Ferinject ®: Carboximaltosa de hierro para la corrección de anemia
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Ferinject ®: Carboximaltosa de hierro para la corrección de anemia
- 1. ferinject ® Carboximaltosa de hierro
- 3. Diagrama conceptual de la relación entre deficiencia de hierro y anemia en una población hipotética Población total Anemia Anemia por deficiencia de hierro (IDA) Deficiencia hierro
- 6. Déficit de hierro 1 g/dL Hb = 150 - 200 mg Fe Depósito Fe medular 2-3 + trazas 0 0 Ferritina (μg/L) 100 ±60 <20 10 <10 Transferrina(μmol/l) 50-65 65 >70 >75 Sat transferrina (%) 35 ±15 <30 <15 <10 Crichton y col .2008 Reservas Transporte Eritrocitos Normal Depleción férrica Eritropoyesis ferropénica Anemia ferropénica
- 7. Déficit de hierro Etapa 1: Depleción de hierro Crichton y col .2008 Reservas Transporte Eritrocitos Normal Depleción férrica Eritropoyesis ferropénica Anemia ferropénica Depósito Fe medular 2-3 + trazas Ferritina (μg/L) 100 ±60 <20 Transferrina(μmol/l) 50-65 65 Sat transferrina (%) 35 ±15 <30 El paciente no presenta síntomas y los niveles de Hb son normales Consecuencia: aumento en la absorción del hierro Los depósitos disminuyen Ferritina disminuye
- 10. Déficit de hierro – Déficit funcional de Fe SAT < 20% saturación de transferrina Indica que la eritropoyesis tiene déficit de hierro Valor normal: 30-40% %GRH > 5%. % de globulos rojos hipocrómicos Es la valoración idónea para medir la disponibilidad de hierro (EBPG*). Indica la cantidad de hierro en los glóbulos rojos. Mide el porcentaje de éstos que poseen una concentración de hemoglobina inferior a 28g/dl. Valor normal es < 2,5%. Ferritina >100 μg/L Normal o aumentada ! Característica de procesos inflamatorios. Valor normal: 100±60 “ Aquella situación en la cual el hierro no es liberado con la rapidez suficiente como para satisfacer las demandas de la médula ósea para la eritropoyesis, a pesar de presentar un depósito corporal de hierro adecuado o incluso aumentado. (Eschbach 1987) ” *European Best Practices Guidelines
- 12. Parámetros para la evaluación de status de hierro Chricton et al. 2008 Parámetro Evaluación Valores deseados Niveles de ferritina Depósitos de hierro >250 ug/Litro Saturación de transferrina (SAT) Hierro funcional 30-40% Proporción de glóbulos rojos hipocrómicos Deficiencia funcional de hierro <2.5% Contenido de hemoglobina en reticulocitos Deficiencia funcional de hierro 35 pg/cell Receptores solubles de transferrina sérica Déficit de hierro Mujeres: 1.9 – 4.4 mg/litro Hombres: 2.2 – 5 mg/litro
- 35. Complejo de hierro Transferrina Unión hierro a transferrina hierro lábil Hierro total sérico Transporte de hierro Tipos de hierro tras su administración
- 36. Complejo de hierro Transferrina Unión hierro a transferrina hierro lábil Hierro total sérico Transporte de hierro Crichton, Danielson and Geisser , ISBN 3-89599-880-X (2005) Tipos de hierro tras su administración =
- 38. ferinject Transferrina Unión hierro a transferrina hierro lábil Hierro total sérico Transporte de hierro Tras administración de ferinject ®
