Source: FDA, National Drug Code (US) Revision Year: 2019
Ferric iron binds dietary phosphate in the GI tract and precipitates as ferric phosphate. This compound is insoluble and is excreted in the stool. By binding phosphate in the GI tract and decreasing absorption, ferric citrate lowers the phosphate concentration in the serum.
Ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the GI tract. After transport through the enterocytes into the blood, oxidized ferric iron circulates bound to the plasma protein transferrin, and can be incorporated into hemoglobin.
Auryxia reduces serum phosphorus levels and has also been shown to increase serum iron parameters, including ferritin, iron and TSAT. In dialysis patients treated with Auryxia for hyperphosphatemia in a 52-week study in which intravenous iron could also be administered, mean (SD) ferritin levels rose from 593 (293) ng/mL to 895 (482) ng/mL, mean (SD) TSAT levels rose from 31% (11) to 39% (17) and mean (SD) iron levels rose from 73 (29) mcg/dL to 88 (42) mcg/dL. In contrast, in patients treated with active control, these parameters remained relatively constant [see Contraindications (4) and Warnings and Precautions (5.1)].
Auryxia may increase hemoglobin levels and has also been shown to reduce serum phosphorus levels. In chronic kidney disease patients not on dialysis treated with Auryxia for iron deficiency anemia in a 16-week placebo-controlled study, mean (SD) phosphorus levels decreased from 4.23 (0.91) mg/dL at baseline to 3.72 (0.60) mg/dL. In comparison, in patients treated with placebo control, mean (SD) phosphorus levels decreased from 4.12 (0.68) mg/dL at baseline to 3.87 (0.68) mg/dL.
Formal pharmacokinetic studies have not been performed with Auryxia. Examination of serum iron parameters has shown that there is systemic absorption of iron from Auryxia [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
Of the drugs screened for an interaction with ferric citrate in vitro, only doxycycline showed the potential for interaction with at least 70% decrease in its concentration. This interaction can be avoided by spacing the administration of doxycycline and ferric citrate [see Drug Interactions (7)].
Six drug interaction studies (N=26-60/study) were conducted to establish the effects of Auryxia (administered as 3 × 2 g/day with meals) on the disposition of concomitantly orally administered clopidogrel, ciprofloxacin, digoxin, diltiazem, glimepiride and losartan in healthy subjects. With the exception of ciprofloxacin, Auryxia did not alter the systemic exposure of the tested drugs, as measured by the area under the curve (AUC) and Cmax of the tested drugs when either co-administered with Auryxia or given 2 hours later. Auryxia decreased the relative bioavailability of concomitantly administered ciprofloxacin by approximately 45%. However, there was no interaction when Auryxia and ciprofloxacin were taken 2 hours apart. Consequently, ciprofloxacin should be taken at least 2 hours before or after Auryxia is dosed [see Drug Interactions (7)].
Data from carcinogenesis studies have shown that ferric citrate is not carcinogenic in mice and rats when administered intramuscularly or subcutaneously. Ferric citrate was neither mutagenic in the bacterial reverse mutation assay (Ames test) nor clastogenic in the chromosomal aberration test in Chinese hamster fibroblasts.
The potential for ferric citrate to impair reproductive performance or to cause fetal malformation has not been evaluated.
The ability of Auryxia to lower serum phosphorus in patients with CKD on dialysis was demonstrated in randomized clinical trials: one 56-week, safety and efficacy trial, consisting of a 52-week active-controlled phase and a 4-week, placebo-controlled, randomized withdrawal period, and one 4-week open-label trial of different fixed doses of Auryxia. Both trials excluded subjects who had an absolute requirement for aluminum containing drugs with meals.
Study KRX-0502-304 was a long-term, randomized, controlled, safety and efficacy trial. After the 2-week washout period during which phosphate binders were held, patients with a mean serum phosphorus of 7.5 mg/dL during washout were randomized 2:1 to Auryxia (N=292) or active control (calcium acetate and/or sevelamer carbonate; N=149). The majority (>96%) of subjects were on hemodialysis. The starting dose of Auryxia was 6 tablets/day, divided with meals. The starting dose of active control was the patient’s dose prior to the washout period. The dose of phosphate binder was increased or decreased as needed to maintain serum phosphorus levels between 3.5 and 5.5 mg/dL, to a maximum of 12 tablets/day.
As shown in the figure below, serum phosphorus levels declined following initiation of therapy. The phosphorus lowering effect was maintained over 52 weeks of treatment.
