Key Words
- •Patients with iron deficiency anemia (IDA) and chronic kidney disease (CKD) remain undertreated; conventional oral iron agents historically have been insufficiently effective due to poor iron absorption and gastrointestinal adverse effects, and their effectiveness lessens as the disease advances.
- •Ferric citrate, approved for the IDA in patients with non-dialysis-dependent CKD (NDD-CKD), significantly improves hemoglobin response and iron parameters, with low rates of serious adverse events like hypophosphatemia, and treatment-related discontinuations.
- •Ferric maltol, approved in Europe and the United States for IDA in adult patients, and sucrosomial iron preparations have been evaluated clinically and have shown encouraging results in patients with NDD-CKD.
- •Additional trials are needed to assess the long-term effects of ferric citrate in NDD-CKD and the role of ferric citrate as an iron-repletion agent in patients with dialysis-dependent CKD.
Anemia in Chronic Kidney Disease
Current Treatment of Anemia in CKD
Iron Therapy
Traditional Oral Iron Formulations
Agent | Elemental Iron per Tablet | Total Salt Content per Tablet | Recommended Dosage |
---|---|---|---|
Ferric citrate or FC (Auryxia) | 210 mg | 1 g | 3 tablets a day (630 mg elemental iron) with meals for IDA in CKD |
Ferric citrate hydrate or FCH (Riona) | 45 mg | 250 mg | 500 mg × 3 times a day for hyperphosphatemia in CKD |
Ferric citrate (Nephoxil) | 105 mg | 500 mg | N/A |
Ferric maltol (Feraccru) | 30 mg | 30 mg | 30 mg twice daily |
Ferrous sulfate (generic) | 65 mg | 325 mg | 1000 mg/d (200 mg/d elemental iron) for IDA in CKD |
Ferrous fumarate (Ferro-Sequels; Slow FE, Apo-Ferrous Gluconate) | 106 mg | 325 mg | 600 mg/d (200 mg/d elemental iron) for IDA in CKD |
Ferrous gluconate (Fergon) | 37.5 mg | 325 mg | 1600 mg/d (200 mg/d elemental iron) for IDA in CKD |
Liposomal iron (Ferrolip) | 30 mg | 30 mg | 30 mg/d (for IDA) |
Heme iron polypeptide (Proferrin) | 12 mg | 12 mg | 3 or 4 tablets/d (for IDA in CKD) |

IV Iron Formulations
Reference | Agents | Patient Population | Dosage and Duration | Changes in Iron Parameters: TSAT (%) and Ferritin (ng/mL) (BL to End of FU) | Changes in Hb g/dL) (BL to End of FU) | Notes on ESA Usage |
---|---|---|---|---|---|---|
Spinowitz 2008 24 | IV ferumoxytol vs ferrous fumarate | CKD stage 1-5, TSAT ≤30%, ferritin ≤600 ng/mL, Hb ≤11.0 g/dL N = 228; N = 76 | 2× 510 mg doses within 5 ± 3 days; FU at day 35 200 mg elemental iron/d on empty stomach, 21 days treatment; FU at day 35 | Mean change (±SD) in TSAT: 9.8 ± 9.2%, 1.3 ± 6.4%, P < 0.0001 Mean change (±SD) in ferritin: 381.7 ± 278.6 ng/mL, 6.9 ± 60.1 ng/mL, P < .0001 | Mean increase in Hb: 0.82 ± 1.24 vs 0.16 ± 1.02 g/dL, P < 0.0001 Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 39.0% vs 18.4% | Yes (36%; 43%) Ferumoxytol resulted in significant Hb increases over placebo in both ESA treated and nontreated patients; mean Hb increase was higher in ESA-treated patients |
Qunibi 2011 25 | IV FCM vs oral iron sulfate | eGFR ≤45 mL/min/1.73 m2, Hb ≤11.0 g/dL, TSAT ≤25%, ferritin ≤300 ng/mL N = 152; N = 103 | 3× 1000 mg infusions and 2 additional infusions pif TSAT <30% and ferritin <500 ng/mL; FU at 8 weeks 195 mg elemental iron/d before meals, 56 days treatment; FU at 8 weeks | Mean change (±SD) in TSAT: 12.1 ± 8.8% vs 7.0 ± 10.3%, P < 0.001 Mean change (±SD) in ferritin: 358.8 ± 178.4 ng/mL, 25.8 ± 49.4 ng/mL, P < 0.001 | Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 60.4% vs 34.7%, P < 0.001 | Yes (24%; 25%) FCM benefited both ESA-treated and nontreated patients; more ESA-treated patients achieved Hb increases |
