Ferric Citrate (AURYXIA®) Drug Monograph

A Comprehensive Clinical Overview of Auryxia® in a Clinical Monograph

How Supplied¹

Tablets — Auryxia 210 mg ferric iron tablets equivalent to 1 g ferric citrate are supplied as 200 tablets in 400 cc high-density polyethylene bottles. The 210 mg ferric iron tablets are film coated, peach colored, and oval-shaped tablet embossed with “KX52”.

Indications¹

Control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

Pharmacology¹²

  • Healthy kidneys excrete phosphate extremely efficiently, but in CKD patients, phosphate excretion becomes unpredictable
  • As CKD progresses, PTH compensation fails in preventing phosphate reabsorption leading to supra-physiological levels of phosphate from reabsorption
  • Upon oral administration, ferric citrate dissociates into ferric iron and citrate
  • Ferric iron binds to several dietary phosphate ions in the GI tract and precipitates as ferric phosphate, which is excreted in the stool
  • Auryxia ultimately reduces serum phosphate levels by preventing reabsorption

Pharmacokinetics

Clinical Efficacy

US Trials in Dialysis Dependent CKD²

Dose-response and Efficacy of Ferric Citrate to Treat Hyperphosphatemia in Hemodialysis Patients¹²³

The study was a phase 3, multicenter, randomized, open-labeled trial comparing three fixed dosed regimens of ferric citrate. The goal of the study was to compare the clinical effectiveness of the three doses of 1g, 6 g, and 8 g ferric citrate. The results of the study concluded that ferric citrate is an effective dietary phosphate binder which reduces phosphorous levels in patients on dialysis.


Ferric Citrate Controls Phosphorous and Delivers Iron in Patients on Dialysis²⁴

This study details the findings of a sequential three-period, 58-week, phase 3 randomized controlled trial. The goal of the study was to assess the safety and efficacy of ferric citrate as a phosphate binder in 441 patients with ESRD requiring dialysis. The conclusion of the study states that ferric citrate is an effective dietary phosphorous binder. It also improves ferritin and TSAT levels in addition to requiring less ESA and IV iron used in patients with CKD on dialysis.


Japan Trials in Dialysis Dependent CKD Patients²

A Randomized Trial of JTT-751 versus Sevelamer Hydrochloride in Patients on Hemodialysis²⁵

This study was a phase 3, multicenter, randomized, active-controlled, open-label, parallel group study. The goal of the study was to directly compare JTT-751 (ferric citrate anhydrate) and sevelamer hydrochloride in HD-dependent CKD patients. The conclusion of the study states that serum phosphate concentrations declined significantly in both groups and that intergroup difference was not significant. The study proved that JTT-751 was non-inferior to sevelamer HCl as a phosphate binder for HD-dependent CKD patients. In addition, the study also concluded that JTT-751 led to higher hemoglobin, hematocrit, serum ferritin, and TSAT than sevelamer.


Long-term Safety and Efficacy of a Novel Iron-containing Phosphate Binder, JTT-751, in Patients Receiving Hemodialysis²⁶

This study was an open-label, phase 3, multicenter, dose-titration trial that recruit subjects at 29 centers in Japan. The goal of this study was to assess the safety and efficacy of JTT-751 (ferric citrate anhydrate). The conclusion of the study states that JTT-751 effectively controlled serum phosphate concentrations in patients receiving hemodialysis during a full year of study. Study also found that patients who used of JTT-751 significantly reduced IV iron use and ESA usage throughout the study.


Taiwan Trials in Hemodialysis Dependent CKD²

Effect of Oral Ferric Citrate on Serum Phosphorus in Hemodialysis Patients²⁷

This study was a phase 3, randomized, double blind, placebo-controlled study intended to assess the efficacy of ferric citrate as a phosphate binder in patients with ESRD on hemodialysis. The study concluded that oral ferric citrate was a safe and effective option for lowering serum phosphorous in CKD patients on hemodialysis.


