Ferric Citrate

7/26/2019 Ferric Citrate

1/15

Hospital Pharmacy 139

Formulary Drug Reviews

Ferric Citrate

Dennis J. Cada, PharmD, FASHP, FASCP (Editor)*

; Jasen Cong, PharmD

; and Danial E. Baker,PharmD, FASHP, FASCP

*Founder and Contributing Editor, The Formulary; Drug Information Resident, College of Pharmacy, Washington State Univer-sity; Director, Drug Information Center, and Professor of Pharmacy Practice, College of Pharmacy, Washington State UniversitySpokane, PO Box 1495, Spokane, Washington 99210-1495. The authors indicate no relationships that could be perceived as aconflict of interest.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documentedmonographs on drugs that are newly released or are in late phase 3 trials. The monographs are tar-geted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summarymonographs on agents that are useful for agendas and pharmacy/nursing in-services. A compre-hensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also providedeach month. With a subscription, the monographs are sent in print and are also available on-line.Monographs can be customized to meet the needs of a facility. A drug class review is now pub-lished monthly with The Formulary Monograph Service. Through the cooperation of The Formu-

lary, Hospital Pharmacy publishes selected reviews in this column. For more information aboutTheFormulary Monograph Service, call The Formulary at 800-322-4349. The February 2015monograph topics are netupitant/palonosetron, naltrxone SR/bupropion SR, nintedanib, pirfeni-done, and ivabradine. The Safety MUE is on netupitant/palonosetron.

Generic Name: Ferric citrateProprietary Name: Auryxia (Keryx Biopharma-

ceuticals)Approval Rating: 5 (new formulation or new

manufacturer)

Therapeutic Class: Phosphate bindersSimilar Drugs: Calcium acetate, calcium car-

bonate, lanthanum carbon-ate, sevelamer hydrochloride,sevelamer carbonate, sucro-ferric oxyhydroxide

Sound-or Look-AlikeNames: Ferric gluconate, ferric sub-

sulfate, ferric carboxymaltose

INDICATIONS

Ferric citrate (KRX-0502) is indicated for thereduction of serum phosphorus in patients withchronic kidney disease (CKD) on dialysis.1,2

Absorption of dietary phosphate occurs in thegastrointestinal (GI) tract and excess phosphorus

is normally excreted in the urine.3Additional phos-phate regulatory mechanisms include increases inparathyroid hormone (PTH) and fibroblast growthfactor-23 (FGF-23) to inhibit renal absorption ofphosphate.4 Patients with end-stage renal disease(ESRD) have a decreased ability to excrete phos-

phate, which can result in hyperphosphatemia.3,5-7Decreased 1,25-dihydroxycholecalciferol productionand dietary calcium absorption can also occur withdecreased renal function.6Potential complications asa result of these events include the development ofCKD-associated mineral and bone disorders (CKD-MBD), extraskeletal calcification of soft tissue, andincreased risk of mortality.3,5,6-8

In addition to dietary phosphate restriction anddialysis, current therapies to lower serum phosphateact by binding phosphate in the gut prior to absorp-tion.3,5Such products include aluminum hydroxide,

calcium-based binders, lanthanum and sevelamerproducts, and iron-based phosphate binders. How-ever, each of these products has specific disadvantages.Long-term aluminum hydroxide therapy can result inaccumulation and aluminum toxicity. Calcium-based

Hosp Pharm 2015;50(2):1391512015 Thomas Land Publishers, Inc.

www.hospital-pharmacy.com

doi: 10.1310/hpj5002-139


2/15

140 Volume 50, February 2015


binders, such as calcium carbonate, calcium acetate,and calcium citrate, can lead to hypercalcemia andmetastatic calcification. Noncalcium-based binders,such lanthanum and sevelamer products, may bindto other medication and increase patient medica-tion costs. Sucroferric oxyhydroxide is a recentlyapproved iron-based phosphate binder in the UnitedStates.3,5,6-8Iron deficiency may also be present withCKD due to factors such as use of erythropoiesis-stimulating agents (ESA), repeated blood sampling,or hemodialysis. As a result, iron supplementationis used to reduce the severity of anemia in patientswith CKD. The intravenous (IV) route is preferred forpatients, especially those on hemodialysis, with oraliron as an alternative option in nondialysis patients.3

As per their special protocol assessment, KeryxBiopharmaceuticals has completed 2 phase 3 clini-

cal trials designed to support regulatory submis-sion for drug approval.9 Outside of ESRD dialysispatients, a phase 2 trial reviewing ferric citrate forserum phosphate reduction and iron-deficiency ane-mia in patients with nondialysis-dependent CKD hasbeen completed.10-12A phase 2 pilot study, expectedto be completed in October 2014, is evaluating theefficacy and safety of ferric citrate for iron deficiencyanemia in stages 3 to 5 nondialysis-dependent CKDpatients.13Under a sublicense from Keryx Biophar-maceuticals, a separate product in Japan designated

ferric citrate hydrate has been developed by JapanTobacco, Inc. and Torii Pharmaceuticals, Co.4,8,14-17

CLINICAL PHARMACOLOGYIron-based phosphate binder complex binds with

phosphate within the GI tract over a wide pH range,which leads to increased phosphate excretion in the fecesand decreased phosphate absorption.3 In normal andazotemic rats, ferric citrate increased fecal phosphateexcretion and decreased intestinal phosphate absorption.Table 1provides a comparison of mechanisms of actionand elemental content of select phosphate binders.The phosphorus-binding capacity of ferric citrate wasestimated to be approximately 84.8 to 87.9 mg ofphosphorus per gram of elemental ferric iron and 19.1to 19.8 mg of phosphorus per gram of ferric citrate.18In comparison, 180 mg of phosphate is estimated to bebound by 1 g of aluminum, 40 mg of phosphate boundby 1 g of elemental calcium (as calcium carbonate), and100 mg of phosphate bound by 1 g of elemental calcium(as calcium acetate).18Studies in human subjects haveobserved similar reductions in serum phosphate withferric citrate as calcium carbonate, calcium acetate, andsevelamer carbonate.19-21