Nagaraju 2013 26 | IV iron sucrose vs oral heme iron polypeptide | (eGFR) ≤60 mL/min/1.73 m2, Hb = 9.0-12.0 g/dL (females) and 9.0-13.5 g/dL (males); serum ferritin <100 ng/mL; ferritin <100 ng/mL or TSAT <20% N = 22; N = 18 | 200 mg infusions monthly for 6 months; FU at 6 months 33 mg elemental iron/d, for 6 months; FU at 6 months | Change in TSAT: 16.5% (BL) to 21.5% (FU) vs 17% (BL) to 21.5% (FU) (P < 0.001) Change in ferritin: 67 ng/mL (BL) to 244 ng/mL (FU) vs 71 ng/mL (BL) to 85.5 ng/mL (FU) | 10.85 g/dL (BL) to 11.3 g/dL (FU) 11.05 g/dL (BL) to 11.7 g/dL (FU) | Yes (32%; 33%) † If the participant was being treated with an ESA, the medication was continued and the dose was adjusted by the blinded study investigator to maintain Hb from 10.0 to 12.0 g/dL. If the participant was not on an ESA at study entry, once the participant was iron replete (TSAT 20%-50% and ferritin 100-500 ng/mL), if the Hb was <10.0 g/dL, an ESA was started. No significant changes in ESA use were observed in either group at 6 months |
Charytan 2013 27
Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study. Nephrol Dial Transpl. 2013; 28: 953-964 | IV FCM vs standard medical care (investigator determined, oral or IV iron) | NDD-CKD patients; Hb ≤11.5 g/dL, TSAT ≤30% and ferritin ≤300 ng/mL (no IV iron within 1 month of study) N = 204; N = 212 | Single dose of 15 mg/kg up to a maximum of 1000 mg IV. FU 30 days Dosing as determined by investigator/physician. FU 30 days | Mean change (±SD) in TSAT: 10.02 ± 8.87% vs 4.93 ± 12.74% (P ≤ 0.001) Mean change (±SD) in ferritin: 295.59 ± 150.78 ng/mL vs 110.58 ± 153.27 ng/mL (P ≤ 0.001) | Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 27.2% vs 20.2% Mean increase in Hb: 0.55 ± 0.92 g/dL vs 0.31 ± 0.85 g/dL (P = 0.008) | Yes (28%; 31%) (stable dose postrandomization) |
Onken 2014 28 ; REPAIR-IDA | IV FCM vs IV iron sucrose | eGFR <60 mL/min/1.73 m2, Hb ≤11.5 g/dL; ferritin <100 ng/mL or ferritin ≤300 ng/mL and TSAT ≤30% N = 1276; N = 1285 | 2× doses of FCM in 1 week 200 mg iron sucrose up to 5 infusions in 14 days FU 56 days | Mean increases in ferritin and TSAT were significantly greater in the FCM group compared to the iron sucrose group | Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 48.6% vs 41.0% (95% CI 3.6-11.6) Mean increase in Hb: 1.13 ± 1.04 g/dL vs 0.92 ± 0.92 g/dL | Yes: stable ESA for 4 weeks prior to randomization (18%; 18%) Benefit from both treatments was similar for ESA-treated and non-ESA-treated patients |
MacDougall 2014 29 ; FIND-CKD | IV FCM vs oral ferrous sulfate | NDD-CKD (GFR <60 mL/min/m2); Hb 9-11 g/dL; ferritin <100 ng/mL or ferritin ≤200 ng/mL and TSAT <20% N = 153; N = 152; N = 308 | High ferritin group: initial dose of 1000 mg IV FCM, then 500 mg IV iron every 4 weeks for 48 weeks Low ferritin group: initial dose of 200 mg IV FCM, then 200 mg IV iron every 4 weeks for 48 weeks 100 mg × 2 times daily (elemental iron) 52 weeks FU: 52 weeks or 12 months | High ferritin group: LS mean change (SE) in TSAT: 15.8 (1.3) %, P = 0.20 LS mean change (SE) from baseline for ferritin: 451 (10) ng/mL, P < 0.001 vs oral iron Low ferritin group: LS mean change (SE) in TSAT: 8.5 (1.3)%, P = 0.001 LS mean change (SE) in ferritin: 81 (11) ng/mL, P < 0.001 vs oral iron LS mean change (SE) in TSAT: 13.8 (1.0)% LS mean change (SE) in ferritin: 137 (8) ng/mL | A greater proportion of patients achieved an Hb increase ≥1 g/dL with high-ferritin FCM vs oral iron (HR: 2.04; 95% CI 1.52-2.72; P < 0.001) High ferritin group: LS mean change (SE) from BL: 1.4 (0.1) g/dL, P = 0.014 vs oral iron Low ferritin group: LS mean change (SE) from BL: 0.9 (0.1) g/dL, P = 0.26 vs oral iron LS mean change (SE) from BL: 1.0 (0.1) g/dL | No |