- 39. ferinject Transferrina Unión hierro a transferrina hierro lábil Hierro total sérico Transporte de hierro Eliminación renal Tras administración de ferinject ®
- 40. Efectos adversos inmediatos Eventos adversos en las primeras 24h de tratamiento, >1 sujeto Efecto Adverso FCM (n=559) n (%) Placebo (n=559) n (%) Hipotensión 6 (1.07) 7 (1.25) Náuseas 17 (3.04) 8 (1.4) Mareos 7 (1.3) 3 (0.5) Dispepsia 4 (0.7) 0 Diarrea 3 (0.5) 6 (1.1) Dolor abdominal 3 (0.5) 1 (0.2) Vómitos 2 (0.4) 1 (0.2) Dolor torácico 2 (0.4) 1 (0.2) Dolor espalda 2 (0.4) 2 (0.4) Disnea 2 (0.4) 0 Alt. abdominales 0 2 (0.4)
- 43. Concentración media de hierro en suero (µg/ml) Geisser, ERA 2008 Parámetro media (SD) 100 mg 500 mg 800 mg 1,000 mg Cmax ( µg/mL) 37 (4) 157 (19) 324 (64) 333 (42) CL (mL/min) 4.4 (0.9) 3.5 (0.5) 2.59 (0.5) 2.7 (0.6)
- 44. Porcentaje de saturación de transferrina Geisser, ERA 2008
- 45. Concentración media de hierro en suero (µg/ml) Hierro total sérico ( µ g/ml) 500 450 400 300 250 200 0 Day 1 6 h Day 8 1 h Day 11 1000 mg 500 mg Pd = pre-dosis 150 50 Day 15 2 h Day 21 Day 22 6 h Tiempo(h) (eje no proporcional) 350 100 Day 1 pd Day 1 1 h Day 1 2 h Day 1 4 h Day 4 Day 7 Day 8 pd Day 8 2 h Day 8 4 h Day 8 6 h Day 14 Day 15 pd Day 15 4 h Day 15 6 h Day 18 Day 22 pd Day 22 2 h Day 22 4 h Day 25 Day 26 Day 15 1 h Day 22 1 h 2 w post 2 w post (Las barras indican standard deviations) Dosis múltiples Data on file No muestra acumulación de hierro luego de dosis repetidas
- 46. 1 ferinject SPC 6 Danielson BG, 1996 7 Wood JK, 1968 100% 80% 60% 50% 0 3 6 9 12 Iron dextran ferinject ® Iron sucrose 40% 20% 0 15 18 21 24 27 30 Time (hours) 33 36 Semivida de eliminación Eliminacion de Ferinject del suero es de 16 horas
- 47. Ferric carboxymaltose: objectives for development 5 Beshara S, 2003 SUV 40 35 30 25 20 15 0 50 100 150 200 Sangre Médula ósea Hígado Bazo 10 5 0 250 300 350 400 450 500 Time (min) Distribución de hierro en el organismo: free iron toxicity + liberación dirigida hacia la médula ósea Utilización por los GR es del 61-99%
- 49. El hierro se almacena en los depósitos fisiológicos de hierro Ferric carboxymaltose: objectives for development Parenquima SRE Datos preclínicos: Depósitos Unidades relativas 6 5 4 3 2 1 0 4d ferinject ® 4d Hierro dextrano 4d Hierro sacarosa 4d Hierro gluconato
- 50. Elevado porcentaje de utilización Ferric carboxymaltose: objectives for development Beshara S, 2003 Utilización (%) 100 90 80 60 50 40 0 4 8 12 Paciente1 (anemia con deficiencia de hierro) Paciente 4 (deficiencia de hierro, no anemia) Paciente 2 (anemia con deficiencia de hierro)) Paciente 5 (anemia renal, déficit funcional) Paciente 3 (anemia con deficiencia de hierro) Paciente 6 (anemia renal, déficit funcional) 30 10 0 16 20 24 28 Tiempo (días) 70 20 % utilización de ferinject ® Alta utilización del hierro, hasta superior al 99%