As an iron-containing product, several trials havesuggested ferric citrate has a potential to increaseiron-related parameters, including serum iron, ferri-tin, hemoglobin, transferrin saturation (TSAT), and

Table 1.Comparative mechanism of action and elemental content of phosphate binders used to treathyperphosphatemia6,17,18,45,49

Drug Mechanism of action Elemental content

Calcium acetate Forms insoluble calcium phosphate by bindingto dietary phosphate

169 mg of elemental calcium per667 mg of calcium acetate

Calcium carbonate Forms insoluble calcium phosphate by bindingto dietary phosphate

400 mg of elemental calcium per1,000 mg of calcium carbonate

Ferric citrate Binds to dietary phosphorus to increase fecalexcretion and decrease intestinal absorption

210 mg of elemental ferric iron per1,000 mg of ferric citrate

Ferric citrate hydrate Binds to dietary phosphorus to increase fecal

excretion and decrease intestinal absorption

62 mg of iron as an anhydride per

250 mg of ferric citrate hydrate

Sucroferric oxyhydroxide Exchange of ligands between dietary phosphateand hydroxyl groups and/or water from sucroferricoxyhydroxide

500 mg of iron per 2,500 mgof sucroferric oxyhydroxide

Lanthanum carbonate Forms insoluble lanthanum phosphate by bindingto dietary phosphate

Sevelamer carbonate Interacts with intestinal phosphate through ionicand hydrogen bonding to decrease absorption

Sevelamer hydrochloride Interacts with intestinal phosphate through ionicand hydrogen bonding to decrease absorption


3/15



total iron-binding capacity (TIBC), as well as topotentially decrease the dose requirements or usageof IV iron and ESA.5,7,20-28

PHARMACOKINETICSThe ferric ion has limited absorption through the

GI tract.29Ferric citrate reduces serum phosphorus ina dose-dependent manner. During a 28-day treatmentperiod, ferric citrate at fixed doses of 1, 6, and 8 g/dayproduced a difference in serum phosphorus from endof therapy to baseline of 0.1, 1.9, and 2.1 mg/dL,respectively. In this study, a dose-response relationshipwas also observed for other lab parameters, such as cal-cium phosphorus product, ferritin, and bicarbonate.5

Ferric citrate hydrate is described to have a largersurface area and faster dissolution rate than ferriccitrate.8,15,16

COMPARATIVE EFFICACYIndication: Hyperphosphatemia in End-Stage RenalDisease Patients on Dialysis Three Times Weekly

Guidelines

Guideline: Kidney Disease Outcomes Quality Initia-tive (KDOQI) clinical practice guidelines for bonemetabolism and disease in CKD

Reference: National Kidney Foundation, 200330Comments: Stage 5 CKD patients unable to control

serum phosphorus or PTH with dietary phosphaterestriction are recommended to start a calcium-basedor noncalcium-, nonaluminum-, nonmagnesium-based phosphate binder. Daily limits of elementalcalcium provided by calcium-based binders shouldnot exceed 1,500 mg, and elemental calcium fromall sources should not exceed 2,000 mg. Calcium-based phosphate binders should be avoided inhypercalcemic patients (eg, corrected serum calciumgreater than 10.2 mg/dL) or patients with PTH lessthan 150 pg/mL. Dialysis patients failing to achieveserum phosphate of less than 5.5 mg/dL with a

single calcium-based or noncalcium-, nonaluminum-,nonmagnesium-based phosphate binder may initiatea combined therapy with these 2 agents. Dialysispatients presenting with severe vascular or calcificationof soft tissue should initiate therapy with noncalcium-based phosphate binders. Four weeks of aluminum-based phosphate binders followed by other bindersthereafter may be considered in patients with serumphosphorus greater than 7 mg/dL. Consideration ofincreased dialysis time or frequency (4 times weekly

or more often) should be given in patients with serumphosphorus greater than 7 mg/dL, uncontrolled onphosphate binders, or unable to tolerate phosphatebinders. Ferric citrate is not mentioned in this version

of the guidelines.Guideline: Kidney Disease: Improving Global Out-comes (KDIGO) clinical practice guideline for thediagnosis, evaluation, prevention, and treatment ofCKD-MBD

Reference: KDIGO CKD-MBD Work Group,200931Comments: Hypophosphatemia treatment in CKDpatients stages 3 to 5, including stage 5 requiringdialysis, consists of dietary phosphate restriction,phosphate binders, and increased dialysis. Main-tenance of serum phosphorus and calcium within

normal range is recommended in CKD stages 3 to 5.Serum phosphorus toward a normal range and cal-cium within normal range is recommended for stage5 CKD requiring dialysis. Preference toward a specificphosphate binder is not expressed in these guidelines.The recommendation for selecting a particular agentis based on CKD staging, complications of CKD-MBD, and medication adverse effects. Guidanceregarding appropriate use of specific agents includesrestriction of calcium-based phosphate binder dose(and potentially calcitriol or vitamin D analogues)in patients with recurrent/persistent hypercalcemia.Reduction of calcium-based binder dose is also rec-ommended in patients with arterial calcification, ady-namic bone disease, or persistently low serum PTH.The use of long-term aluminum-based phosphatebinders should be avoided during CKD stages 3 to 5.CKD patients requiring dialysis or unable to toleratephosphate binders are recommended to increase fre-quency or duration of dialysis to reduce serum phos-phate. Additional recommendations regarding dialy-sis include a dialysate calcium concentration between2.5 to 3 mEq/L and avoidance of aluminum dialysate

contamination. Brief commentary on tolerability offerric citrate is mentioned in this version of the guide-line; however, a place in therapy is not stated.