Agarwal 2015 30 ; REVOKE | IV iron sucrose vs oral ferrous sulfate | eGFR between >20 and ≤60 mL/min/1.73 m2; Hb <12 g/dL and ferritin <100 ng/mL or TSAT <25% N = 67; N = 69 | 5× infusions of 200 mg IV iron sucrose at weeks 0, 2, 4, 6, and 8 after randomization 200 mg elemental iron/day for 8 weeks FU = 24 months | Serum ferritin concentration was significantly higher in the IV iron group only from baseline to 6 months No statistically significant difference in TSAT between groups during FU | Hemoglobin levels improved over time in both groups, and no statistically significant difference between mean levels in the treatment groups was noted during FU | Yes (9%; 7%) The average ESA use over the course of 2 years was similar in the 2 groups |
Kalra 2016 31 | IV iron isomaltoside 1000 vs oral ferrous sulfate | eGFR between 15 and 59 mL/min/1.73 m2 Hb <11.0 g/dL, either or both serum ferritin <200 ng/mL and TSAT <20%; no ESA treatment in the last 8 weeks N = 233; N = 118 | IV iron calculated by Ganzoni's formula (maximum of 1000 mg iron per dose or IV bolus injections of 500 mg iron until full repletion achieved) 200 mg elemental iron/d for 8 weeks | Statistically significant larger increase in serum ferritin and TSAT concentration from baseline to weeks 1, 2, 4, and 8 in the IV iron group compared with oral iron group (P < 0.001 for serum ferritin; P = 0.004 at week 8 for TSAT) | Statistically significant larger increase in Hb concentration from baseline to week 8 in IV iron group compared with oral iron group (P < 0.001) | No |
Pisani 2015 32 | IV iron gluconate vs oral pyrophosphate liposomal iron | CKD stage 3-5: eGFR ≤60 mL/min/1.73 m2, not on dialysis; Hb ≤12 g/dL, ferritin ≤100 ng/mL, TSAT ≤25% N = 33; N = 66 | 8 × 125 mg infusions IV iron gluconate weekly over 3 months, 30 mg/day for 3 months | TSAT from 17.0 ± 2.1 to 21.5 ± 5.2; P < 0.05 vs BL Ferritin from 67.7 ± 31.6 to 238.5 ± 49.7; P < 0.05 vs BL TSAT from 16.5 ± 2.2 to 18.3 ± 4.3; P < 0.05 vs IV iron Ferritin from 71.4 ± 23.7 to 85.5 ± 31.3; P < 0.05 vs IV iron | Mean increases in Hb levels from BL to 3 months were 9.3% and 5.6% Proportion of patients achieving an increase in Hb of ≥0.6 g/dL at 3 months: 56.2% vs 43.5%, P < 0.05 | Yes (4%; 5%) ESA dose not changed during experimental period |
Agent Study/Reference | Agents | Patient Population | Dosage/Duration | Changes in Iron Parameters: TSAT (%) and Ferritin (ng/mL) (BL to End of FU) | Changes in Hb (g/dL) (BL to End of FU) | Notes on ESA Usage |
---|---|---|---|---|---|---|
Li and Wang 2008 33 | IV iron sucrose vs oral ferrous succinate | Patients on maintenance peritoneal dialysis with stable condition for at least 1 month, ferritin <500 ng/mL, TSAT<30%, Hb 6.0-9.0 g/dL, and hematocrit 18%-27% N = 26; N = 20 | 200 mg IV iron sucrose after dialysis once a week for 4 weeks and then once in 2 weeks until week 8 200 mg oral ferrous succinate thrice a day (210 mg elemental iron) taken without food for 8 weeks | Mean change (±SD) in TSAT: 93.9 ± 26.7, 33.6 ± 45.2 (P < 0.05) Mean change (±SD) in ferritin: 326.8 ± 80.1 ng/mL, 170.9 ± 71.2 ng/mL (P < 0.05) | Proportion of patients achieving an increase in Hb of ≥1.5 g/dL: 94.8% vs 55.0%, P < 0.05 Mean increase in Hb: 3.41 ± 1.65 g/dL vs 2.21 ± 1.67 g/dL (P < 0.05) | Yes: all patients received EPO After 8 weeks, the mean EPO dose in the IV iron group was significantly lower than that in the oral iron group |
Li and Wang 2008 34 | IV iron sucrose vs oral ferrous succinate | Patients on maintenance hemodialysis (2-3 times a week), serum ferritin <500 ng/mL, TSAT <30%, Hb 6.0-9.0 g/dL N = 70; N = 66 | 100 mg IV iron sucrose after dialysis twice a week for 8 weeks and once a week until week 12 200 mg oral ferrous succinate thrice a day (210 mg elemental iron) taken without food for 12 weeks | Mean change (±SD) in TSAT: 94.1 ± 86.3, 33.6 ± 47.5 (P < 0.05) Mean change (±SD) in ferritin: 386.3 ± 380.8 ng/mL, 187.9 ± 272.3 ng/mL (P < 0.05) | Mean increase in Hb: 2.41 ± 1.79 g/dL vs 1.21 ± 1.65 g/dL (P < 0.05) | Yes: all patients received EPO After 12 weeks, the mean EPO dose in the IV iron group was significantly lower than that in the oral iron group |
