FDA approves ferric citrate to treat hyperphosphatemia in dialysis patients

Steven Lemieux

Kevin ChamberlinFerric citrate (Auryxia; Keryx Biopharmaceuticals) is an iron-based phosphate binder. FDA approved it September 5, 2014, for the treatment of hyperphosphatemia in chronic kidney disease (CKD) patients on dialysis.

Overview

In CKD, progressive inability of the kidneys to eliminate phosphorus can result in hyperphosphatemia. First-line treatment is restriction of dietary phosphorus. When this is insufficient to maintain serum phosphorus within normal limits, treatment with a phosphate binder begins. As a class, these medications consist of cations that, when taken with meals, bind anionic dietary phosphorus, forming insoluble complexes that are then excreted, limiting phosphate absorption.

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Efficacy

Ferric citrate’s capacity to lower serum phosphorus in CKD patients on dialysis has been examined in two clinical trials. In both instances, ferric citrate use was associated with decreased serum phosphorus levels throughout the study duration.

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Study 1 was a 56-week trial consisting of a 52-week active-controlled phase in which ferric citrate was compared to calcium acetate and sevelamer carbonate, followed by a four-week placebo-controlled, randomized withdrawal period.

Before randomization, patients were required to undergo a two-week washout period, during which phosphate binder administration was prohibited. Patients randomized to use ferric citrate initiated treatment with a dose of 6 g per day; those randomized to calcium acetate or sevelamer carbonate resumed their maintenance dose prior to the washout period. The dose of all phosphate binders was titrated up to a maximum of 12 tablets per day to achieve serum phosphorus levels between 3.5 mg/dL and 5.5 mg/dL.

Ferric citrate use led to decreases in serum phosphorus comparable to those of the active control group throughout the 52-week treatment duration. Ferric citrate-treated patients were then randomized to either continue treatment or receive placebo during the four-week withdrawal period.

At its end, those on placebo experienced an increase in serum phosphorus by 2.2 mg/dL compared to patients using ferric citrate, an effect that achieved statistical significance (P<0.0001).

The second efficacy study was a fixed-dose, open-label trial in which 154 hyperphosphatemic CKD patients on dialysis underwent a one- to two-week washout period and were then randomized to receive 1 g, 6 g, or 8 g of ferric citrate per day for four weeks.

Dose-dependent decreases in serum phosphorus levels were seen by day 7 and were maintained throughout the remainder of the study. By week 4, those receiving 6 g and 8 g of ferric citrate per day achieved statistically significant decreases in mean serum phosphorus levels compared to those taking only 1 gram per day (P<0.0001).

Safety

The most common adverse effects associated with ferric citrate are diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). Ferric citrate, an iron-containing product, has also been shown to cause discoloration of the feces.

Because of its iron content, ferric citrate requires special monitoring during administration. Ferric citrate users have been shown to have increased serum ferritin and transferrin saturation levels, particularly with concomistant use of intravenous iron. These parameters should be measured before ferric citrate use begins and then regularly throughout therapy. Ferric citrate is contraindicated in patients with hemochromatosis and other iron-overload syndromes.

Ferric citrate has not been studied in pregnant women or in any animal reproduction studies. in a comparison between 106 patients aged 65 years and older and nongeriatric patients, no differences were observed with respect to safety and efficacy. Ferric citrate has not been studied in pediatric patients or in patients with inflammatory bowel disease or active gastrointestinal bleeding, as these individuals were excluded from the clinical trials.

Dosing

Ferric citrate is supplied as 1-g tablets, each containing 210 mg of ferric iron. It should be taken with meals in divided doses, beginning with an initial dose of two tablets orally three times per day. The dose may be titrated by one to two tablets weekly, up to a maximum of 12 tablets daily, to achieve goal serum phosphorus levels. The manufacturer’s labeling makes no recommendations regarding dose adjustments in patients with hepatic dysfunction.

Patients should be counseled that there is no need to take a dose of ferric citrate when skipping a meal. In vitro, ferric citrate caused a 70% decrease in the concentration of concurrently administered doxycycline. Therefore, doxycycline should be given at least one hour before administration of ferric citrate, to ensure adequate bioavailability.

Steven Lemieuxis a PGY-1 Pharmacy Resident at John Dempsey Hospital/UConn Health, University of Connecticut School of Pharmacy, Storrs, Conn. Kevin Chamberlinis associate clinical professor and assistant department head, pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.