Contraindications/Warnings/Precautions¹²

  • Iron overload syndromes such as hemochromatosis (excessive elevations in iron stores)
  • Accidental overdose of iron (leading cause of fatal poisoning in children under 6 years of age)
  • Patients with inflammatory bowel disease or active/symptomatic gastrointestinal bleeding were excluded from clinical trials. Safety not established in these patients

Adverse Effects¹²

  • May cause discolored (dark) stools, however, this staining is typical with most medications containing iron
  • Diarrhea
  • Nausea
  • Constipation
  • Vomiting

Drug Interactions¹²

  • No empirical data on avoiding drug interactions between Auryxia and most concomitant oral drugs.
  • For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration between the two drugs.
  • Separation with Auryxia depends on absorption characteristics of the medications administered concomitantly (such as time to reach peak systemic levels or whether the drug is an immediate or extended release product)
  • Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range

Drug/Food/Nutrient Interactions

  • N/A

Dosage Guidelines and Monitoring¹

  • Auryxia 210 mg ferric iron, equivalent to 1 g ferric citrate, film coated, peach colored, and oval-shaped tablet embossed with “KX52”.

Pediatric Dosing: N/A¹

  • The safety and efficacy of Auryxia have not been established in pediatric patients

Administration Options¹²

  • Take two 1gram tablet orally 3 times per day with meals
  • Maximum dose of 12 tablets daily
  • Dose can be titrated at 1-week or longer intervals

Monitoring parameters¹²

  • Monitor serum phosphorous levels
  • Titrate in decrements or increments of 1 to 2 tablets per day as needed to maintain target serum phosphorous levels
  • Monitor for signs and symptoms of iron overload and accidental iron overdose

Medication Safety Issues¹

Pregnancy

  • Pregnancy Category B
  • No adequate and well-controlled studies in pregnant women
  • Overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes, and fetal malformation

Labor and Delivery

  • Effects of Auryxia on labor and delivery are unknown

Nursing Mothers

  • Data from rats have shown transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1).
  • Possibility of infant exposure when Auryxia is administered to a nursing woman

Geriatric Use

  • Clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of Auryxia

Overdose

  • No data available regarding overdose of Auryxia
  • Maximum dose studied was 12 tablets per day
  • May lead to excessive elevations in iron stores (especially with concomitant IV iron use)
  • Keep away from children to prevent accidental overdose

Storage

  • Store at 20°C to 25°C (68°F to 77°F)
  • Excursions permitted to 15°C to 30°C (59°F to 86°F)
  • Protect from moisture

Cost Comparison²

Conclusion and Recommendations²⁸

Auryxia is comparable to other non-calcium based phosphate binders in terms of efficacy and price. The major advantage of Auryxia are the studies supporting the reduction in use of IV iron and ESAs. An additional study utilizing Lewis et al. trial projected a cost savings of $2,101 per patient per year with approximately $1,585 of the savings directly related from less use of ESAs. Since CKD is a chronic disease requiring regular use of IV iron and ESAs, we the study states that cost savings could continue for the entire duration of treating a CKD patient

Auryxia is a safe and effective phosphate binder with limited side effects and limited drug interactions. It has the potential to reduce IV iron use and ESA usage which could potentially impact cost savings.

References:

  1. Full Prescribing Information. Auryxia, ferric citrate tablets. Keryx Biopharmaceuticals, Boston, MA, 2016.
  2. Pennoyer A, Bridgeman MB. Ferric Citrate (Auryxia) for the Treatment of Hyperphosphatemia. Pharmacy and Therapeutics. 2015;40(5):329–339.
  3. Dwyer JP, Sika M, Schulman G, et al. Dose–response and efficacy of ferric citrate to treat hyperphosphatemia in hemodialysis patients: a short-term randomized trial. Am J Kidney Dis. 2013;61:759–766.
  4. Lewis JB, Sika M, Koury MJ, et al. Ferric citrate controls phosphorus and delivers iron in patients on dialysis. J Am Soc Nephrol. 2014;26:e1–e11.
  5. Yokoyama K, Akiba T, Fukagawa M, et al. A randomized trial of JTT-751 versus sevelamer hydrochloride in patients on hemodialysis. Nephrol Dial Transplant. 2014;29:1053–1060.
  6. Yokoyama K, Akiba T, Fukagawa M, et al. Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis. J Ren Nutr. 2014;24:261–267.
  7. Lee CT, Wu IW, Chiang SS, et al. Effect of oral ferric citrate on serum phosphorus in hemodialysis patients: multicenter, randomized, double-blind, placebo-controlled study. J Nephrol. 2015;28:105–113.
  8. Rodby R, Umanath K, Hsieh A, et al. Phosphorus binding with ferric citrate reduces erythropoiesis-stimulating agent (ESA) and IV iron usage and cost in patients with ESRD [abstract] Am J Kidney Dis. 2014;63:B95.