Kapoian et al 2008 35 ; DRIVE 2 study: 6-week observational extension of the DRIVE study | IV ferric gluconate vs no iron | Patients on hemodialysis for ≥90 days, ferritin 500-1200 ng/mL, TSAT ≤25%, and Hb ≤11.0 g/dL Stable dose of ESAs N = 56; N = 56 | 1 g of IV ferric gluconate administered in eight 125-mg doses over 6 weeks; IV iron dose as clinically indicated from week 6 to week 12 No iron for first 6 weeks; IV iron dose as clinically indicated from week 6 to week 12 FU at the end of observational period of 12 weeks | TSAT and serum ferritin levels remained higher in the intravenous ferric gluconate group than in the control group (P < 0.001, and P = 0.014, respectively) | Hemoglobin levels remained higher in the intravenous ferric gluconate group than in the control group (P = 0.062) | Yes, all patients received ESAs Patients in the IV iron group required significantly lower ESA doses against baseline (−7527 ± 18,021 IU/wk, P = 0.003) compared with control |
Provenzano 2009 36 | IV ferumoxytol vs oral ferrous fumarate | Patients with stage 5 CKD, on hemodialysis and stable ESAs Hb ≤11.5 g/dL, TSAT ≤30%, serum ferritin ≤600 ng/mL N = 114; N = 116 | 2× 510 mg IV ferumoxytol within 5 ± 3 days. Follow-up at day 35 200 mg elemental iron/day 21 days treatment; FU at day 35 | Mean (±SD) change in TSAT: 6.44 ± 12.59% vs 0.55 ± 8.34%, P < 0.0001. Mean increase in ferritin: 233.9 ± 206.95 ng/mL vs −59.23 ± 106.22 ng/mL, P < 0.0001 | Mean increase in Hb: 1.02 ± 1.13 g/dL vs 0.46 ± 1.06 g/dL (P = 0.0002) Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 49.0% vs 25.0%, P = 0.0002 | Yes, all patients received EPO |
Charytan 2013 27
Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study. Nephrol Dial Transpl. 2013; 28: 953-964 | IV ferric carboxymaltose vs standard medical care (investigator determined, oral or IV iron) | Patients on hemodialysis for the last 6 months not needing repletion therapy Hb ≤12.5 g/dL, TSAT ≤30%, and ferritin ≤500 ng/mL N = 50; N = 47 | 200 mg bolus IV ferric carboxymaltose 30-60 min into dialysis session. Follow-up 30 days Dosing as determined by investigator/physician. FU 30 days | Mean change (±SD) in TSAT: 2.55 ± 15.26% vs 5.80 ± 13.84% Mean change (±SD) in ferritin: 15.87 ± 106.60 ng/mL vs 71.77 ± 105.57 ng/mL (P = 0.013) | Proportion of patients achieving an increase in Hb of ≥1.0 g/dL: 19.1% vs 30.4% Mean increase in Hb: 0.22 ± 0.89 g/dL vs 0.42 ± 1.00 g/dL, P = 0.299 | Almost all patients received ESAs |
Bhandari 2015 37 | IV iron isomaltoside 1000 vs IV iron sucrose | Patients on hemodialysis for ≥90 days, Hb between 9.5 and 12.5 g/dL, ferritin <800 ng/mL, TSAT <35%, ESAs at stable dose for prior 4 weeks N = 234; N = 117 | Cumulative dose of 500 mg iron Single IV dose of iron isomaltoside 1000 bolus of 500 mg or split dose IV iron sucrose, 100 mg at BL, 200 mg at weeks 2 and 4 FU 6 weeks | There was an increase in serum iron and TSAT concentration from baseline to week 6 in both groups; however, no statistically significant changes were observed between the treatment groups | Majority of patients in either group were able to maintain Hb between 9.5 and 12.5 g/dL at week 6 No statistically significant change in Hb concentrations between groups | Treatment with ESA stable during trial |
Novel Oral Iron Therapies
Ferric Citrate
Chemical Properties

Approvals and Indications
Clinical Studies With Ferric Citrate—Efficacy Data for Iron Repletion
Reference | Study Design/Endpoint | Patient Inclusion Criteria | Dosage and Duration | Changes in Iron Parameters | Changes in Hb | Notes on ESA/IV Iron Usage |
---|---|---|---|---|---|---|
