Sucroferric Oxyhydroxide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hyperphosphatemia in CKD on dialysis — control of serum phosphorus | Adults | Component of CKD-MBD management | FDA Approved |
| Hyperphosphatemia in CKD on dialysis — pediatric | ≥9 years | Component of CKD-MBD management | FDA Approved |
Sucroferric oxyhydroxide is a calcium-free, iron-based phosphate binder that uses a polynuclear iron(III)-oxyhydroxide core, stabilised by a carbohydrate shell of sucrose and starch. It binds dietary phosphate in the gastrointestinal lumen via ligand exchange, forming insoluble complexes that are eliminated in faeces. It was approved by the FDA in 2013 for adult dialysis patients and received a pediatric indication expansion in 2024 for patients 9 years and older. Its primary clinical advantage over sevelamer and lanthanum is a substantially lower pill burden (average 3–4 tablets/day vs 8–9 for sevelamer), which may improve adherence. Unlike calcium-based binders, sucroferric oxyhydroxide does not contribute calcium load. Although each tablet contains 500 mg of iron, systemic iron absorption is negligible in CKD patients (median 0.04%).
Hyperphosphatemia in CKD not on dialysis (evidence: limited) — The FDA indication specifies dialysis patients. Some clinicians consider sucroferric oxyhydroxide in pre-dialysis CKD patients with progressive hyperphosphatemia refractory to dietary measures, though formal trial data in this population are limited.
Dosing
Adults and Pediatric ≥12 Years
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Phosphate binder–naïve or switching from another binder | 500 mg TID with meals (1500 mg/day) | 1500–2000 mg/day (3–4 tablets) | 3000 mg/day (6 tablets) | Titrate by 500 mg/day (1 tablet) as often as weekly Chew or crush; never swallow whole; take with meals |
| Unequal meal distribution | Administer larger dose with the largest meal of the day | If daily dose cannot be divided equally among meals Resume missed dose at next food intake | ||
Pediatric 9 to <12 Years
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CKD on dialysis, ≥9 to <12 years | 500 mg BID with meals (1000 mg/day) | Titrate to target; median ~1500 mg/day | 3000 mg/day (studied) | Titrate by 500 mg/day as often as weekly Chew or crush; same administration instructions as adults |
In the phase 3 trial, the average daily pill burden with sucroferric oxyhydroxide was 3.3 tablets compared to 8.7 tablets with sevelamer carbonate, with equivalent phosphorus control (Floege 2014). Non-adherence (defined as <70% expected tablets taken) was lower with sucroferric oxyhydroxide (15.1% vs 21.3% with sevelamer). At 52 weeks, the proportion of adherent patients on Velphoro was 86% (FDA PI). For patients struggling with the high tablet count of sevelamer or calcium-based binders, switching to sucroferric oxyhydroxide can reduce pill burden by approximately 50–60% while maintaining phosphorus control.
Each 500 mg tablet contains approximately 1.4 g of carbohydrates (750 mg sucrose, 700 mg starches). At a typical dose of 3 tablets daily, this contributes approximately 4.2 g of additional carbohydrate intake. This is generally not clinically significant but should be considered in patients on strict carbohydrate-controlled diets, particularly those with diabetes.
Pharmacology
Mechanism of Action
Sucroferric oxyhydroxide consists of a polynuclear iron(III)-oxyhydroxide core stabilised by a carbohydrate shell (sucrose and starch). The active moiety, polynuclear iron(III)-oxyhydroxide, is practically insoluble and cannot be absorbed intact across the intestinal mucosa. In the aqueous environment of the GI tract, phosphate binding occurs via ligand exchange: hydroxyl groups and water molecules on the surface of the iron oxyhydroxide are exchanged for phosphate ions from the diet. The resulting iron-phosphate complex is highly stable and passes through the GI tract unabsorbed, reducing both serum phosphorus and calcium-phosphorus product levels. Unlike sevelamer (an ion-exchange resin), sucroferric oxyhydroxide binds phosphate through chemisorption (surface exchange), which provides a high phosphate-binding capacity per gram of material, allowing for a lower daily pill burden. The phosphate-binding capacity peaks at pH 2.5 (96% adsorption) but remains robust across the entire physiologically relevant pH range of 1.2–7.5.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Active moiety (pn-FeOOH) is practically insoluble and not absorbed; mononuclear iron species can be released and absorbed minimally; median iron uptake from radiolabelled Velphoro: 0.04% in CKD patients, 0.43% in healthy volunteers with low iron stores | Negligible systemic iron exposure in CKD; no evidence of clinically meaningful iron accumulation over 1 year of treatment |
| Distribution | Not applicable — active moiety remains in GI lumen; sucrose and starch components are digested and can be absorbed as simple sugars | Each tablet contributes ~1.4 g carbohydrate; relevant for diabetic patients |
