Key points from the evidence

The content of this evidence summary was up-to-date in January 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Sucroferric oxyhydroxide (Velphoro) is an iron‑based phosphate binder. In 1 open‑label, randomised controlled trial (RCT), sucroferric oxyhydroxide at a mean dose of 1500 mg iron (3 tablets) per day was non‑inferior to sevelamer carbonate at a mean dose of 6.4 g (8 tablets) per day for lowering phosphate levels in adults with chronic kidney disease (CKD) who were on haemodialysis or peritoneal dialysis. More people in the sucroferric oxyhydroxide group withdrew from the study because of adverse events. The most common adverse events with sucroferric oxyhydroxide were gastrointestinal, particularly diarrhoea and discoloured faeces.

Regulatory status: Sucroferric oxyhydroxide (Velphoro) is the first iron‑based phosphate binder to be licensed in Europe for the control of serum phosphate levels in adults with CKD who are on haemodialysis or peritoneal dialysis. It was launched in the UK in January 2015.

Effectiveness

  • Sucroferric oxyhydroxide at a mean dose of 1500 mg (3 tablets) per day was non‑inferior to sevelamer carbonate at a mean dose of 6.4 g (8 tablets) per day for lowering phosphate levels at week 12

    • mean difference 0.08 mmol/litre in the per protocol set (1 RCT, n=685)

    • mean difference 0.10 mmol/litre in the full analysis set (1 RCT, n=1041)

  • There is no RCT evidence of the efficacy of sucroferric oxyhydroxide on patient‑orientated outcomes such as cardiovascular or all‑cause mortality, or surrogate end points such as bone mineral density or vascular calcification.

Safety

  • Sucroferric oxyhydroxide is contraindicated in people with haemochromatosis and any other iron accumulation disorder. There are also warnings about use in people with a recent history of peritonitis, significant gastric or hepatic disorders and people with major gastrointestinal surgery. Sucroferric oxyhydroxide can cause discoloured (black) faeces which may visually mask gastrointestinal bleeding (Velphoro 500 mg chewable tablets summary of product characteristics)

  • Gastrointestinal adverse events were more common with sucroferric oxyhydroxide (45.1%) than with sevelamer carbonate (33.6%; 1 RCT, safety set n=1055).

  • There was more diarrhoea, discoloured faeces and hyperphosphataemia with sucroferric oxyhydroxide; and more constipation and nausea with sevelamer carbonate (1 RCT, safety set n=1055).

Patient factors

  • More people withdrew from the study because of adverse events in the sucroferric oxyhydroxide group (15.7%) than in the sevelamer carbonate group (6.6%; 1 RCT, safety set n=1055).

  • Sucroferric oxyhydroxide (Velphoro) is a chewable tablet.

  • The reduced number of tablets of sucroferric oxyhydroxide that may need to be taken compared with some other phosphate binders may be preferable for some patients.

Resource implications

  • The 28‑day cost of 3 to 6 tablets of sucroferric oxyhydroxide (Velphoro 500 mg tablets) is £167.07 to £334.13 (personal communication Fresenius Medical Care [UK] Limited, December 2014).

  • The 28‑day cost of other phosphate binders is between £7.75 (calcium acetate) and £389.76 (sevelamer hydrochloride) (Drug Tariff and MIMS, December 2014).

Introduction and current guidance

Hyperphosphataemia occurs in people with advanced CKD because of insufficient filtering of phosphate from the blood by poorly functioning kidneys. High serum phosphate levels can directly and indirectly increase parathyroid hormone secretion, leading to development of secondary hyperparathyroidism. Left untreated, secondary hyperparathyroidism increases morbidity and mortality and may lead to renal bone disease, with people experiencing bone and muscular pain, increased incidence of fracture, abnormalities of bone and joint morphology, vascular and soft tissue calcification, and cardiovascular disease.

The NICE guideline on hyperphosphataemia in chronic kidney disease: management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease recommends that, in addition to dietary management to control serum phosphate, calcium acetate is the first‑line phosphate binder for adults with stage 4 or 5 CKD. Calcium carbonate should be considered if calcium acetate is not tolerated or if patients find it unpalatable. Non‑calcium‑based phosphate binders are recommended in certain circumstances, such as if hypercalcaemia develops.