Ferric citrate preparations in DD-CKD | ||||||
Sinsakul 2012 52 | Phase 2 open-label study of safety and tolerability of FC as a phosphate binder Endpoints: short-term safety, tolerability, and iron absorption | Patients on hemodialysis (3 times a week), serum phosphorus ≥2.5 mg/dL (cohort I) or ≥3.5 mg/dL (cohort II), ferritin <1000 mg/L; TSAT <50% IV iron permitted if ferritin <500 mg/L and TSAT <30% N = 55 | Cohort I: 4.5 g/d; cohort II: 6 g/d (375 mg capsules of FC) FU at 4 weeks | Mean change (range) in TSAT: 5.35% (–20.5 to 40.5) (P = 0.001) Mean change in ferritin: 54.71 ng/mL (–326.5 to 582.5) (P = 0.02) | Not reported | 45% of patients received IV iron during the treatment period; there was no significant difference in serum iron and TSAT from BL to FU |
Yokoyama 2014 53 | Phase 3 open-label dose titration long-term study of FCH as a phosphate binder Endpoints: serum phosphate, calcium, PTH; ferritin, TSAT, doses of ESA and IV iron | Patients on hemodialysis (3 times a week), serum phosphate 3.5-10.0 mg/dL for patients receiving medication for hyperphosphatemia, and 6.1-10.0 mg/dL for patients not on any treatment N = 180 | 1.5 g/d (6 tablets/d); titrated up to 6.0 g/day (24 tablets/d) according to [phosphate] 52-week treatment period FU at 52 weeks | Median (range) TSAT and BL and FU BL: 23.0% (17.8-29.4) FU: 36.35% (28.2-50.05) Median (range) ferritin at BL and FU BL: 57.35 ng/mL (24.75-117.00) FU: 227.00 ng/mL (143.00-342.50) | Mean ± SD Hb at BL and FU BL: 10.97 ± 1.04 FU: 11.15 ± 1.18 | Mean weekly ESA dose reduced by 25% from BL (4541 IU/wk) to end-of-treatment (3412 IU/wk) Mean 4 weekly IV iron dose: 57.3 mg (weeks 0-12), 12.8 mg (weeks 12-28), and 3.6 mg (weeks 28-52) |
Yokoyama 2014 54 | Phase 3 open-label dose-adjusted study of FCH as a phosphate binder Endpoints: serum phosphate, calcium, PTH; ferritin, TSAT, doses of ESA and IV iron | Patients on peritoneal dialysis for ≥12 weeks who had discontinued phosphate binders with serum phosphate between 5.6 and 10.0 mg/dL N = 56 | Dose adjusted between 1.5 and 6.0 g of FCH a day according to serum phosphate FCH doses taken after meals | Median (25th, 75th percentile ferritin at BL and FU BL: 85.4 ng/mL (49.0, 128.0) FU: 224.5 ng/mL (173.5, 270.5) P < 0.001 Median (25th, 75th percentile) TSAT at BL and FU BL: 32.2% (28.0, 39.2) FU: 47.6% (37.2, 62.0) P < 0.001 | Mean ± SD Hb at BL and FU BL: 10.67 ± 1.05 g/dL FU: 11.52 ± 1.26 P < 0.001 | 98% of patients used ESAs |
Lewis 2015 48 | Phase 3 trial of FC as a phosphate binder in patients with ESRD, on hemodialysis or peritoneal dialysis Endpoints: mean change in phosphorus; secondary: ferritin, TSAT, IV iron, ESA usage | Serum ferritin <1000 ng/mL, TSAT <50%, serum phosphorus ≥2.5 and ≤8.0 mg/dL at screening Endpoints: safety and ability to supplement iron stores and reduce ESA and IV iron usage | 52-week active control period followed by 4-week open-label placebo control period (at 52 weeks, patients re-randomized to FC or placebo) FC dose adjustments per titration for phosphate levels Active control: calcium acetate, or sevelamer carbonate | Mean ± SD TSAT at BL and FU BL: 31.3% ± 0.7% FU: 39.3% ± 1.1% BL: 30.9% ± 1.0% FU: 29.7% ± 1.0% P < 0.001 for FC vs control Mean ± SD ferritin at BL and FU BL: 593 ± 18 ng/mL FU: 899 ± 31 ng/mL BL: 609 ± 26 ng/mL FU: 628 ± 31 ng/mL P < 0.001 for FC vs control | At FU, mean ± SD Hb: BL:11.61 ± 0.08 FU:11.42 ± 0.10 BL: 11.71 ± 0.11 FU: 11.14 ± 0.12 (P = 0.02 for adjusted mean difference FC vs control) | Yes (82%; 82%) Patients on FC received less IV iron (median = 12.9 mg/wk ferric citrate; 26.8 mg/wk active control; P < 0.001) and less ESA (median epoetin-equivalent units/wk: 5303 units/wk FC; 6954 units/wk active control; P = 0.04) |