- 54. Dosificación CORRECIÓN RÁPIDA Y CÓMODA DE LA ANEMIA Y DE LA DEFICIENCIA DE HIERRO Dosis de hierro para la corrección de la anemia por déficit de hierro (adaptada de Ganzoni)* Peso (kg) y Cálculo de la necesidad total de hierro (mg) Anemia leve/moderada Rango de dosis Dosis de ferinject ® 500-1000 mg Dosis única (15 min) Anemias severas Rango de dosis** Dosis de ferinject ® > 1000 mg 2 infusiones (separadas 1 semana) * La dosis de hierro es redondeada a múltiplo de 100. ** Aplica a pacientes con peso normal. Para evitar la sobrecarga de hierro la dosis calculada no debe excederse
- 57. * Por razones de estabilidad, se deben evitar diluciones menores de 2 mg de hierro/ml. Solo se debe usar solución de cloruro sódico al 0.9% para la dilución Máxima dosis infundida: 15 mg/kg o 1000 mg de hierro por semana Dosificación CORRECIÓN RÁPIDA Y CÓMODA DE LA ANEMIA Y DE LA DEFICIENCIA DE HIERRO Dosis semanal máxima hasta la dosis calculada máxima de 2500mg Infusión intravenosa Cantidad de hierro por administración Número de viales Dilución máxima* Tiempo mínimo de administración No hay límite de tiempo 6 minutos 15 minutos Utilidad de los viales pequeños SIN DOSIS DE PRUEBA
- 58. Dosificación CORRECIÓN RÁPIDA Y CÓMODA DE LA ANEMIA Y DE LA DEFICIENCIA DE HIERRO Cantidad de hierro por administración Número de viales Dilución Velocidad de administración Administración en bolus Máxima dosis en bolus: 600 mg/ semana (200 mg 3x/semana) SIN DOSIS DE PRUEBA
- 66. 2080 sujetos expuestos a Ferinject en 12 estudios multicéntricos y 2 estudios PK/PD Postpartum VIT-IV-CL-009 ( Breymann) 1VIT-03001(Van Wyck ) 1VIT-06011 1VIT-05006 N=700 Hemodialisis VIT-IV-CL-015 *( Schaefer) VIT-53214 VIT-05006 N=300 HUB VIT-04002/VIT-04003 (Gordon) VIT-05006 N=352 IBD VIT-IV-CL-008 (Kulnigg) VIT-IV-CL-03 VIT-05006 N=247 CKD VIT-04004 (Quinibi) VIT-05005 VIT-05006 N=228 Otros VIT-05006 (Seid) N=1153 PK/PD VIT-IV-CL-01 VIT-IV-CL-02 N=30 ICC FER-CARS-01* N=30 * Comparado con hierro sacarosa COMPARADORES (N=1571) Hierro oral = 834 , hierro sacarosa = 145 , Placebo = 592 Ensayos clínicos
- 68. Buena cantidad de evidencia clinica en varias areas terapeuticas Ob&Gyn VIT-IV-CL-009 1VIT03001 1VIT06011 1VIT04002/03 HD 53214 VIT-IV-CL-015 CKD 1VIT04004 1VIT05005 IBD VIT-IV-CL-008 Estudios fase 2 y 3 Seguridad 1VIT05006
- 80. Ferinject ® en IBD Patients – 4 (Study: VIT-IV-CL-008) Efectiva y rápida corrección de la anemia … DOSIS Ferinject ® : La media calculada de dosis de hierro fue de 1405.5 mg (rango 937–2102 mg) y requirió 1–3 administraciones por individuo en dosis semanales. Ferrous sulfate: 2x 100 mg/dia por 12 semanas (total 16800 mg). No-inferioridad al Ferinject ® confirmado en el primary endpoint.
- 81. Ferinject ® en IBD Patients – 5 (Study: VIT-IV-CL-008) … y del déficit de los depósitos de hierro DOSIS Ferinject ® : La media calculada del déficit de hierro fue de 1405.5 mg (rango 937–2102 mg), requiriendo 1–3 administraciones por individuo con intervalos semanales por dosis. Ferrous sulfate: 2x 100 mg/dia por 12 sem (total 16800 mg). No-inferioridad al Ferinject ® confirmado en el primary endpoint.