Full text of Introduction and current guidance.

Product overview

Sucroferric oxyhydroxide (Velphoro) is an iron‑based phosphate binder licensed for the control of serum phosphate levels in adult CKD patients on haemodialysis or peritoneal dialysis. It is a chewable tablet containing 500 mg iron as sucroferric oxyhydroxide. Clinical studies have demonstrated that the systemic absorption of iron from sucroferric oxyhydroxide is low (Velphoro 500 mg chewable tablets summary of product characteristics).

The recommended starting dose is 1500 mg iron (3 tablets) per day, divided across the meals of the day. Tablets must be chewed and not swallowed whole; tablets may be crushed. Serum phosphate levels must be monitored and the dose of sucroferric oxyhydroxide up‑ or down‑titrated in increments of 500 mg iron (1 tablet) per day every 2 to 4 weeks until an acceptable serum phosphate level is reached, with regular monitoring afterwards. People who respond to sucroferric oxyhydroxide usually achieve optimal serum phosphate levels at doses of 1500 mg to 2000 mg iron (3 to 4 tablets) per day. The maximum recommended dose is 3000 mg iron (6 tablets) per day (Velphoro 500 mg chewable tablets summary of product characteristics).

Full text of Product overview.

Evidence review

  • This evidence summary is based on a 27‑week open‑label, phase III RCT which compared sucroferric oxyhydroxide (also called PA21) with sevelamer carbonate in 1059 people on haemodialysis (92%) or peritoneal dialysis (8%) who had a history of hyperphosphataemia and phosphate binder treatment (Floege et al. 2014). In stage 1 of the study, participants were randomised to sucroferric oxyhydroxide or sevelamer carbonate for 24 weeks. In stage 2 of the study, 99 people on haemodialysis who had been in the sucroferric oxyhydroxide group were re‑randomised to either the same dose of sucroferric oxyhydroxide they had been taking at the end of stage 1 or low‑dose sucroferric oxyhydroxide for 3 weeks.

  • The primary efficacy end point was an analysis of the superiority of a maintenance dose of sucroferric oxyhydroxide compared with a low dose of sucroferric oxyhydroxide in maintaining the phosphate lowering effect. This was assessed in stage 2 of the study by comparing serum phosphate levels at week 24 and week 27 in 93 patients on haemodialysis who had been in the sucroferric oxyhydroxide group in stage 1 of the study, and were then re‑randomised at week 24 to either continue their maintenance dose or receive a low dose of 250 mg per day. At week 24, patients randomised to continue their maintenance dose of sucroferric oxyhydroxide had a mean serum phosphate level of 1.5 mmol/litre and this did not change significantly at week 27. In the low‑dose group, at week 27, mean serum phosphate levels increased by 0.6 mmol/litre from 1.6 mmol/litre at week 24. The difference was statistically significant between groups (p<0.001).

  • The key secondary efficacy end point was an analysis of the non‑inferiority of sucroferric oxyhydroxide compared with sevelamer carbonate in lowering serum phosphate. This was assessed in stage 1 of the study by comparing the change in serum phosphate levels from baseline to week 12. In the per protocol set (n=685), mean serum phosphate levels reduced by 0.71 mmol/litre with sucroferric oxyhydroxide and by 0.79 mmol/litre with sevelamer carbonate; a difference of 0.08 mmol/litre. In the full analysis set (n=1041) the reduction was 0.66 mmol/litre with sucroferric oxyhydroxide and 0.76 mmol/litre with sevelamer carbonate; a difference of 0.10 mmol/litre. In both data sets, the upper bound of the 97.5% CI was less than the pre‑defined margin of 0.19 mmol/litre; meaning sucroferric oxyhydroxide was non‑inferior to sevelamer carbonate for lowering phosphate levels. However, the European public assessment report for Velphoro reports that the change in phosphate levels from baseline to week 12 was statistically significantly greater with sevelamer than with sucroferric oxyhydroxide (p=0.011). It also reports that more people in the sevelamer group than in the sucroferric oxyhydroxide group had serum phosphate levels within a target range at week 12 (p=0.010) but not at week 24 based on logistic models.

