Following IV administration of Maxifer, iron sucrose is dissociated by the reticuloendothelial system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy treated with iron sucrose containing iron 100 mg 3 times weekly for 3 weeks, significant increases in serum iron and serum ferritin and significant decreases in total iron-binding capacity occurred 4 weeks from the initiation of iron sucrose treatment.
In healthy adults treated with IV doses of Maxifer, its iron component exhibits first-order kinetics with an elimination t½
of 6 hrs, total clearance of 1.2 L/hr, nonsteady state apparent volume of distribution of 10 L and steady state apparent volume of distribution of 7.9 L. Since iron disappearance from serum depends on the need for iron in the iron stores and iron utilizing tissues of the body, serum clearance of iron is expected to be more rapid in iron-deficient patients treated with Maxifer as compared to healthy individuals. The effects of age and gender on the pharmacokinetics of Maxifer have not been studied. Maxifer is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro
studies, the amount of iron sucrose in the dialysate fluid was below the levels of detection of the assay (<2 parts/million).
In healthy adults receiving IV doses of Maxifer, its iron component appears to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Maxifer containing iron 100 mg labeled with 52pe/59pe in patients with iron deficiency shows that a significant amount of the administered iron distributes in the liver, spleen and bone marrow and that the bone marrow is an iron trapping compartment and not a reversible volume of distribution.
Metabolism and Elimination:
Following IV administration of Maxifer, iron sucrose is dissociated into iron and sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single IV dose of Maxifer containing sucrose 1,510 mg and iron 100 mg in 12 healthy adults (9 female, 3 male; age range 32-52 years), 68.3% of the sucrose was eliminated in urine in 4 hrs and 75.4% in 24 hrs. Some iron is also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single IV dose of iron sucrose containing iron 500-700 mg in 26 anemic patients on erythropoietin therapy (23 female, 3 male; age range 16-60 years), approximately 5% of the iron was eliminated in urine in 24 hrs at each dose level.
Drug-drug interactions involving Maxifer have not been studied. However, like other parenteral iron preparations, Maxifer may be expected to reduce the absorption of concomitantly administered oral iron preparations.
Maxifer is used to replenish body iron stores in patients with iron deficiency on chronic hemodialysis and receiving erythropoietin. In these patients, iron deficiency is caused by blood loss during dialysis procedure, increased erythropoiesis and insufficient absorption of iron from the gastrointestinal tract. Iron is essential to the synthesis of hemoglobin to maintain oxygen transport and to the function and formation of other physiologically important heme and nonheme compounds. Most hemodialysis patients require iron IV to maintain sufficient iron stores to achieve and maintain hemoglobin of 11-12 g/dL. Three clinical trials were conducted to assess the safety and efficacy of Maxifer. Two studies were conducted in United States (100 patients) and 1 was conducted in South Africa (131 patients).
Study A was a multicenter, open-label, historically controlled study in 101 hemodialysis patients (77 patients with Maxifer treatment and 24 in the historical control group) with iron deficiency anemia. Eligibility for Maxifer treatment included patients undergoing chronic hemodialysis 3 times weekly, receiving erythropoietin, hemoglobin concentration >8 and <11 g/dL for at least 2 consecutive weeks, transferrin saturation <20% and serum ferritin <300 ng/mL. The mean age of the patients in the treatment group was 65 years with the age range being 31-85 years. The erythropoietin dose was to be held constant throughout the study. The protocol did not require administration of a test dose; however, some patients received a test dose at the physician's discretion. Exclusion criteria included significant underlying disease, asthma, active inflammatory disease, or serious bacterial or viral infection. Maxifer 5 mL (1 ampoule) containing elemental iron 100 mg was administered through the dialysis line at each dialysis session either as slow injection or a saline diluted slow infusion for a total of 10 dialysis sessions with a cumulative dose elemental iron 1,000 mg. A maximum of 3 vials of Maxifer was administered per week. No additional iron preparations were allowed until after the day 57 evaluation. The mean change in hemoglobin from baseline to day 24 (end of treatment), day 36 and day 57 was assessed. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Maxifer, who were off iron IV for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31-36 for at least 2 months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29-80 years. Patient age and serum ferritin levels were similar between treatment and historical control patients. Of the 77 patients in the treatment group, 44 (57%) were male and 33 (43%) were female. The mean baseline hemoglobin, hematocrit, were higher and erythropoietin dose was lower in the historical control population than the Maxifer-treated population. Patients in the Maxifer-treated population showed a statistically significantly greater increase in hemoglobin and hematocrit than did patients in the historical control population. (See table.)
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Serum ferritin increased significantly (p=0.0001) at endpoint of study from baseline in the Maxifer-treated population (165.3±24.2 ng/mL) compared to the historical control population (-27.6±9.5 ng/mL). Transferrin saturation also increased significantly (p=0.0016) at endpoint of study from baseline in the Maxifer-treated population (8.8±1.6%) compared to this historical population (-5.1±4.3%).
Study B was a multicenter, open-label study of Maxifer in 23 iron-deficient hemodialysis patients who had been discontinued from iron dextran due to intolerance. Eligibility criteria and Maxifer administration were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21-79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: 8 Caucasians (35%); 8 Blacks (35%); 1 Asian (4%); 6 Hispanics (26%). The mean change from baseline to the end of treatment (day 24) in hemoglobin, hematocrit and serum iron parameters was assessed.
All 23 enrolled patients were evaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±0.2 g/dL), hematocrit (3.6±0.6%), serum ferritin (266.3±30.3 ng/mL) and transferrin saturation (8.7±2%) were observed from baseline to end of treatment.
Study C was a multicenter, open-label, 2-period (treatment followed by observation period) study in iron deficient hemodialysis patients. Eligibility for this study included chronic hemodialysis patients with a hemoglobin ≤10 g/dL, a serum transferrin saturation ≤20% and a serum ferritin ≤200 ng/mL, who were undergoing maintenance hemodialysis 2-3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16-70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: 30 Caucasians (23%); 30 Blacks (23%); 6 Asians (5%); 64 others or mixed ethnicity (49%). Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A and B. Maxifer, was administered in doses of 100 mg during sequential dialysis sessions until a predetermined (calculated) total dose of iron was administered. Patients received Maxifer at each dialysis session, 2-3 times weekly. One hr after the start of each session, 5 mL iron sucrose (iron 100 mg) in 100 mL NaCl 0.9% was administered into the hemodialysis line. A 50-mg dose (2.5 mL) was given to patients within 2 weeks of study entry. Patients were treated until they reached an individually calculated total iron dose based on baseline hemoglobin level and body weight. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study. Changes from baseline to observation week 2 and 4 (end of study) were analyzed. The modified intention-to-treat population consisted of 131 patients. Significant (p<0.0001) increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained significantly increased (p<0.0001) at week 4 of the observation period.
Toxicology: Preclinical Safety Data:
Single IV doses of Maxifer at iron 150 mg/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and iron 100 mg/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes and bleeding in the gastrointestinal tract and lungs.