Studies

Drug: Ferric citrateReference: Dwyer JP, et al, 20135Study Design: Phase 3, randomized, multicenter,open-label trialStudy Funding: Keryx Biopharmaceuticals


4/15



Patients: One hundred fifty-four adult patientsrandomized (79.2% completed) with ESRD onhemodialysis 3 times a week and taking 3 to15 pills of a phosphate binder daily (calcium ace-

tate 667 mg or sevelamer 800 mg per pill). Studyincluded patients with a serum ferritin level lessthan 1,000 mcg/L, TSAT less than 50%, serumphosphate between 3.5 to 8 mg/dL at screen-ing, and serum phosphorus of 6 mg/dL or moreafter 2 weeks of washout. At baseline, the intent-to-treat (ITT) population ranged from 52.8 to56.5 years of age and 57.8% to 64% were male;50% to 60.8% of patients were Black and 13% to21% were White. Baseline laboratory parametersincluded mean phosphorus of 7.3 to 7.6 mg/dL,mean ferritin of 515.2 to 558.2 mg/dL, and mean

TSAT of 29.8% to 33.8%.Intervention: Patients were randomized 1:1:1 toferric citrate 1, 6, or 8 g/day. Ferric citrate wasprovided as 1 g caplets containing ferric iron210 mg taken at meals or within 1 hour of eat-ing. Following a 1- to 2-week washout of pre-vious phosphate-binder therapy, patients wereprovided 28 days of therapy. Patients discontin-ued therapy if serum phosphorus was 2.5 mg/dL or less at day 7 or was outside the range of2.5 to 9 mg/dL on days 14 or 21. Permitted con-current therapies included vitamin D, vitamin Danalogues, and cinacalcet held at constant doses.Calcium supplements were to be taken at bedtimeor 2 hours outside of mealtime. IV iron therapywas allowed for patients with serum ferritin of1,000 mcg/L or less and TSAT of 50% or less.The ITT cohort included randomized patientswith a baseline and postbaseline assessment. Thesafety cohort included patients receiving at least1 study medication dose.ResultsPrimary Endpoint(s)

Regression analysis confirmed a dose-responsechange in serum phosphorus from baseline(P< .001).

Secondary Endpoint(s) Compared with baseline, ferric citrate 1, 6, and

8 g/day decreased serum phosphate by a meanof 0.1 mg/dL, 1.9 mg/dL, and 2.1 mg/dL,respectively, at day 28 in the ITT population.

Mean difference in change of serum phosphatefrom baseline of 1 g/day versus 6 g/day was1.3 mg/dL (95% CI, 0.69 to 1.9; P< .001).

Mean difference in change of serum phosphatefrom baseline of 1 g/day versus 8 g/day was1.5 mg/dL (95% CI, 0.86 to 2.1; P< .001).

Mean difference in change of serum phosphatefrom baseline of 6 g/day versus 8 g/day was0.21 mg/dL (95% CI, 0.39 to 0.81; P= .5).

No statistically significant dose response wasobserved for calcium or TSAT.

A statistically significant dose response wasobserved for ferritin. Change in ferritin frombaseline to day 28 was 14.4 mg/dL, 90.1 mg/dL,and 90.2 mg/dL for ferric citrate 1, 6, and 8 g/day,respectively.

Comments: This trial was conducted across 15 sites inthe United States. A total of 22 patients (15.1%) wereconsidered treatment failures by day 28 due to serumphosphorus being 2.5 mg/dL or less (7 patients) orserum phosphorus 9 mg/dL or more (15 patients).High serum phosphorus was seen more often in the 6and 8 g/day cohorts, and low serum phosphorus wasseen more often in the 1 g/day cohort.Limitations: This study may have limited applica-bility in patients with active GI bleeding, inflam-matory bowel disease, parathyroidectomy in thepast 6 months, hyperphosphatemia of 10 mg/dLor more, and a history of malignancy in the past5 years since they were excluded from participation.

Drug: Ferric citrate versus active control

Reference: Umanath K, et al, 2013; Lewis JB, et al,20146,20,21,25-28,32-37Study Design: Phase 3, randomized, 3-period, inter-national, multicenter trialStudy Funding: Keryx BiopharmaceuticalsPatients: Four hundred forty-one ESRD patientswho were 18 years and older on 3 times weeklyhemodialysis or peritoneal dialysis taking 3 to18 pills of a phosphate binder daily. Study includedpatients with a serum ferritin level less than1,000 mcg/L, TSAT less than 50%, and serum phos-phate between 2.5 to 8 mg/dL at screening. Baselinecharacteristics of the ferric citrate and active con-trols arms in the safety period were similar. At base-line, the ferric citrate arm of the safety period hada mean age of 54.9 years and 62.7% were male;52.7% of patients were Black and 42.5% wereWhite. In this cohort, mean ferritin was 594 mg/dL,TSAT was 30.9%, and hemoglobin was 11.6 g/dL.Intervention: Patients with serum phosphorus of atleast 6 mg/dL after up to 2 weeks of washout wererandomized 2:1 to ferric citrate or active control


5/15



(calcium acetate 667 mg and/or sevelamer carbon-ate 800 mg) in a 52-week, open-label, safety assess-ment period. Ferric citrate was provided as 1 gcaplets containing ferric iron 210 mg, and patients

were started on 6 g/day titrated up to 12 g/day.Active control was provided at the dose used priorto washout and titrated to a maximum of 12 pillsdaily. Doses were titrated to achieve a normal serumphosphorus level of 3.5 to 5.5 mg/dL. Compliantpatients taking 12 pills/caplets of assigned phosphatebinder and serum phosphorus greater than 9 mg/dLwere discontinued as treatment failures. In thesafety period, 192 ferric citrate patients were re-ran-domized 1:1 ferric citrate or placebo in a 4-week,open-label, efficacy assessment period. Patients withserum phosphorus of 9 mg/dL or more during this

period were considered treatment failures. Allowedconcurrent therapies included IV iron preparations(for ferritin 1,000 ng/mL or lower and TSAT of30% or lower), vitamin D, vitamin D analogues,cinacalcet, dialysate calcium concentrations, andESA according to the treating physician. Calciumsupplements were allowed if not taken with food.

Results

Primary Endpoint(s)

Ferric citrate decreased mean serum phospho-rus from 5.1 mg/dL at week 52 to 4.9 mg/dL at

week 56 (end of efficacy period) compared with5.4 mg/dL at week 52 to 7.2 mg/dL at week 56with placebo. The least squares mean treatmentdifference was 2.18 mg/dL (95% CI, 2.59 to1.77; P< .001).