Lee 2015 55 | Phase 3 trial of FC in patients with ESRD on maintenance hemodialysis Endpoints: serum phosphorus at week 8 secondary: serum phosphorus at week 4, calcium × phosphorus product at week 4 and week 8, safety was evaluated based on AEs, SAEs, changes in hematological and biochemical laboratory parameters | Patients on maintenance hemodialysis (3 times a week) All patients had serum phosphorus levels of 5.5-10 mg/dL after a 1 to 2-week washout period N = 75 (4 g); N = 72 (6 g); N = 36 | 4 g (840 mg elemental ferric iron) of FC or 6 g (1260 mg elemental ferric iron) per day of FC or placebo FU 56 days/8 weeks | Median (IQR) change in ferritin from BL to FU 73.90 (3.00-129.60) ng/mL 103.40 (14.00-157.80) ng/mL −41.75 (−131.15 to 13.60) ng/mL Changes against placebo: P = .008 for 4 g and .003 for 6 g Median (IQR) change in TSAT from BL to FU 5.35 (−0.50 to 12.20)% 4.95 (−1.80 to 9.90)% −1.15 (−7.00 to 6.65)% Changes not significant vs placebo | Hb from BL to week 8 was not different between the 3 groups 0.30 (−0.50 to 0.70) g/dL 0.60 (−0.10 to 1.30) g/dL 0.35 (−0.40 to 0.65) g/dL (P = 0.104) However, as compared to BL, Hb level in the 6 g/d group showed a significant increase at week 4 and week 8 (median 11.1 g/dL at week 4 and 11.3 g/dL at week 8 vs 10.6 g/dL at baseline, P ≤ 0.001 for both) | Not available |
Ferric citrate preparations in NDD-CKD | ||||||
Yokoyama 2014 56 | Phase 3, double blind, placebo-controlled study of FCH vs placebo in NDD-CKD Endpoints: serum phosphate, calcium, calcium × phosphate product, total iron, ferritin, TIBC, TSAT, safety | Serum phosphate ≥5.0 and <8.0 mg/dL during screening period N = 57; N = 29 | 1.5 g/day FCH after a meal vs placebo for 12 weeks Dose adjustment per phosphate levels Follow-up at 12 weeks | Mean ± SD TSAT at BL and FU BL: 27.22 ± 11.30% FU: 44.19 ± 20.88% BL: 24.99 ± 12.75% FU: 27.03 ± 12.60% P < 0.001 for FC vs control Mean ± SD ferritin at BL and FU BL: 69.00 ± 50.92 ng/mL FU: 204.01 ± 106.54 ng/mL BL: 105.98 ± 95.58/mL FU: 93.66 ± 82.70 ng/mL P < 0.001 for FC vs control | Although there was no significant difference between groups, Hb increased from 10.3 to 10.7 g/dL (P = 0.04) in the FCH group | ESA: N/A IV iron usage was permitted |
Block 2015 57 | Phase 2 randomized study of FC vs placebo in patients with non-dialysis-dependent CKD Endpoints: change in TSAT and serum phosphate from BL to end of study Secondary: change from BL in ferritin, hemoglobin, iFGF23, urinary phosphate, eGFR | eGFR <60 mL/min/1.73 m2, iron deficiency anemia (Hb between 9.0 and 12.0 g/dL; TSAT ≤30%, serum ferritin ≤300 ng/mL), serum phosphate ≥4.0 to 6.0 mg/dL N = 72; N = 69 | FC initiated at a dose of 3 × 210 mg/d elemental iron given after meals, dose adjusted based on serum phosphate Treatment for 12 weeks | Mean change (±SD) in TSAT from BL to FU BL: 22% ± 7% FU: 32% ± 14% BL: 21% ± 8% FU: 20% ± 8% Treatment effect difference for TSAT: 11.3% [95% CI 8.0-14.7] Mean change (±SD) in ferritin from baseline to follow-up BL: 116 ± 83 ng/mL FU: 189 ± 122 ng/mL BL: 110 ± 81 ng/mL FU: 106 ± 94 ng/mL | Mean change in Hb BL: 10.5 ± 0.8 g/dL FU: 11.0 ± 1.0 g/dL; BL: 10.6 ± 1.1 g/dL FU: 10.4 ± 1.1 g/dL Treatment effect difference: 0.6 (95% CI 0.4-0.9), P < 0.001 vs placebo | No ESAs within 4 weeks or IV iron within 8 weeks |