- 88. Ferinject ® en HD Patients – 4 (Study: VIT-IV-CL-015) Ferinject ® muestra eficacia mas pronunciada en todos los parámetros de eficacia investigados y es, por lo menos, tan seguro como Venofer ®
- 92. Ferinject ® en CKD Patients – 4 (Study: 1VIT04004 ) Ferinject ® es significativamente superior al hierro oral en incrementar Hb y repletar los depositos de hierro en pacientes con o sin tratamiento concomitante de EPO
- 99. Ferinject ® en PP Anaemia Patients – 4 (Study: VIT-IV-CL-009) Ferinject ® es no-inferior en el incremento de la Hb, sin embargo, es significativamente superior al hierro oral, en la respuesta de la ferritina
- 103. Ferinject ® en PP Anaemia Patients – 4 (Study: 1VIT03001) Ferinject ® alcanzó el exito en mas del 90% en incrementar Hb (> 2.0 g/dl)
- 104. Ferinject ® en PP Anaemia Patients – 5 (Study: 1VIT03001) Ferinject ® es significativamente superior al hierro oral en términos de corrección de la anemia, tiempo para el éxito, repleción de los depósitos de hierro y en el ratio de desórdenes gastrointestinales
- 105. Ferinject ® en PP Anaemia Patients – 6 (Study: 1VIT03001) Ferinject ® es significativamente superior al hierro oral en corregir la anemia independientemente de la severidad inicial Baseline Hb
- 109. Ferinject ® en PP Anaemia Patients – 4 (Study: 1VIT06011) Ferinject ® es significativamente superior al hierro oral en normalizar la hemoglobina y repletar los depósitos de hierro
- 113. Ferinject ® en HUB Patients – 4 (Study: 1VIT04002/1VIT04003) Ferinject ® es significativamente superior al hierro oral en corregir la anemia, con éxito sostenido y de repletar los depósitos de hierro.
- 114. Estudio que investiga los efectos del tratamiento de hierro en IDA en sujetos con HMB Van Wyck DB et al. Transfusion. 2009;49:2719-28
- 117. Logro de incremento de Hb con hierro EV comparado con hierro oral Proporcion significativamente mayor de pacientes en hierro EV (ferric carboxymaltose) que alcanzaron primary y secondary endpoint comparados con hierro oral (ferrous sulphate) Van Wyck DB et al. Transfusion. 2009;49:2719-28
- 118. Tolerabilidad de hierro EV y del hierro oral Reduccion de dosis debido a evento adverso ala droga fue reportado en sólo 1 paciente en el grupo de hierro EV; sin embargo, en el grupo de hierro oral, 27 pacientes con hierro oral, requerieron modificar la dosis o suspender tratameitno debido a evento adverso Van Wyck DB et al. Transfusion. 2009;49:2719-28 Oral iron (%) I.V. iron (%) Constipacion 14.2 3.0 Nausea 11.9 3.5 Diarrea 4.4 1.7 Dolor de cabeza 4.4 6.5 Vomitos 3.1 0.4 Mareos 0.4 2.2 Fatiga transitoria 0 2.2 Rash 0 2.2
- 122. Buena y abundante evidencia clinica de Ferric Carboxymaltose en muchas áreas terapéuticas ND-CKD: Non-dialysis Chronic Kidney Disease PP: Post Partum IBD: Inflammatory Bowel Disease HD-CKD: CKD stage 5 (Hemodialysis) CHF: Chronic Heart Failure HMB: Heavy Menstrual Bleeding Publication in peer-reviewed journal Presented at international congress Hem/Onc Steinmetz 2010 PP & HUB Breymann 2008 (PP) Van Wyck 2007 (PP) Seid 2008 (PP) Van Wyck 2009 (HMB) IBD Kulnigg 2007 Evstatiev 2010 Safety Bailie 2010 Qunibi 2008 HD-CKD Covic/Mircescu 2010 Evenepoel 2009 ND-CKD Qunibi 2010 CHF Anker NEJM 2009
- 123. Publication Plan Oncology Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2010 2011 Q1 Q2 Q3 Q4 2012 Abstract publication Manuscript publication Congress Abstracts: German NIS Patient record Prevalence data ID Full paper Health economic paper German NIS ID symptoms, Prevalence Clinical Review Preclinical Review ESMO ASH Manuscript submission DGHO EHA EHA MASCC ASCO Poster publication ASH
Notas do Editor
- Ahora veremos las diferentes etapas desde una situación normal al desarrollo de anemia ferropénica.