Secondary Endpoint(s)

During the 52-week safety period, mean serumphosphorus decreased from 7.4 mg/dL at base-line to 5.4 mg/dL at week 52 with ferric citrateand from 7.6 mg/dL at baseline to 5.4 mg/dL atweek 52 with active control. At week 52 of thesafety period, 63% of 281 ferric citrate patients

compared with 63.7% of patients achievedserum phosphorus of 5.5 mg/dL or less. During the safety period, ferric citrate increased

serum iron from 72.6 mcg/dL at baseline to88.4 mcg/dL at week 52 compared with serumiron remaining at approximately 69 mcg/dLthroughout the safety period in active control(P< .001).

During the safety period, ferric citrate increasedmean serum ferritin from 593 ng/mL at base-line to 899 ng/mL at week 52 compared with

609 ng/mL at baseline to 628 ng/mL at week 52for active control (P< .001).

During the safety period, ferric citrate changedthe mean TSAT from 31.3% at baseline to

39.3% at week 52 with ferric citrate comparedwith 30.9% at baseline to 29.7% active control(P< .001).

During the safety period, TIBC changed from233 mcg/dL at baseline to 227 mcg/dL at week52 with ferric citrate compared with 225 mcg/dL at baseline to 235 mcg/dL at week 52(P< .001).

Median elemental IV iron use was 12.9 mg/week with ferric citrate compared with26.8 mg/week with active control for a treat-ment difference of 52% (P< .001). In the last

9 months of the study, 42% of patients were offIV iron compared with 11% in active control. Median ESA use was 5,303 epoetin equivalent

units per week with ferric citrate comparedwith 6,954 epoetin equivalent units per weekwith active control for a treatment difference of24% (P< .04).

Endpoint(s) Mean hemoglobin during the safety period

decreased from 11.6 g/dL at baseline to11.4 g/dL at week 52 with ferric citrate com-pared with 11.7 g/dL at baseline to 11.1 g/dL at

week 52 with active control (P< .05). During the safety period, serum cal-cium increased from 8.9 mg/dL at baseline to9.1 mg/dL at week 52 with ferric citrate com-pared with 9 mg/dL at baseline to 9.3 mg/dL atweek 52 with active control.

In a subgroup analysis of the safety period, 74patients taking ferric citrate who were not givenIV iron over the 52-week period saw improve-ment in serum iron, ferritin, and TSAT at week52 compared with baseline. In 207 patients pro-vided IV iron, improvements were seen in serumiron, ferritin, TSAT, and hemoglobin at week 52compared with baseline. Between group differ-ences (IV iron vs no IV iron) at week 52 werenot statistically significant.

Comments: This trial was conducted at 60 sitesacross the United States and Israel. In the safetyperiod, 35 of 98 patients discontinued ferric citrateand 8 of 34 patients discontinued active controldue to adverse events. In the efficacy period, 2 of5 patients discontinued ferric citrate and 2 of 10patients discontinued placebo due to adverse events.


6/15



An open-label extension trial exposed 168 patients,who successfully completed the original 58-weekstudy, to ferric citrate for an additional 48 weeks.Preliminary data over the 48-week period reported

serum phosphorus ranging from 5.2 to 5.5 mg/dL(baseline, 5.7 mg/dL), TSAT ranging from 36%to 38% (baseline 32%), and hemoglobin rangingfrom 11.1 to 11.6 g/dL (baseline, 11.1 g/dL) over48 weeks. Ferritin increased from 700 ng/mL atbaseline to a maximum of 848 ng/mL at week 24 anddropped to 717 ng/mL at week 48. Mean monthlyIV iron dose per patient was 32 mg/month, andweekly mean ESA dose per patient was 4,500 unitsper week. Approximately 69% of patients in thisperiod did not require IV iron.38,39 Pharmacoeco-nomic analysis of similar data concluded that the

use of ferric citrate may reduce the cost associatedwith anemia-management drugs, and total healthcare cost of these patients may be reduced.40,41Limitations: This study may have limited applica-bility in patients with active GI bleeding or inflam-matory bowel disease, parathyroidectomy in thepast 6 months, serum phosphorus 10 mg/dL ormore 3 months prior to screening, and a historyof malignancy in the past 5 years since they wereexcluded from participation.

Drug: Ferric citrate versus placebo

Reference: Lee CT, et al, 20147

Study Design: Phase 3, randomized, multicenter,double-blind, placebo-controlled study

Study Funding: Panion and BF Biotech Inc.Patients: One hundred eighty-three randomizedpatients (36 received placebo; 75 received ferriccitrate 4 g/day; 72 received ferric citrate 6 g/day)who were 18 years and older on 3 times weeklyhemodialysis and a stable dose of a phosphatebinder. Included patients also had a urea reduc-tion ratio greater than 65%, hematocrit greaterthan 20%, and serum calcium between 8.5 to

10.5 mg/dL. Baseline characteristics of placebo andboth ferric citrate groups were similar. At baseline inthe ferric citrate groups, mean age ranged from 53.4to 56.4 years, 56.9% to 62.7% were male, base-line serum phosphorus was 7 mg/dL, and averagedietary phosphorus intake was 1,165 to 1,240 mg.Intervention: Patients with serum phosphorusbetween 5.5 and 10 mg/dL following a washout ofprevious phosphate binders for up to 2 weeks wererandomized 1:2:2 to 8 weeks of placebo, ferric citrate

4 g/day, and ferric citrate 6 g/day. Ferric citrate wasprovided as 500 mg capsules containing ferric iron105 mg. Patients were withdrawn from the studyif they developed serum phosphorus of 9 mg/dL or

more or TSAT of 55% or more. Stables doses of vita-min D analogues were allowed during the study, whileiron-containing medications and oral and IV ironwere prohibited. The efficacy cohort (166 patients)included patients with serum phosphorus measure-ment baseline and at day 14 or later. The safetycohort received at least 1 dose of study medication.ResultsPrimary Endpoint(s) Change of serum phosphorus from baseline to

week 8 was 0.08 with placebo and 1.6 and2.27 with ferric citrate 4 and 6 g/day, respec-

tively. Changes in serum phosphorus with theferric citrate 4 and 6 g/day groups were bothsignificantly greater than placebo. Changein serum phosphorus between the ferric citrate4 and 6 g/day groups was also significantly dif-ferent (P< .001).