| Metabolism | Active moiety not metabolized (insoluble); not a substrate or inhibitor of CYP enzymes; degradation product (mononuclear iron) follows normal iron homeostasis pathways | No metabolic drug interactions anticipated |
| Elimination | Bound phosphate complex eliminated in faeces; no classical PK studies possible due to insolubility | Must be administered with meals for phosphate binding to occur; causes expected stool discolouration (black) |
Side Effects
Safety data from two active-controlled studies involving 778 adults on hemodialysis and 57 on peritoneal dialysis exposed for up to 55 weeks, plus a 6-week fixed-dose study (N=128 sucroferric oxyhydroxide vs N=26 sevelamer HCl) (FDA PI 2024).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 24% (55-wk study) / 6% (6-wk study) | Majority mild and transient; occurs early after initiation and resolves with continued treatment; most common reason for withdrawal (4%) |
| Discolored feces (black) | 16% (55-wk study) / 12% (6-wk study) | Expected pharmacological effect of iron-containing compound; benign but can be confused with GI bleeding; did not occur in sevelamer group |
| Nausea | 10% (55-wk study) | Led to withdrawal in 2% of patients; comparable to rates seen with other phosphate binders |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Product taste abnormal | 2% (led to withdrawal) | Berry-flavoured tablets; taste is subjective; second most common withdrawal reason |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Iron accumulation (patients with hemochromatosis or iron overload disorders) | Theoretical risk (not studied) | Chronic use | Monitor iron homeostasis (ferritin, TSAT); these patients were excluded from trials |
| Tooth discoloration | Uncommon (postmarketing) | With ongoing use | Dental hygiene counselling; generally cosmetic; may be more pronounced with chewing |
Sucroferric oxyhydroxide causes black stool discolouration in up to 16% of patients, which is an expected and benign effect of iron-containing compounds. This must be distinguished from melena (GI bleeding), which has a characteristic tarry appearance and offensive odour. Counsel patients that dark or black stools are normal with this medication, but advise them to report stool that appears tarry, sticky, or has an unusual odour, as well as any symptoms of GI bleeding.
Drug Interactions
Sucroferric oxyhydroxide is not systemically absorbed and does not inhibit CYP enzymes. Unlike many phosphate binders, it has a favourable drug interaction profile. In vivo studies (N=40 each) with losartan, furosemide, digoxin, omeprazole, and warfarin showed no alteration in systemic exposure. Post-hoc analyses confirmed no impact on statin efficacy or calcitriol’s PTH-lowering effect. However, in vitro studies identified binding potential with certain anionic drugs.
Monitoring
- Serum PhosphorusWeekly during titration; regularly once stable
RoutineTarget: 3.5–5.5 mg/dL (KDOQI). Titrate as often as weekly by 500 mg/day increments. Most patients achieve control on 1500–2000 mg/day. - Serum Calcium & iPTHPer CKD-MBD protocol
RoutineMonitor as part of standard CKD-MBD assessment. Sucroferric oxyhydroxide does not add calcium load; clinical studies showed no impact on calcitriol’s PTH-lowering effect. - Iron ParametersBaseline; then periodically
RoutineMonitor serum ferritin and TSAT. No clinically meaningful changes in iron parameters were observed in clinical trials over 1 year. However, monitor iron homeostasis in patients with hemochromatosis or other iron accumulation disorders. - GI SymptomsEvery visit, especially in first weeks
RoutineDiarrhea is most common in early treatment and typically resolves. Distinguish black stool (benign, iron-related) from melena. Reassure patients about stool colour change. - TSHIf taking levothyroxine concurrently
Trigger-basedLevothyroxine must be taken at least 4 hours before Velphoro. Monitor TSH to ensure adequate thyroid hormone replacement.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA PI. Sucroferric oxyhydroxide has no formal contraindications in the current prescribing information.
Relative Contraindications (Specialist Input Recommended)
- Hemochromatosis or other iron accumulation disorders — although systemic iron absorption is minimal (0.04% in CKD), these patients were excluded from clinical trials and theoretical risk of iron accumulation exists with long-term use.
- Significant gastric or hepatic disorders — not studied; monitor effect and iron homeostasis if used.
- Following major GI surgery — patients in this category were excluded from trials.
- Peritonitis during peritoneal dialysis — not studied during active peritonitis.
Use with Caution
- Patients requiring levothyroxine — iron-containing compounds reduce levothyroxine absorption; strict dosing separation (≥4 hours) is essential.
- Diabetes mellitus with strict carbohydrate control — each tablet contains ~1.4 g carbohydrates (sucrose and starch); account for additional carbohydrate load at typical doses.
- Patients on concomitant doxycycline, aspirin, or cephalexin — in vitro interaction demonstrated; separate dosing by at least 1 hour.