Figure 1. Serum Phosphorus Control over 52 Weeks:
Following completion of the 52-week active-controlled phase, Auryxia-treated patients were eligible to enter a 4-week placebo-controlled randomized withdrawal phase, in which patients were re-randomized in a 1:1 ratio to receive Auryxia (N=96) or placebo (N=96). During the placebo-controlled period, the serum phosphorus concentration rose by 2.2 mg/dL on placebo relative to patients who remained on Auryxia.
Table 3. Effect of Auryxia on serum phosphorus during randomized withdrawal:
| Primary Endpoint (Week 56) | Auryxia | Placebo | Treatment Difference (95% CI) | p-value |
|---|---|---|---|---|
| Serum phosphorus (mg/dL) | ||||
| Mean baseline (Week 52) | 5.12 | 5.44 | ||
| Mean change from baseline (Week 56) | -0.24 | 1.79 | −2.18 (−2.59, −1.77) | <0.0001a |
a The LS mean treatment difference and p-value for the change in mean were created via an ANCOVA model with treatment as the fixed effect and Week-52 baseline (phosphorus) as the covariate. Between-treatment differences were calculated as the LS mean (Auryxia) - LS mean (placebo or active control).
Note: Analyses using ANCOVA with last observation carried forward. ANCOVA=analysis of covariance; CI=confidence interval.
Following a 1- to 2-week washout from all phosphate-binding agents, 154 patients with hyperphosphatemia (mean serum phosphorus of 7.5 mg/dL) and CKD on dialysis were randomized in a 1:1:1 ratio to 1, 6, or 8 tablets/day of Auryxia for 4 weeks. Auryxia was administered with meals; subjects receiving 1 tablet/day were instructed to take it with their largest meal of the day, and subjects on 6 or 8 tablets/day took divided doses in any distribution with meals. Dose-dependent decreases in serum phosphorus were observed by Day 7 and remained relatively stable for the duration of treatment. The demonstrated reductions from baseline to Week 4 in mean serum phosphorus were significantly greater with 6 and 8 tablets/day than with 1 tablet/day (p<0.0001). Mean reduction in serum phosphorus at Week 4 was 0.1 mg/dL with 1 tablet/day, 1.9 mg/dL with 6 tablets/day, and 2.1 mg/dL with 8 tablets/day.
The efficacy of Auryxia for the treatment of iron deficiency anemia in adult patients with CKD not on dialysis was demonstrated in a 24-week study consisting of a 16-week, randomized, double-blind, placebo-controlled, efficacy period followed by an 8-week open-label safety extension period in which all patients remaining in the study, including the placebo group, received Auryxia. Patients with eGFR <60 mL/min/1.73m², who were intolerant of or have had an inadequate therapeutic response to oral iron supplements, with Hgb ≥9.0 g/dL and ≤11.5 g/dL, serum ferritin ≤200 ng/mL and TSAT ≤25% were enrolled. Patients were randomized to treatment with either Auryxia (n=117) or placebo (n= 117). Dosing with Auryxia or placebo was initiated at 3 tablets/day with meals. Dose titration could occur at Weeks 4, 8 and 12 during Randomized Period, and at Weeks 18 and 20 during Safety Extension Period based on Hgb response. Use of oral or intravenous iron, erythropoiesis stimulating agents (ESAs) was not permitted at any time during the study.
The mean age of the patients was 65 years (range 26 to 93); 63% were female, 69% Caucasian, 30% were African American and <2% were other races.
The main efficacy outcome measure was the proportion of subjects achieving an increase in Hgb of ≥1.0 g/dL at any time point between baseline and the end of the 16-week Randomized Period.
Table 4. Efficacy of Auryxia in Iron Deficiency Anemia in Chronic Kidney Disease (Not on Dialysis):
| Auryxia (N=117) | Placebo (N=115) | p-value | |
|---|---|---|---|
| Proportion of patients achieving an increase in hemoglobin of ≥1.0 g/dL at any time point during the 16 week randomized period | 52% | 19% | <0.001 |
During the 16-week randomized period 49% of subjects in the Auryxia arm and 15% of subjects in the placebo arm (p <0.001) had a mean change in hemoglobin from baseline ≥0.75 g/dL over any 4-week time period provided that an increase of at least 1.0 g/dL had occurred during that 4-week period. Increases in mean hemoglobin (0.75 ± 0.09 g/dL), serum ferritin (163 ± 9 ng/mL) and transferrin saturation (18 ± 1%) were observed from baseline during the 16-week randomized period in the Auryxia arm.
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