Secondary Endpoint(s) Percentage of patients achieving serum phos-

phorus of 5.5 mg/dL or less at week 8 was16.7%, 57.6%, and 74.1% with the placebo,ferric citrate 4 g/day, and ferric citrate 6 g/daygroups, respectively.

Change in serum ferritin from baseline to week8 was 41.75 ng/mL in the placebo group, 73.9ng/mL (P= .008 vs placebo) in the ferric citrate4 g/day group, and 103.4 ng/mL (P= .003) inthe ferric citrate 6 g/day group.

Change in TSAT from baseline to week 8 was1.15%, 5.35%, and 4.95% in the placebo,ferric citrate 4 g/day, and ferric citrate 6 g/daygroups, respectively. Change in TSAT was notsignificantly different at either ferric citratedoses compared with placebo.

Change in hemoglobin from baseline to week

8 was 0.35, 0.3, and 0.6 g/dL in the placebo,ferric citrate 4 g/day, and ferric citrate 6 g/daygroups, respectively. Change in hemoglobin wasnot significantly different at either ferric citratedoses compared with placebo.

Change in bicarbonate from baseline toweek 8 was 0.15, 0.6, and 0.45 mmol/L in theplacebo, ferric citrate 4 g/day, and ferric citrate6 g/day groups, respectively. Change in bicar-bonate was not significantly different at eitherferric citrate doses compared with placebo.


7/15



Change in serum calcium from baseline to week8 was 0.17, 0.15, and 0.18 mg/dL with placebo,ferric citrate 4 g/day, and ferric citrate 6 g/day,respectively.

Comments: Twenty-four placebo patients discontin-ued the study; most cases were voluntary withdrawal.Three cases were due to adverse events and 1 casewas due to serum phosphorus greater than 9 mg/dL.Nine patients given ferric citrate 4 g/day discontinuedtreatment, with 2 cases due to adverse events and 1case due to serum phosphorus greater than 9 mg/dL.Eighteen patients given ferric citrate 6 g/day discon-tinued treatment, with 7 cases due to adverse effects.Limitations: This study was conducted in 5 medi-cal centers in Taiwan; it was unspecified if this wasthe KRX-0502 formulation of ferric citrate. This

study may have limited applicability in patientswith GI abnormality, tertiary hyperparathyroid-ism, heart failure, diabetes mellitus with clinicallyrelevant gastroparesis, unstable medical or psychi-atric conditions, clinically significant electrocar-diogram abnormalities, serum ferritin greater than800 ng/mL, history of hemochromatosis, or activemalignancy, except basal/squamous cell carcinoma,as these patients were excluded from participation.

Indication: Hyperphosphatemia and Iron DeficiencyAnemia in Stages 3 to 5 Nondialysis-Dependent Chronic

Kidney Disease Patients

Guidelines

Guideline: KDOQI clinical practice guidelines forbone metabolism and disease in CKD

Reference: National Kidney Foundation, 200330Comments: In patients with stage 3 or 4 CKD, theseguidelines recommend phosphate binders if serumphosphorus or intact PTH cannot be controlledwith dietary phosphate restrictions with or withoutvitamin D therapy. Calcium-based binders are men-

tioned as a potential first-line agent. Ferric citrate isnot mentioned in this version of the guidelines.

Studies

Drug: Ferric citrate versus placeboReference: Block GA, et al, 201410,11,12,42Study Design: Phase 2 randomized, multicenter,double-blind, placebo-controlled trialStudy Funding: Keryx BiopharmaceuticalsPatients: One hundred forty-nine randomized adultpatients (141 included in ITT cohort) with an esti-

mated glomerular filtration rate less than 60 mL/min/1.73 m2, serum ferritin 300 ng/mL or less, TSAT30% or less, hemoglobin between 9 to 12 g/dL, andserum phosphorus between 4 and 6 mg/dL. Baseline

demographics between ferric citrate and placebogroups appeared similar. The ferric citrate cohortat baseline was a mean age of 66 years, 31% weremale, and 79% were White. Stage 4 CKD was themost prevalent (53%), followed by stage 5 (28%)and stage 3 (18%). Baseline laboratory values of thiscohort included mean phosphate of 4.5 mg/dL, ironsaturation of 22%, hemoglobin of 10.5 g/dL, ferritinof 116 ng/mL, intact FGF-23 of 159 pg/mL, 24-hoururine phosphate of 730 mg/ day, and estimated glo-merular filtration rate of 26 mL/min/1.73 m2.Intervention: Following a 2-week washout of phos-

phate binders, patients were randomized 1:1 to ferriccitrate or placebo for a 12-week treatment period.Ferric citrate was provided as tablets (elemental iron210 mg each) 3 times daily with meals and titrated to12 tablets daily for achievement of serum phospho-rus less than 3.5 mg/dL. Results were analyzed in themodified ITT cohort consisting of patients receiving1 study drug and at minimum 1 baseline value withlast observation carried forward for missing values.IV iron and ESA use were prohibited in the periodleading up to and during the trial.

ResultsPrimary Endpoint(s) Ferric citrate decreased mean serum phosphate

from 4.5 mg/dL at baseline to 3.9 mg/dL atweek 12 compared with 4.7 mg/dL at baselineto 4.4 mg/dL at week 12 with placebo (P< .001).

Ferric citrate increased TSAT from 22% atbaseline to 32% at week 12, whereas TSATremained unchanged at approximately 20%with placebo (P< .001).

Secondary Endpoint(s) Mean hemoglobin increased from 10.5 g/dL

at baseline to 11 g/dL at week 12 with ferriccitrate compared with 10.6 g/dL at baseline to10.4 g/dL with placebo (P< .001).

Mean ferritin increased from 116 ng/mL atbaseline to 189 ng/mL at week 12 with ferriccitrate compared with 110 ng/mL at baseline to106 ng/mL with placebo (P< .001).