  • From baseline to week 24, the mean dose of sucroferric oxyhydroxide was 1500 mg iron (3 tablets) and for sevelamer carbonate it was 6.4 g (8 tablets). In the sucroferric oxyhydroxide group, non‑adherence to study treatment (defined as taking less than 70% of the expected number of tablets) occurred in 15.1% of patients compared with 21.3% of the sevelamer carbonate group (no statistical analysis reported).

  • Gastrointestinal adverse events were the most frequent type of adverse events reported in the RCT, and were more common with sucroferric oxyhydroxide (45.1%) than with sevelamer carbonate (33.6%). Adverse events reported more frequently with sucroferric oxyhydroxide were diarrhoea (20.1% compared with 7.5% with sevelamer), discoloured faeces (15.4% compared with 0.3% with sevelamer) and hyperphosphataemia (11.2% compared with 7.8% with sevelamer). Constipation was reported more frequently with sevelamer (7.2% compared with 3.8% with sucroferric oxyhydroxide), as was nausea (11.2% with sevelamer compared with 7.2% with sucroferric oxyhydroxide). No statistical analysis was reported for any of these comparisons.

  • More people in the sucroferric oxyhydroxide group (15.7%) than in the sevelamer carbonate group (6.6%) withdrew from the study because of adverse events. The most frequent adverse events leading to withdrawal in the sucroferric oxyhydroxide group were diarrhoea (2.8% compared with 0.6% with sevelamer), nausea (1.6% compared with 0.6% with sevelamer), abnormal product taste (1.6% compared with 0.3% with sevelamer) and hyperphosphataemia (1.4% compared with 0% with sevelamer). No statistical analysis was reported for any of these comparisons.

  • The phase III RCT was open‑label because a double‑blind study was not possible. This can introduce bias in assessing outcomes because investigators and trial participants are aware of treatment allocation.

  • The main efficacy end points of the phase III study were disease‑orientated changes in serum phosphate levels. As with other phosphate binders, there is no RCT evidence of the efficacy of sucroferric oxyhydroxide on patient‑orientated outcomes such as cardiovascular or all‑cause mortality, or surrogate end points such as bone mineral density or vascular calcification. Longer term studies assessing the efficacy and safety of sucroferric oxyhydroxide would be useful, as would studies comparing it to other phosphate binders, particularly calcium‑based phosphate binders.

Full text of Evidence review.

Context

Sucroferric oxyhydroxide is the first iron‑based phosphate binder to be licensed in Europe. Other phosphate binders include the calcium‑based phosphate binders, calcium acetate and calcium carbonate; and the non‑calcium phosphate binders, sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, aluminium hydroxide and magnesium carbonate.

The cost of sucroferric oxyhydroxide (Velphoro 500 mg tablets) is £179 for 90 tablets (personal communication Fresenius Medical Care [UK] Limited, December 2014).

Full text of Context.

Estimated impact for the NHS

The non‑calcium based phosphate binder, sucroferric oxyhydroxide (Velphoro), is licensed for the control of serum phosphate levels in adults with CKD who are on haemodialysis or peritoneal dialysis. Unlike some other phosphate binders, it is not licensed for the control of serum phosphate levels in people with CKD who are not on dialysis.

Sucroferric oxyhydroxide was not available when the NICE guideline on hyperphosphataemia in chronic kidney disease was published. However other non‑calcium based phosphate binders are recommended for people with stage 5 CKD on dialysis when they remain hyperphosphataemic despite adherence to the maximum recommended or tolerated dose of a calcium‑based phosphate binder, or if serum phosphate is controlled by the current diet and phosphate binder regimen but serum calcium goes above the upper limit of normal or serum parathyroid hormone levels are low.

Local decision makers will need to consider the available evidence on efficacy and safety, as well as cost and individual patient factors, when making decisions about using sucroferric oxyhydroxide or another non‑calcium based phosphate binder. There are no RCTs comparing sucroferric oxyhydroxide with calcium‑based phosphate binders and, as with other phosphate binders, there is no RCT evidence of the efficacy of sucroferric oxyhydroxide on patient‑orientated outcomes such as cardiovascular or all‑cause mortality.

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.