- El hierro ideal cubre las necesidades no satisfechas al sobrepasar las limitaciones de las preparaciones actuales: No riesgo alergenico, no riesgo de toxicidad, Permite administracion de grandes dosis en forma rapida No requiere “dosis de prueba”. Muy seguro
- To explain how ferinject’s breakthrough profile did come true, it is necessary to provide information on some underlying molecular mechanisms that form the backbone of the two safety dimensions Immunogenicity and Free iron toxicity . Low immunogenicity basically is a direct consequence of the lack of any dextran in the formulation. In addition, it was also shown that there is no cross-reaction with dextran-antibodies. As a result, ferinject ® can be administered safely without the requirement of a test dose. The lack of labile iron toxicity is primarily due to high complex stability and targeted delivery. After injection, the complex starts releasing the iron in a controlled fashion to the endogenous transport system, ensuring highly targeted delivery to physiologic storage tissues and to the site of erythropoiesis, the bone marrow, for optimal iron utilisation. As the process is highly integrated into the metabolic pathways, there is virtually no labile iron available at any time to exert toxic effects on tissues. As a result, ferinject ® can be given as a high single dose up to 1000 mg in only 15 minutes or as a fast bolus of up to 200 mg.
- The properties of the new generation compound with the brand name ferinject® are designed to fullfill the following parameters: it is water soluble. as in ferritin, the iron is stored within the macromolecule carboxymaltose. ferinject® has a molecular weight of 150’000 Daltons which ensures minimal renal elimination.
- No histotoxicological effects at a dose of 200 mg Fe/kg b.w. have been observed after injection in mice. At this dose no necrosis of the liver was detected. After ferinject administration, the iron is deposited in the RES and not in the parenchyma and does not induce oxidative stress reactions
- The pharmacokinetics following a single intravenous infusion of 0, 100, 500, 800 or 1000mg iron as ferric carboxymaltose within 15 minutes was studied in 6 iron deficient patients. This indicated a terminal half life of 7 to 16 hours and a mean residence time of about 48 hours. The maximal total serum iron concentration after the infusion was about 300ug/ml. The most commonly reported side event was hypotension . The study concluded that dosages up to 1000mg are safe and well tolerated. A single-center, randomized, double-blind, placebo-controlled multiple dose study Study included single IV doses of 100, 500, 800 and 1,000 mg via IV infusion or bolus (Injectafer; n = 6, placebo; n = 2) A total of 32 patients were studied
- Mean total serum iron over time show no accumulation after repeated injections of ferric carboxymaltose: Several 500mg doses were compared to one 1000mg injection followed by a 500mg injection. The result showed no accumulation over time
- Serum elimination of ferric carboxymaltose (as indicated by the half-life) is 16 hours in humans. In comparison, the half-life of iron sucrose is only 5 hours.
- After injection of 100mg ferric carboxymaltose in anaemic patients [is this correct?] the compound was distributed similarly to the liver, spleen and bone marrow. However, a larger amount was rapidly distributed to the bone marrow. Splenic uptake reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. This demonstrates that high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of the complex reflects the physiologic uptake of polysaccharide complexes.
- The rapid and selective uptake by the bone marrow (BM) is also evidenced through PET-imaging of tracer-labelled drug. In this patient, maximum radioactivity concentration in the BM after 8 h is up to 103 times higher than average body concentration, proving highly targeted delivery.
- The iron from ferric carboxymaltose is bound as polynuclear non-ionic iron III hydroxide. Due to its similarity with ferritin, ferinject® it is taken up from the plasma by the macrophages of the reticuloendothelial system. From there, the iron molecules enter the physiologic iron pathway. The sucrose shell around the complex is eliminated by the kidneys, in the same way as for iron sucrose . Only minimal amounts of carboxymaltose are absorbed by the parenchyma. Compared to iron gluconate, ferric carboxymaltose can therefore be given in much higher doses, without the risk of damaging the liver parenchyma or causing haemorrhagic necroses. Iron in the parenchyma may cause irreversible damage depending on the concentration. Toxicity occurs at much lower iron concentrations in the parenchyma, because, unlike the reticuloendothelial system, this tissue is not specialised for iron storage.