Mean intact FGF-23 changed from 319 pg/mLat baseline to 200 pg/mL at week 12 with ferriccitrate compared with 263 to 293 pg/mL withplacebo (P= .017).


8/15



Mean C-terminal FGF-23 changed from468 pg/ mL at baseline to 316 pg/mL at week12 with ferric citrate compared with 511 to579 pg/mL with placebo (P< .001).

Comments: This study was conducted in 20 sitesacross the United States. Statistically significantfindings in both primary endpoints were prespeci-fied to consider the trial results as positive. Dis-continuation of ferric citrate occurred in 14 of 75(19%) patients, with 1 case due to a hemoglobinless than 9 g/dL and 6 cases due to adverse events.Discontinuation of placebo occurred in 24 of74 (32%) patients, with 9 cases due to hemoglo-bin less than 9 g/dL and 3 cases due to adverseeffects.Limitations: Study results were only available as

posters, meeting abstracts, and press releases fromthe manufacturer. This study may have limitedapplicability in patients with active GI bleeding,inflammatory bowel disease, parathyroidectomyin the last 24 weeks, history of hemochromatosis,history of malignancy in the past 5 years, recentneed for dialysis, or anemia due to causes otherthan CKD or iron deficiency anemia, as they wereexcluded from participation.

CONTRAINDICATIONS, WARNINGS, AND

PRECAUTIONSContraindicationsFerric citrate is contraindicated in patients with

known iron overload syndromes (eg, hemochroma-tosis).1 Ferric citrate should be used cautiously inpatients at risk of or presenting with hemochromato-sis. Part of the inclusion criteria used in ferric citratestudies included a serum ferritin less than 1,000mcg/L and TSAT less than 50%.5,6In 1 study, patientswith a history of hemochromatosis or a serum fer-ritin greater than 800 ng/mL were excluded fromparticipation.7

Warnings and PrecautionsIron absorption from ferric citrate may lead to

excessive elevations in iron stores, as reflected byincreases in serum ferritin and transferrin saturationlevels.1 Additionally, clinical studies have reflectedthe potential of ferric citrate and ferric citratehydrate to increase iron-related parameters follow-ing ferric citrate administration.4,5,7,17,20,25-27 A phase3 clinical trial administering ferric citrate at 1, 6, or8 g/day for 4 weeks noted significant dose response

with ferritin. Compared with baseline, serum ferri-tin at day 28 with 1, 6, and 8 g/day of ferric citratechanged by 14.4, 90.1, and 90.2 mg/dL, respec-tively.5A 52-week safety period of a phase 3 studyadministering 6 to 12 g/day of ferric citrate com-pared the impact of iron-related parameters withcalcium acetate or sevelamer carbonate. During thisperiod, significant treatment differences with ferriccitrate compared with active control were observedwith serum ferritin, TSAT, hemoglobin, serum iron,and TIBC.20,25-27A phase 3 study of ferric citrate inTaiwan noted increases in ferritin with 4 and 6 g/dayof ferric citrate from baseline to week 8 comparedwith placebo.7 Assessment of iron parameters(eg, serum ferritin, TSAT) should occur prior to thestart of the ferric citrate and be monitored through-out therapy.1

Ferric citrate is an iron-containing product andshould be kept out of reach of children. Accidentaloverdose may occur with any iron-containing prod-uct and is the leading cause of fatal poisoning in chil-dren younger than 6 years.1

Patients should be provided counseling regard-ing the potential of ferric citrate to discolor thestool.43Counseling should also convey the informa-tion that stool discoloration (dark/tarry stools) mayalso serve as 1 of the signs and symptoms of poten-tial GI bleeding.44 Stool discoloration was a com-mon adverse effect of ferric citrate recorded during

clinical trials.5,7,33 In a 28-day phase 3 trial withferric citrate, fecal discoloration was reported in29 of 151 patients (19%).5 During the 52-weeksafety assessment period of a phase 3 trial, fecal dis-coloration was noted in 17% of 289 patients givenferric citrate compared with 0% of 149 patientsgiven sevelamer carbonate or calcium acetate.33 Ina phase 3 trial of ferric citrate conducted in Tai-wan, discoloration of stool was reported in 2 of36 patients given placebo compared with 28 of75 patients given ferric citrate 4 g/day and 27 of 72patients given ferric citrate 6 g/day.7

Cautious use may be warranted in patients with ahistory or current GI disorders. In ferric citrate stud-ies, patients with GI abnormality, active GI bleed-ing, inflammatory bowel disease, or diabetes mellituswith clinically relevant gastroparesis were excludedfrom participation.1,5,7A majority of adverse effectsreported in clinical trials with ferric citrate and ferriccitrate hydrate involved the GI tract. Some patientsdiscontinued therapy with ferric citrate or fer-ric citrate hydrate due to treatment-related adverseeffects that involved the GI tract.5,7,8,10,17,33,35


9/15



Not enough information is available regardingthe metabolic effects of alkali absorption of citrate.3In a clinical trial administering ferric citrate at 1, 6, or8 g/day for 4 weeks, a significant dose response wasobserved for bicarbonate. Compared with baseline,bicarbonate values at day 28 with 1, 6, and 8 g/dayof ferric citrate changed by 0.1, 1.6, and 1.5 mEq/L,respectively.5A phase 3 trial of ferric citrate in Taiwandid not observe a significant change of bicarbonatefrom baseline to week 8 between placebo, ferric citrate4 g/day, and ferric citrate 6 g/day groups. However, atweek 8, the bicarbonate level was 23.75 mmol/L inthe ferric citrate 6 g/day group compared with 21.8mmol/L in the placebo group (P= .028).7In a phase2 trial providing ferric citrate 4.5 to 11.25 g/day for4 weeks, an increase in bicarbonate from 22.2 mEq/Lat baseline to 23.7 mEq/L at end of study was noted.29

Ferric citrate is classified as Pregnancy CategoryB; no adequate and well-controlled studies in preg-nant women have been conducted.1

