"The US Food and Drug Administration (FDA) is ordering stricter warnings and contraindications for the anemia drug ferumoxytol (Ferumoxytol, AMAG Pharmaceuticals), stating that even with current warnings, there have been 79 anaphylactic r"...
Mechanism Of Action
Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.
In a randomized, positive-and placebo-controlled, parallel-group study, healthy subjects received a supratherapeutic regimen of Feraheme (1.02 g given as two 510 mg doses within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control). Results demonstrated no effect of Feraheme on QT interval durations. No clinically meaningful effect of Feraheme on heart rate was observed.
The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Feraheme exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 15 hours in humans. The clearance (CL) was decreased by increasing the dose of Feraheme. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t½) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Feraheme administered intravenously within 24 hours were 69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Feraheme PK parameters. No gender differences in Feraheme PK parameters were observed. Feraheme is not removed by hemodialysis.
The safety and efficacy of Feraheme for the episodic treatment of iron deficiency anemia in patients with CKD were assessed in three randomized, open-label, controlled clinical trials (Trial 1, 2 and 3). These trials also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anemia could receive two additional 510 mg intravenous injections of Feraheme. The major efficacy results from the controlled phase of each study are shown in Table 2.
In all three trials, patients with CKD and iron deficiency anemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg intravenous single doses and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes assessed the change in hemoglobin from baseline to Day 35. Trial 1 and 2 enrolled patients with non-dialysis dependent CKD and Trial 3 enrolled patients who were undergoing hemodialysis.
In Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at baseline.
In Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at baseline.
In Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs.
Table 2 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL), transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group for Trial 1, 2, and 3.
Table 2: Changes from Baseline to Day 35 in
Hemoglobin, Transferrin Saturation and Ferritin (Intent to Treat Population)
|ENDPOINT||Trial 1 Non-Dialysis CKD||Trial 2 Non-Dialysis CKD||Trial 3 CKD on Dialysis|
n = 226
n = 77
n = 228
n = 76
n = 114
n = 116
|Baseline Hgb (mean ± SD, g/dL)||9.9 ± 0.8||9.9 ± 0.7||10.0 ± 0.7||10.0 ± 0.8||10.6 ± 0.7||10.7 ± 0.6|
|Hgb change from Baseline at Day 35 (mean ± SD, g/dL)||1.2* ± 1.3||0.5 ± 1.0||0.8* ± 1.2||0.2 ± 1.0||1.0* ± 1.1||0.5 ± 1.1|
|Baseline TSAT (mean ± SD, %)||9.8 ± 5.4||10.4 ± 5.2||11.3 ± 6.1||10.1 ± 5.5||15.7 ± 7.2||15.9 ± 6.3|
|TSAT change from Baseline at Day 35 (mean ± SD, %)||9.2 ± 9.4||0.3 ± 4.7||9.8 ± 9.2||1.3 ± 6.4||6.4 ± 12.6||0.6 ± 8.3|
|Baseline ferritin (mean ± SD, ng/mL)||123.7 ± 125.4||146.2 ± 136.3||146.1 ± 173.6||143.5 ± 144.9||340.5 ± 159.1||357.6 ± 171.7|
|Ferritin change from Baseline at Day 35 (mean ± SD,ng/mL)||300.7 ± 214.9||0.3 ± 82.0||381.7 ± 278.6||6.9 ± 60.1||233.9 ± 207.0||-59.2 ± 106.2|
|* p ≤ 0.001 for main efficacy endpoint|
Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anemic could receive two additional 510 mg intravenous injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients received two additional 510 mg intravenous injections of Feraheme, and on Day 35 following these additional injections, the majority of these patients (70%) experienced an increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD) in hemoglobin level from the retreatment baseline for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for all patients.
Last reviewed on RxList: 4/7/2015
This monograph has been modified to include the generic and brand name in many instances.
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