- The investigation on 6 patients showed high red cell iron utilisation up to 99%. The two patients with lower utilisation had renal anaemia but were not iron deficient and did not have functional iron deficiency. Therefore, the labelled iron was in competition with endogenous iron for incorporation in red blood cells.
- Venofer indicado para el tratamiento del déficit de hierro en las siguientes indicaciones: necesidad clínica de suministro rápido de hierro a los depósitos, pacientes que no toleren terapia con hierro oral o no se adhieran al tratamiento, en enfermedad inflamatoria intestinal activa, cuando los preparados de hierro oral sean ineficaces.
- Deficiencia de hierro acumulativa
- Anemia leve moderada: incremento de Hb 0.5-3.0
- necesidad de equipo de reanimación cardiopulmonar Valorar beneficio-riesgo No con bacteriemia en curso. No recomendado para menores de 14 años
- In order to achieve a broad labelling, Ferinject ® was clinically investigated in several therapeutic areas such as non-dialysis CKD, haemodialysis (HD), Inflammatory Bowel Disease (IBD), and Ob&Gyn including postpartum anaemia (PP) and anaemia from heavy uterine bleeding (HUB).
- With regard to safety, Ferinject ® has a very appealing profile. To date, the clinical use of single doses up to 1000 mg iron did not reveal any serious or life-threatening adverse reactions as demonstrated in the cross-over placebo-controlled study which involved different patient cohorts (renal disease, IBD and postpartum/heavy uterine bleeding). In comparative trials, the overall rate of adverse reactions was found to be less than oral iron, and similar to Venofer ® . In the comparative trial vs. Venofer ® , the administered doses were 200 mg iron bolus injections.
- One open-label comparative trial vs. oral iron in Inflammatory Bowel Disease (IBD) shows high efficacy of Ferinject ® in terms of Hb recovery/correction, and replenishment of iron stores. In addition, there were fewer GI adverse effects than in the oral iron group. This becomes even more relevant as patients with history of non-tolerance to oral iron were excluded from the study. Therefore, patients in the oral arm were expected to have a good tolerability to oral iron.
- Two studies investigated Ferinject ® in haemodialysis patients. In the non-comparative trial, Ferinject ® was shown to be safe and effective in increasing Hb to a clinically meaningful extent, without modifying EPO dosing during the study. The second study was a comparative trial vs. Venofer ® and revealed a trend towards better efficacy in all assessed parameters for Ferinject ® , while both preparations were found to be equally safe.
- Ferinject ® was investigated in two trials involving non-dialysis dependent chronic kidney disease (CKD) patients. In the first study, oral iron was the comparator regimen and Ferinject ® was found to be significantly superior to oral iron in rising Hb and replenishing iron stores in anaemic CKD patients. In addition, significantly less adverse drug events were noted in the Ferinject ® group. The second trial aimed to show benefits of a maintenance regimen with Ferinject ® , enrolling patients from the former correction-phase study. Primary objective was to achieve Hb levels at or above 11 g/dl through periodic drug administration for maintaining ferritin and TSAT levels in a given range. After 44 weeks, a high percentage of patients benefited from the maintenance treatment with Ferinject ® .
- Four clinical trials were conducted in the Ob&Gyn setting investigating the usefulness of Ferinject ® compared to oral iron in the correction of either postpartum anaemia or anaemia due to heavy uterine bleeding. In general, Ferinject ® was found to be non-inferior in Hb response and significantly superior in Hb recovery speed, and in replenishing iron stores. In some of the studies, additional efficacy parameters as the sustainability of the outcomes or quality of life (QoL) were also found to be in favour of Ferinject ® .