Fishbane 2017 51 | Phase 3 randomized study of FC vs placebo in patients with non-dialysis-dependent CKD and IDA Endpoint: proportion of patients who achieved ≥1.0 g/dL increase in Hb at any time during a 16-week randomized period | eGFR <60 mL/min/1.73 m2 and iron deficiency anemia (Hb between 9.0 and 11.5 g/dL inclusive, ferritin ≤200 ng/mL, TSAT ≤25%) Intolerant of, or with inadequate response to oral iron, and serum phosphate ≥3.5 mg/dL N = 117; N = 116 | 16 weeks (and 8-week open-label extension period) FC initiated at a dose of 3 × 210 mg/d elemental iron given after meals, dose was titrated at weeks 4, 8, and 12 aiming to achieve an increase in Hb by >1.0 g/dL above BL | Mean relative changes (FC vs placebo) in TSAT at week 16: 18.4% (95% CI 14.6-22.2; P < 0.001) Mean relative changes (FC vs placebo) in ferritin at week 16: 170.3 ng/mL (95% CI 144.9-195.7 ng/mL; P < 0.001) | Mean relative change in Hb (FC vs placebo) at week 16: 0.84 g/dL (95% CI 0.58-1.10 g/dL) (P < 0.001) Patients randomized to FC were significantly more likely to achieve the primary endpoint (≥1 g/dL increase in Hb) 61 of 117 [52.1%] vs 22 of 115 [19.1%]; P < 0.001 | Patients with ESA or IV iron use within 4 weeks of screening were excluded |
Effect on Ferric Citrate Treatment on the Use of ESAs and IV Iron
Safety of Ferric Citrate
Reference | Study Design | Patient Population | FC Dosage and Duration | Incidence of AEs in FC-Treated Patients Overall, Serious | Most Common AEs in ≥5% of FC-Treated Patients (Incidence in %) | Discontinuations due to AEs in FC-Treated Patients, n (%) |
---|---|---|---|---|---|---|
Ferric citrate preparations in DD-CKD | ||||||
Sinsakul 2012 52 | Phase 2 open-label study of safety and tolerability of FC as a phosphate binder | Patients on maintenance hemodialysis, (3 times a week) N = 55 | Cohort I: 4.5 g/d; cohort II: 6 g/d (375 mg capsules of FC) Follow-up at 4 weeks | TEAEs: Overall: not reported Serious: 4 (7%)—liver infection, bacteremia, suicide attempt, and congestive heart failure | TEAEs: change in stool color (62%); constipation (15%); bloating (7%); diarrhea (7%); nausea (5%); stomach pain (5%) | TEAEs: 6 (11%) constipation (7%), bloating (4%), diarrhea (4%) |
Yokoyama 2014 53 | Phase 3 open-label dose titration long-term study of FCH as a phosphate binder | Patients on maintenance hemodialysis (3 times a week) N = 180 | 1.5 g/d (6 tablets/d); titrated up to 6.0 g/d (24 tablets per day) according to [phosphate] 52-week treatment period | ADR (drug-related): Overall: 49 (27%) Serious: 2 (0.6%)—both unrelated to drug (pneumonia, putaminal hemorrhage) | ADR (drug-related): gastrointestinal disorders (19%); diarrhea (12%) | ADR (drug-related): 8 (4%) elevated hemoglobin (2%), diarrhea (1%), elevated ferritin, liver dysfunction, elevated serum aluminum |
Yokoyama 2014 54 | Phase 3 open-label dose-adjusted study of FCH as a phosphate binder | Patients on peritoneal dialysis for ≥12 weeks N = 56 | Dose adjusted between 1.5 and 6.0 g of FCH per day according to serum phosphate FCH doses taken after meals | ADR (drug-related): Overall: 21 (38%) Serious: 1 (2%) Abnormal hepatic function | ADR: diarrhea (7%); constipation (7%); nausea (5%); vomiting (5%); frequent bowel movements (5%) | ADR: 1 (2%) cardiac failure (not drug-related) |
Lewis 2015 48 | Phase 3 trial of FC as a phosphate binder in DD-CKD (hemodialysis or peritoneal dialysis) | DD-CKD, hemodialysis or peritoneal dialysis usage N = 292 N = 149 | 52-week active control period followed by 4-week open-label placebo control period (at 52 weeks, patients re-randomized to FC or placebo) FC dose adjustments per titration for phosphate levels Active control: calcium acetate or sevelamer carbonate | TEAEs: Overall: 261 (90.3%) vs 261 (89.3%) Serious: 113 (39.1%) vs 113 (49.0%) | TEAEs: GI serious AEs: 6.9% vs 12.8% Infection serious AEs: 12.5% vs 18.1% Cardiac serious AEs: 7% vs 12.1% | Not reported |
Lee 2015 55 | Phase 3 trial of FC in DD-CKD (maintenance hemodialysis) | Patients on maintenance hemodialysis (3 times a week) N = 36 N = 75 (4 g) N = 72 (6 g) | 4 g (840 mg elemental ferric iron) or 6 g (1260 mg elemental ferric iron)/day of FC or placebo Follow-up 56 days | Overall AE incidence not reported In the 4 g/d group, 1 (1%) experienced serious AEs (not related) In the 6 g/d group, 4 (6%) experienced serious AEs (not related) | Most common treatment-related AEs in 4 g/d group: discolored feces (37.3%); diarrhea (6.7%) In 6 g/d group: discolored feces (37.5%) In placebo: discolored feces (5.6%); diarrhea (5.6%) | Discontinuations because of AEs: 2 (3%) in 4 g/d group 7 (10%) in the 6 g/d group |