Animal studies found some transfer of iron intomilk; it may be possible for breast-feeding infants tobe exposed to ferric citrate.1

Safety and efficacy have not been established inpediatric patients.1

No known differences have been establishedbetween elderly and younger patients treated withferric citrate.1

ADVERSE REACTIONSTreatment-related GI adverse effects (eg, diar-

rhea [21%], discolored feces, constipation [8%],nausea [11%], vomiting) were the most commonlyreported across several clinical trials with ferriccitrate.1,5,7,29,33,37

A phase 3 study administering ferric citrate 1,6, and 8 g/day for 4 weeks noted the lower rate ofadverse events in the 1 g/day cohort and similar ratein the 6 and 8 g/day cohorts. The rate of drug-related

adverse events, serious adverse events, or events lead-ing to discontinuation increased with the dose.5

In a phase 3 trial of fixed-dose ferric citrate, 91of 151 events (60.2%) were graded as mild to moder-ate, with 53 of 151 events (35.1%) determined to berelated to the study drug. The most common adverseeffects in the study involved the GI tract and includednausea, vomiting, diarrhea, constipation, fecal discol-oration, and upper abdominal pain.5

In a 52-week safety period of a phase 3 study, 289patients were provided with ferric citrate 6 to 12 g/day, and 149 were provided active control (up to 12tablets of calcium acetate 667 mg or sevelamer car-bonate 800 mg) over 52 weeks. Treatment-emergentadverse events were reported in 90.7% of patientstaking ferric citrate and 89.3% of active controlpatients. The GI tract was the most common system

organ class reported with treatment-emergent adverseeffects, which affected 56.4% of patients with ferriccitrate and 46.3% of active control patients. Most ofthe GI treatment-emergent adverse effects were nonse-rious and occurred in 49.4% of ferric citrate patientscompared with 34.2% of active control patients.Event rates of select GI adverse effects are shown inTable 2. Serious adverse effects occurred in 39.4% ofpatients taking ferric citrate and 49% of active con-trol patients (Table 3). A total of 19.1% of patientstaking ferric citrate had a serum ferritin greater than1,500 ng/mL compared with 10.1% of patients with

active control. In both groups, IV iron administrationwas most frequently determined to be the causativefactor, with 7.6% of the ferric citrate group comparedwith 4.7% in the active control group.33

Treatment-emergent adverse events leadingto study drug discontinuation occurred in 21% ofpatients with ferric citrate compared with 14% withactive control. The most common reasons for treat-ment discontinuation in both groups were renaltransplant and GI events.1,33

Table 2. Select gastrointestinal adverse effects during a 52-week safety assessment period of a phase 3 trial33Adverse effect Ferric citrate

(n= 289)Active control(n= 149)

Diarrhea 25.6% 14.1%

Fecal discoloration 17% 0%

Nausea 14.2% 14.1%

Vomiting 9% 14.8%

Constipation 8% 5.4%

Abdominal pain 6.2% 6%


10/15



The most common adverse events in a phase 3 trialof 166 patients in Taiwan were related to the GI tractand were reported at 27.8%, 61.3%, and 58.3% ofplacebo, ferric citrate 4 g/day, and ferric citrate 6 g/dayarms, respectively. The 2 most commonly treatedrelated adverse effects across all cohorts were fecal dis-coloration and diarrhea. Fecal discoloration occurredin 2 patients with placebo and in 28 and 27 patientstaking ferric citrate 4 and 6 g/day, respectively. Diarrheaoccurred in 2 patients with placebo and in 5 patientsand 3 patients taking ferric citrate 4 and 6 g/day, respec-

tively. Adverse effects led to study discontinuation in3 patients with placebo, 2 patients with ferric citrate4 g/ day, and 7 patients with ferric citrate 6 g/day.7

DRUG INTERACTIONSFerric citrate is an iron-containing product.1,5-7

Medications that may interact with iron, including, butnot limited to, antacids, ascorbic acid, calcium salts,levodopa, levothyroxine, fluoroquinolones, tetracy-clines, and doxycycline, should be appropriately admin-istered separately or avoided with ferric citrate.45-47Mostdrugs should not be administered at the same time as

the ferric citrate dose. Medications that can be coadmin-istered with ferric citrate include amlodipine, aspirin,atorvastatin, calcitriol, clopidogrel, digoxin, doxercal-ciferol, enalapril, fluvastatin, levofloxacin, metoprolol,pravastatin, propranolol, sitagliptin, and warfarin.1

RECOMMENDED MONITORINGSerum phosphorus should be assessed at base-

line and monitored as often as clinically indicatedthroughout therapy with ferric citrate. In clinical

trials with ferric citrate, serum phosphorus wasevaluated at various intervals that included weeklyassessments; weekly assessment for the first 2 weeks,then every other week thereafter; or assessment everyother week for 12 weeks followed by monthly there-after.5,6,7,10,37Various criteria were utilized in clinicaltrials to determine discontinuation of therapy withferric citrate. In 2 clinical trials, patients discontinuedtherapy or were considered treatment failures withferric citrate if they had 2 consecutive serum phos-phorus measurements above 8 to 9 mg/dL.6,7A third

clinical trial discontinued ferric citrate therapy ifpatients had a serum phosphorus of 2.5 mg/dL or lesson day 7 and a reading of 2.5 mg/dL or less or 9 mg/dL or higher on day 14 or 21.5

It may be advisable to assess baseline iron-relatedparameters and monitor them as often as clinicallyindicated with ferric citrate therapy. In 1 clinicaltrial, iron parameters were monitored at a minimumof every 12 weeks.6Clinical studies have shown thepotential of ferric citrate and ferric citrate hydrate toimprove iron-related parameters, such as serum iron,ferritin, hemoglobin, TSAT, and TIBC, following fer-

ric citrate administration.4,5,7,8,17,20,25-27,37

DOSINGThe recommended dose by the manufacturer is

2 tablets (ferric iron 210 mg per tablet; equivalentto ferric citrate 1 g per tablet) orally 3 times per daywith meals. Patients should be instructed to take theirother medications at a different time. The dose of fer-ric citrate should be adjusted based on the patientsserum phosphorus levels. Decrements or increments

