Feraheme (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ferumoxytol was not tested for carcinogenic effects. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.

No adverse effects on fertility or general reproductive performance were noted in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats. In a pre and postnatal development study in rats, intravenous administration of ferumoxytol from gestation day 6 until lactation day 20 at doses up to 60 mg/kg/day (approximately 3 times the daily human dose based on body surface area comparisons assuming a 60-kg person) had no effect on maternal delivery or numbers of liveborn offspring. Male offspring (F1) of pregnant rats (F0) administered ferumoxytol at a dose of 60 mg/kg/day had delayed sexual maturation and decreased reproductive competence. Female offspring (F1) of pregnant rats (F0) administered ferumoxytol at doses of 30 mg/kg/day or 60 mg/kg/day had delayed sexual maturation and decreased reproductive competence. Doses of 30 mg/kg/day and 60 mg/kg/day are approximately 2 and 3 times the daily human dose based on body surface area comparisons assuming a 60-kg person, respectively.

14 CLINICAL STUDIES

14.1 Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or Have Had Unsatisfactory Response to Oral Iron

IDA-301 Trial (referred to as IDA Trial 1) (NCT 01114139), IDA-302 Trial (referred to as IDA Trial 2) (NCT 01114204) and IDA-304 Trial (referred to as IDA Trial 3) (NCT 02694978)

The safety and efficacy of Feraheme in patients with iron deficiency anemia, regardless of etiology and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used, were assessed in two randomized, controlled clinical trials (IDA Trial 1 and 2) with Feraheme administered as a rapid intravenous injection (prior method of administration no longer approved). In IDA Trial 1, patients were randomized to treatment with Feraheme or placebo. In IDA Trial 2, patients were randomized to treatment with Feraheme or iron sucrose. Feraheme (510 mg) and placebo were administered as two intravenous single dose injections over 3-8 days, and iron sucrose (200 mg) was administered as 5 intravenous injections or infusions over a period of 14 days.

In IDA Trial 1, the mean age of patients was 45 years (range, 18 to 91); 89% were female; 56% were Caucasian, 25% were Black, 16% were Asian, and 3% were other races.

In IDA Trial 2, the mean age of patients was 48 years (range, 18 to 89); 83% were female; 84% were Caucasian, 11% were Asian, 1% were Black, and 4% were other races.

Table 3 shows changes from baseline to Week 5 in hemoglobin and transferrin saturation in IDA Trial 1 and 2.

Table 3: Changes from Baseline to Week 5 in Hemoglobin (Hgb) and Transferrin Saturation in IDA Trial 1 and 2 (Intent to Treat Population)
* p≤0.001 for main efficacy endpoint
ENDPOINT IDA Trial 1 IDA Trial 2
FerahemeN = 608 PlaceboN = 200 FerahemeN = 406 Iron SucroseN = 199
Baseline Hgbmean (SD), g/dL 8.9 (0.9) 8.8 (0.9) 8.9 (0.9) 8.8 (1.0)
Proportion of patients with Hgb Increase of ≥2.0 g/dL at any time from Baseline toWeek 5, % 81.1 5.5 84.0 81.4
Treatment Difference (%, 95% CI) 75.6* (71.2, 80.0) 2.6(-3.9, 9.1)
Mean change in Hgb from Baseline to Week 5mean (SD), g/dL 2.6 (1.5) 0.1 (0.9) 2.9 (1.6) 2.7 (1.3)
Proportion of patients with Hgb ≥12 g/dL at any time from Baseline to Week 5, % 50.5 3.0 66.7 48.2
Baseline TSATmean (SD) , % 7.0 (12.9) 5.4 (4.9) 6.1 (9.9) 5.5 (10.3)
Mean change in TSAT from Baseline to Week 5mean (SD), % 11.4 (15.1) 0.4 (5.8) 15.7 (16.8) 11.9 (14.4)

In IDA Trial 1, fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue). After 5 weeks, Feraheme-treated patients reported greater improvement from baseline in the fatigue score (+11.7 ± 11.73 points) than did patients in the placebo arm (+6.8 ± 9.51 points) with a treatment difference of 4.9 (95% CI: 3.08-6.71) points.

The safety of Feraheme in IDA patients with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used was also assessed in another randomized, multicenter, double-blind safety clinical trial (IDA Trial 3). Patients were randomized in a 1:1 ratio to either two infusions of 510 mg (1.020 g) of Feraheme (n=997) or two infusions of 750 mg (1.500 g) of ferric carboxymaltose (FCM) (n=1000). Both IV irons were infused over a period of at least 15 minutes. Most patients received their second infusion of Feraheme or FCM 7(+1) days after the first infusion. This study included patients with any etiology of IDA including CKD excluding dialysis-dependent CKD.

In IDA Trial 3, the mean age of patients was 55 years (range, 18 to 96); 76% were female; 71% were Caucasian, 24% were Black, 3% were Asian, and 2% were other races.

The study met the primary endpoint to demonstrate non-inferiority to FCM with respect to the percentage of patients who experienced moderate-to-severe hypersensitivity reactions (including anaphylaxis) or moderate-to-severe hypotension (Feraheme: 0.6%; FCM: 0.7%; treatment difference: -0.1%; exact 95% confidence interval: -0.91% to +0.70%).

Table 4 shows the mean increase from baseline to week 5 in hemoglobin (Hgb) per treatment (Feraheme 2 x 510 mg; FCM 2 x 750 mg) and per gram of iron administered (Feraheme 1.020 g; FCM 1.500 g) in IDA Trial 3.

Table 4: Summary of Hemoglobin (Hgb) Changes per Treatment and per Gram of Iron Administered From Baseline to Week 5 (Intent to Treat Population) in IDA Trial 3
a Adjusted for difference in baseline Hgb
ENDPOINT Feraheme2 x 510mgN = 997 Ferric Carboxymaltose (FCM)2 x 750mg N = 1000
Baseline Hgbmean (SD); g/dL 10.42 (1.48) 10.39 (1.46)
Mean change in Hgb from Baseline to Week 5 per Gram of Iron Administeredmean (SD); g/dL 1.35 (1.35) 1.10 (1.05)
Treatment Difference Per Gram of Irona (%, 95%CI) 0.26 (0.17, 0.36)
Mean change in Hgb from Baseline to Week 5mean (SD); g/dL 1.38 (1.35) 1.63 (1.54)
Treatment Differencea (%, 95% CI) -0.24 (-0.35, -0.13)

In IDA Trial 3, the incidence of severe hypophosphatemia (defined by blood phosphorous of <0.6 mmol/L at week 2) in the patients receiving Feraheme (0.4% of patients) was less than those receiving FCM (38.7% of patients).

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