Ferric citrate preparations in NDD-CKD | ||||||
Yokoyama 2014 56 | Phase 3, double-blind, placebo-controlled study of FCH vs placebo in NDD-CKD | Serum phosphate ≥5.0 and <8.0 mg/dL during screening period N = 60; N = 30 | 1.5 g/d FCH after a meal vs placebo for 12 weeks Dose adjustment per phosphate levels Follow-up at 12 weeks | Overall AEs: 41 (68.3%) vs 18 (60.0%) Overall serious AEs: 8 (13.3%) vs 3 (10%) ADR (drug-related): 19 (32%) vs 8 (26.7%) | Most common adverse drug reactions: diarrhea (13%), constipation (12%), abdominal discomfort (5%), abdominal distension (5%) | Discontinuations due to AEs: 5 (8%) vs 1 (3%) |
Block 2015 57 | Phase 2 randomized study of FC vs placebo in patients with NDD-CKD | Patients with NDD-CKD and IDA (Hb between 9.0 and 12.0 g/dL; TSAT ≤30%, serum ferritin ≤300 ng/mL), serum phosphate ≥4.0-6.0 mg/dL N = 72; N = 69 | FC initiated at a dose of 3 × 210 mg/d elemental iron given after meals, dose adjusted based on serum phosphate Treatment for 12 weeks | Overall TEAEs: 52 (69.3%) vs 43 (58.9%) Overall serious TEAEs: 8% vs 12% (none related to treatment) | Most common TEAEs: discolored feces (32%); diarrhea (20%); constipation (6.7%); vomiting (5%); upper respiratory tract infections (5%) nausea (7%) | Discontinuations due to AEs: 13% vs 11% |
Fishbane 2017 51 | Phase 3 randomized study of FC vs placebo in patients with NDD-CKD and IDA | Patients with NDD-CKD and IDA N = 117; N = 116 | 16 weeks (and 8-week open-label extension period) FC initiated at a dose of 3 × 210 mg/d elemental iron given after meals, dose was titrated at weeks 4, 8, and 12 aiming to achieve an increase in Hb by >1.0 g/dL above BL | Overall TEAEs: 93 (79.5%) vs 75 (64.7%) Drug-related TEAEs: 35 (29.9%) vs 26 (22.4%) Overall serious AEs (not related to treatment): 14 (12%) vs 13 (11.2%) | Most common TEAEs: diarrhea (21%); constipation (19%); discolored feces (15%); nausea (11%); abdominal pain (6%); hyperkalemia (7%) | Not reported |
Ferric Maltol
Chemical Properties and Preclinical Studies
Approvals and Indications
Shield Therapeutics announces submission of a New Drug Application (NDA) for Feraccru® for the treatment of iron deficiency with the US Food and Drug Administration (FDA) [news release]. Shield Therapeutics plc; October 1, 2018. https://www.shieldtherapeutics.com/rns_news/submission-of-an-nda-for-feraccru-with-the-fda/. Accessed June 19, 2019.
Clinical Studies
Sucrosomial Iron Chemical Properties
Preclinical Data
Clinical Evaluation in Chronic Kidney Disease
Conclusions
Acknowledgments
References
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Article Info
Footnotes
Financial disclosures: P.E.P., S.F., T.G. received no financial support for writing this article.
Conflicts of interest: P.E.P. is a consultant to Akebia Therapeutics, Inc. (Akebia), Gilead, AstraZeneca, Reata, Keryx, and ExThera. As the principal investigator for many pharmaceutical companies including Akebia and Keryx Biopharmaceuticals, Inc. (now a wholly owned subsidiary of Akebia), his institution has received research support. S.F. is a research consultant to Keryx, AstraZeneca, mega Pro, and Akebia. T.G. is a shareholder and scientific advisor of Intrinsic LifeSciences and Silarus Therapeutics, and consultant to Ambys, Ionis Pharmaceuticals, Keryx Biopharmaceuticals, La Jolla Pharmaceutical Company, Akebia, Gilead, Global Blood Therapeutics, and Sierra Oncology.
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