (4) 731-7
    CrossrefPubMedGoogle Scholar
  • 4 Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004; 53 (8) 1190-7
    CrossrefPubMedGoogle Scholar
  • 5 Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel Dis. 2000; 6 (2) 142-50
    CrossrefPubMedGoogle Scholar
  • 6 Dejaco C, Gasche C. [Anemia in chronic inflammatory intestinal disease: an often underestimated problem]. Dtsch Med Wochenschr. 2002; 127 (15) 805-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Child JA, Brozovic B, Dyer NH, Mollin DL, Dawson AM. The diagnosis of iron deficiency in patients with Crohn’s disease. Gut. 1973; 14 (8) 642-8
    CrossrefPubMedGoogle Scholar
  • 8 Locatelli F. Appendix B: assessment of iron stores and functional iron deficiency. Nephrol Dial Transplant. 2004; 19 (Suppl 2) 39-41
    CrossrefPubMedGoogle Scholar
  • 9 Royal College of Physicians. National Collaborating Centre for Chronic Conditions. Anaemia management in chronic kidney disease: national clinical guideline for management in adults and children. Available from: http://guidance.nice.org.uk/CG39/Guidance/pdf/English Accessed 18 June 2009.
    PubMed
  • 10 Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckardt KU et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004; 19 (Suppl 2) ii1-ii47
    CrossrefPubMedGoogle Scholar
  • 11 MacDougall IC, Cavill I, Hulme B, Bain B, McGregor E, McKay P et al. Detection of functional iron deficiency during erythropoietin treatment: a new approach. Br Med J. 1992; 304 (6821) 225-226
    CrossrefPubMedGoogle Scholar
  • 12 Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood. 1992; 80 (7) 1639-1647
    PubMedGoogle Scholar
  • 13 Means RT Jr. Advances in the anemia of chronic disease. Int J Hematol. 1999; 70 (1) 7-12
    PubMedGoogle Scholar
  • 14 Crichton RR, Danielson BG, Geisser P. Iron therapy –with special emphasis on intravenous administration. 4th ed Bremen: UNI-Med; 2008
    Google Scholar
  • 15 De Domenico I, McWey Ward D, Kaplan J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nature. 2008; 9: 72-81
    PubMedGoogle Scholar
  • 16 Gasche C, Berstad A, Befrits R, Beglinger C, Dignass A, Erichsen K et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis. 2007; 13 (12) 1545-53
    CrossrefPubMedGoogle Scholar
  • 17 Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol Dial Transplant. 2005; 20 (7) 1443-9
    CrossrefPubMedGoogle Scholar
  • 18 Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006; 21 (2) 378-82
    CrossrefPubMedGoogle Scholar
  • 19 Fishbane S, Kowalski EA. The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate. Semin Dial. 2000; 13 (6) 381-4
    PubMedGoogle Scholar
  • 20 Schreiber S, Howaldt S, Schnoor M, Nikolaus S, Bauditz J, Gasche C et al. Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. N Engl J Med. 1996; 334 (10) 619-23
    CrossrefPubMedGoogle Scholar
  • 21 Fiechter R, Batschwaroff M, Conen D. [Anaphylactic reaction after Fe-injection]. Schweiz Rundsch Med Prax. 2005; 94 (6) 209-12
    PubMedGoogle Scholar
  • 22 Funk F, Ryle P, Canclini C, Neiser S, Geisser P. The new generation of intravenous iron: chemistry, pharmacology and toxicology of ferric carboxymaltose. Arzneimittelforschung. 2010; 60 (6a) 345-353
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Beshara S, Sorensen J, Lubberink M, Tolmachev V, Langstrom B, Antoni G et al. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol. 2003; 120 (5) 853-9
    CrossrefPubMedGoogle Scholar
  • 24 Geisser P, Banké-Bochita J. Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia. Arzneimittelforschung. 2010; 60 (6a) 362-372
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Ganzoni AM. [Intravenous iron-dextran: therapeutic and experimental possibilities]. Schweiz Med Wochenschr. 1970; 100 (7) 301-3
    PubMedGoogle Scholar
  • 26 Kumar V, Hagler HK Normal reference range table. Interactive case study companion to Robbins pathologic basis of disease. 6th ed. Available from: http://pathcuric1.swmed.edu/PathDemo/nrrt.htm Accessed 25 October 2008.
    PubMed
  • 27 Longmore JN, Wilkinson I, Török E. Oxford handbook of clinical medicine. 5th ed. Oxford: Oxford University Press; 2001
    Google Scholar
  • 28 Gasche C, Dejaco C, Waldhoer T, Tillinger W, Reinisch W, Fueger GF et al. Intravenous iron and erythropoietin for anemia associated with Crohn disease. A randomized, controlled trial. Ann Intern Med. 1997; 126 (10) 782-7
    CrossrefPubMedGoogle Scholar
  • 29 KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target Am J Kidney Dis. 2007; 50 (3) 471-530
    CrossrefPubMed
  • 30 Cavill I. Iron status as measured by serum ferritin: the marker and its limitations. Am J Kidney Dis. 1999; 34 (4 Suppl 2) S12-S17
    CrossrefPubMedGoogle Scholar
  • 31 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005; 352 (10) 1011-23
    CrossrefPubMedGoogle Scholar
  • 32 Ali M, Rigolosi R, Fayemi AO, Braun EV, Frascino J, Singer R. Failure of serum ferritin levels to predict bone-marrow iron content after intravenous iron-dextran therapy. Lancet. 1982; 1 (8273) 652-5
    PubMedGoogle Scholar
  • 33 Beshara S, Lundqvist H, Sundin J, Lubberink M, Tolmachev V, Valind S et al. Pharmacokinetics and red cell utilization of iron(III) hydroxide-sucrose complex in anaemic patients: a study using positron emission tomography. Br J Haematol. 1999; 104 (2) 296-302
    CrossrefPubMedGoogle Scholar
  • 34 Yee J, Besarab A. Iron sucrose: the oldest iron therapy becomes new. Am J Kidney Dis. 2002; 40 (6) 1111-21
    PubMed
  • 35 Chandler G, Harchowal J, MacDougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis. 2001; 38 (5) 988-91
    CrossrefPubMedGoogle Scholar
  • 36 Schaefer RM, Khasabov NN, Todorov NG, Evenepoel P. The efficacy and safety of intravenous ferric carboxymaltose compared to iron sucrose in haemodialysis patients with iron deficiency anaemia. Nephrol Dial Transplant Plus. 2008; 1 (Suppl 2) ii360
    PubMedGoogle Scholar
  • 37 Kulnigg S, Stoinov S, Simanenkov V, Dudar LV, Karnafel W, Garcia LC et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (Ferinject®) randomized controlled trial. Am J Gastroenterol. 2007; 102: 1-11
    CrossrefPubMedGoogle Scholar
  • 38 Schröder O, Mickisch O, Seidler U, de WA, Dignass AU, Herfarth H et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease –a randomized, controlled, open-label, multicenter study. Am J Gastroenterol. 2005; 100 (11) 2503-9
    CrossrefPubMedGoogle Scholar