- Study background: The objective was to evaluate efficacy and safety of rapid, large-dose intravenous (IV) administration of ferric carboxymaltose compared to oral iron in correcting iron deficiency anemia due to heavy mentrual bleeding. Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- After enrolment onto the study, 246 patients were randomised to I.V. iron. Of these 246 patients, 16 did not receive I.V. iron and 2 patients did not have Hb levels measured after baseline. Whilst 231 patients were randomised to oral iron, of these 231 patients, 5 did not receive oral iron and 1 patient did not have Hb levels measured after baseline. Secondary measures of efficacy included change in Hb from baseline by visit; the proportion of subjects attaining a Hb level of more than 12.0 g/dL (correction of anaemia); the proportion of patients achieving an increase in Hb of 3.0 g/dL or more; time to achieve the primary outcome; peak Hb increase from baseline; time to peak Hb increase; maximum increase in ferritin, transferrin saturation, reticulocyte count, or reticulocyte Hb content (CHr); number of subjects requiring intervention; time to intervention; proportion of patients with a Hb increase of 2.0 g/dL or more combined with a ferritin increase of 160 ng/ml or more; and proportion of patients with improved quality of life. Among patients evaluated for safety, the mean cumulative per-patient dose of I.V. ferric carboxymaltose administered was 1568 mg and the mean cumulative dose of oral iron was 7302 mg. There were 483 total injections of I.V. iron administered: five patients received only one infusion, 197 patients received two infusions, and 28 received three infusions. Of the 230 patients assigned to receive I.V. iron, 225 (97.8%) received total doses that exceeded 1000 mg. Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- A significantly greater proportion of patients assigned to I.V. ferric carboxymaltose, compared to those assigned to oral iron, achieved the primary endpoint, an increase in Hb level of 2.0 g/dL or more, within 42 days after baseline (82.0% vs. 61.8%; 95% CI of treatment difference, 12.2%-28.3%; p < 0.001). Between-group differences were significant at each study visit. In patients assigned to the I.V. ferric carboxymaltose group, the proportion of patients who achieved an increase in Hb level of 3.0 g/dL or more was greater at each treatment interval after Day 14 than in those treated with oral ferrous sulphate. The proportion of patients treated with I.V. ferric carboxymaltose who experienced an increase in Hb level of more than 12.0 g/dL was greater (72.8% vs. 49.8%, 95% CI of treatment difference, 14.3-31.7; p < 0.001) than for those who were treated with ferrous sulphate. Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- Patients assigned to oral iron therapy were more likely to experience drug-related gastrointestinal complaints constipation (14.2% vs. 3.0%) nausea (11.9% vs. 3.5%) diarrhoea (4.4% vs. 1.7%) vomiting (3.1% vs. 0.4%) Whereas those assigned to I.V. iron therapy were more likely to report transient fatigue (2.2% vs. 0%) headache (6.5% vs. 4.4%) dizziness (2.2% vs.0.4%) dysgeusia (2.6% vs. 0.9%) rash (2.2% vs. 0%) The percentage of patients who discontinued from the study were 6.2% for oral iron and 8.3% for I.V. iron. Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- Compared to patients assigned to oral iron treatment, patients assigned to I.V. ferric carboxymaltose showed greater improvement in the physical component summary of SF-36. This was primarily due to a greater responses in physical functioning, vitality and role physical components. I.V. ferric carboxymaltose treated patients also showed improved resolution of fatigue in the linear analogue scale assessment. Adherence, defined as milligrams received as a percentage of milligrams prescribed, was greater among patients assigned to I.V. iron compared to those assigned to oral iron (mean percent adherence, 99.9 ± 1.2% vs. 90.3 ± 2.5%, mean ± 95% confidence interval [CI], p < 0.001). Of 129 patients in the oral iron group who showed less than 100% adherence unrelated to adverse events, 121 received counselling about the importance of taking the prescribed treatment from study personnel. Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- Reference: Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009 ;49(12):2719-28.
- The features of Ferinject ® create significant healtheconomic value through increasing clinical efficacy. The most important value propositions of Ferinject ® are the EPO sparing effect, avoidance of transfusions and the time savings for patients and health carers due to the unparalleled ease of use.