Each chewable tablet contains 500 mg iron. Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, following major GI surgery, or with a history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies. Monitor effect and iron homeostasis in such patients.
Patient Counselling
Purpose of Therapy
Sucroferric oxyhydroxide helps control high phosphorus levels in the blood by binding phosphorus from food in the digestive tract. Keeping phosphorus under control is important for protecting bones and blood vessels in kidney disease.
How to Take
Chew or crush the tablets before swallowing — do not swallow them whole. Take with each meal. The tablets have a berry flavour. If you miss a dose, take it with your next meal. Follow the phosphorus-restricted diet prescribed by your renal dietitian.
Sources
- VELPHORO (sucroferric oxyhydroxide) chewable tablet — Full Prescribing Information. Fresenius Medical Care Renal Therapies Group, LLC. Revised 07/2024. FDA LabelPrimary source for all dosing (including pediatric), contraindications, adverse reactions, drug interaction Table 1, and pharmacokinetic data.
- Floege J, Covic AC, Ketteler M, et al; PA21 Study Group. A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients. Kidney Int. 2014;86(3):638–647. doi:10.1038/ki.2014.58Pivotal phase 3 trial (Study-05A; N=1055): demonstrated non-inferiority of sucroferric oxyhydroxide to sevelamer carbonate in phosphorus lowering, with average 3.3 vs 8.7 tablets/day and better adherence.
- Floege J, Covic AC, Ketteler M, et al. Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. Nephrol Dial Transplant. 2015;30(6):1037–1046. doi:10.1093/ndt/gfv006Extension study (Study-05B; 28 weeks): confirmed sustained phosphorus control and maintained safety profile through 12 months; adherence was 86% at 52 weeks; no clinically meaningful iron accumulation.
- Wüthrich RP, Chonchol M, Covic A, et al. Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients. Clin J Am Soc Nephrol. 2013;8(2):280–289. doi:10.2215/CJN.04230412Phase 2 dose-finding study (Study-03A; N=154): established dose-response for sucroferric oxyhydroxide 250–2500 mg/day; efficacy demonstrated at all doses except 250 mg/day with no dose-dependent GI trends.
- Coyne DW, Ficociello LH, Parameswaran V, et al. Real-world effectiveness of sucroferric oxyhydroxide in patients on chronic hemodialysis: a retrospective analysis of pharmacy data. Clin Nephrol. 2017;88(8):59–67. doi:10.5414/CN109053Real-world retrospective study (N=1029): switching to sucroferric oxyhydroxide reduced pill burden from 9.6 to 3.8 pills/day and increased the proportion of patients achieving phosphorus ≤5.5 mg/dL.
- Covic AC, Floege J, Ketteler M, et al. Iron-related parameters in dialysis patients treated with sucroferric oxyhydroxide. Nephrol Dial Transplant. 2017;32(8):1330–1338. doi:10.1093/ndt/gfw242Post-hoc analysis of phase 3 iron parameters: no clinically meaningful changes in ferritin, TSAT, or transferrin over 1 year; confirms minimal systemic iron absorption.
- Chong E, Kalia V, Willsie S, et al. Drug-drug interactions between sucroferric oxyhydroxide and losartan, furosemide, omeprazole, digoxin and warfarin in healthy subjects. J Nephrol. 2014;27(6):659–666. doi:10.1007/s40620-014-0098-yFive in vivo drug interaction studies (N=40 each): confirmed no alteration in systemic exposure of losartan, furosemide, omeprazole, digoxin, or warfarin when co-administered with sucroferric oxyhydroxide.
- KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD. Kidney Int Suppl. 2017;7(1):1–59. doi:10.1016/j.kisu.2017.04.001Current global guideline for CKD-MBD management; recommends phosphate-lowering therapy for progressive hyperphosphatemia and suggests restricting calcium-based binder use.
- Cozzolino M, Funk F, Rakov V, Phan O, Teitelbaum I. Preclinical pharmacokinetics, pharmacodynamics and safety of sucroferric oxyhydroxide. Curr Drug Metab. 2014;15(10):953–965. doi:10.2174/1389200216666141127160000Comprehensive preclinical review of sucroferric oxyhydroxide pharmacology, demonstrating high phosphate-binding capacity across pH range, minimal iron absorption, and absence of systemic toxicity.
- Wilhelm M, Gaillard S, Rakov V, Funk F. The iron-based phosphate binder PA21 has potent phosphate binding capacity and minimal iron release across a physiological pH range in vitro. Clin Nephrol. 2014;81(4):251–258. doi:10.5414/CN108046In vitro characterization: demonstrated robust phosphate binding (96% at pH 2.5) with minimal iron release, supporting the favourable systemic safety profile.