Table 3.Summary of the most common severe adverse effects occurring in 5% or more of patients during a52-week safety assessment period of a phase 3 trial33

System organ class Ferric citrate(n= 289)

Active control(n= 149)

Infections and infestations 12.5% 18.1%

Surgical and medical procedures 7.6% 6.7%

Vascular 7.6% 9.4%

General disorders and administration site 7.3% 8.1%

Cardiac 6.9% 11.4%

Gastrointestinal 6.9% 12.1%

Respiratory, thoracic, and mediastinal 6.6% 8.7%

Injury, poisoning, and procedural 5.2% 6%

Metabolism and nutrition 5.2% 5.4%


11/15



of 1 to 2 tablets per day, done at intervals of 1 weekor longer, should be used to maintain the serum phos-phorus at target levels. The daily maximum dose is12 tablets.1The average dose required in the clinicaltrials to achieve the target serum phosphorus levelwas 8 to 9 tablets per day.1

PRODUCT AVAILABILITYA special protocol agreement was arranged with

the US Food and Drug Administration (FDA) to aidwith phase 3 trials for regulatory approval of ferriccitrate.9The filing of a new drug application for ferriccitrate was accepted by the FDA in October 2013.14The initial Prescription Drug User Fee Act date wasextended by 3 months in May 2014.48Ferric citratewas approved by the FDA on September 5, 2014.2

The product is available as a film-coated tabletcontaining ferric iron 210 mg (equivalent to ferriccitrate 1 g) in 200-count polyethylene bottles. Theproduct should be stored at controlled room tem-perature 68F to 77F (20C to 25C) and protectedfrom moisture.1

DRUG SAFETY/RISK EVALUATION AND MITIGATIONSTRATEGY (REMS)

No REMS is required for ferric citrate.2

CONCLUSION

Ferric citrate is indicated for phosphate reductionin ESRD patients on hemodialysis with hyperphos-phatemia. As part of the special protocol assessmentwith the FDA, Keryx Biopharmaceuticals completed2 phase 3 trials to support the approval of this indica-tion. Two additional clinical trials with ferric citrateare currently being conducted in slightly differentpopulations: hyperphosphatemia with iron deficiencyanemia in nondialysis-dependent CKD patients, andiron deficiency anemia in CKD patients. In clinicaltrials funded by Keryx Biopharmaceuticals, 1 g offerric citrate is estimated to provide approximately

210 mg of elemental iron. It is estimated that 85 gof phosphate is bound per gram of elemental iron.In addition to ferric citrates dose-dependent effectof serum phosphate reduction, secondary end-points in clinical trials hint at an additional benefitof an increase in iron-related parameters as well asa potential decrease in the need for parenteral ironor ESA. However, because of these potential effectson iron-related parameters, it may be advisable toappropriately monitor patients for prevention of ironoverload. GI adverse effects were the most commonly

reported treatment-related adverse effects. Despitethe results shown with ferric citrate thus far, moststudies evaluated surrogate endpoints (eg, change inphosphate level) rather than hard endpoints (eg, vas-cular calcification, left ventricular hypertrophy, car-diovascular mortality, CKD progression, mortality inCKD).

REFERENCES1. Auryxia (ferric citrate) [prescribing information]. NewYork: Keryx Biopharmaceuticals; November 2014.

2. Stockbridge N. FDA approval letter: Ferric citrate tablets(NDA 205874). US Food and Drug Administration Web site.http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205874Orig1s000ltr.pdf. Published September 5, 2014.Accessed September 8, 2014.

3. Nastou D, Fernndez-Fernndez B, Elewa U, et al. Next-generation phosphate binders: Focus on iron-based binders.Drugs. 2014;74(8):863-877.

4. Yokoyama K, Hirakata H, Akiba T, et al. Ferric citratehydrate for the treatment of hyperphosphatemia in nondi-alysis-dependent CKD. Clin J Am Soc Nephrol. 2014;9(3):543-552.

5. Dwyer JP, Sika M, Schulman G, et al; Collaborative StudyGroup. Dose-response and efficacy of ferric citrate to treathyperphosphatemia in hemodialysis patients: A short-termrandomized trial. Am J Kidney Dis. 2013;61(5):759-766.

6. Umanath K, Sika M, Niecestro R, et al; CollaborativeStudy Group. Rationale and study design of a three-period,

58-week trial of ferric citrate as a phosphate binder in patientswith ESRD on dialysis. Hemodial Int. 2013;17(1):67-74.

7. Lee CT, Wu IW, Chiang SS, et al. Effect of oral fer-ric citrate on serum phosphorus in hemodialysis patients:Multicenter, randomized, double-blind, placebo-controlledstudy [published online ahead of print May 20, 2014].J Nephrol.

8. Yokoyama K, Akiba T, Fukagawa M, et al. A randomizedtrial of JTT-751 versus sevelamer hydrochloride in patientson hemodialysis. Nephrol Dial Transplant. 2014;29(5):1053-1060.

9. Keryx Biopharmaceuticals announces special proto-

col assessment agreement with FDA for phase 3 registrationprogram of Zerenex in the treatment of hyperphosphatemia[press release]. Keryx Biopharmaceutical Web site. http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-newsArticle&ID=1370711&highlight. Published January 5,2010, Accessed November 13, 2014.

10. Block GA, Fishbane S, Wolf M, et al. Zerenex (ferriccitrate coordination complex) for the treatment of iron-defi-ciency anemia and reduction of serum phosphate in non-dial-ysis dependent CKD [abstract]. Presented at: 2014 NationalKidney Foundation Spring Clinical Meeting; April 23-26,2014; Las Vegas, NV.


12/15



11. Block GA, Fishbane S, Shemesh S, Sharma A, ChertowGM. Zerenex (ferric citrate) for the treatment of iron-defi-ciency anemia and reduction of serum phosphate in non-dial-ysis dependent CKD [abstract]. Presented at: 2014 NationalKidney Foundation Spring Clinical Meeting; April 2326,

2014; Las Vegas, NV. Abstract 423.12. Keryx Biopharmaceuticals announces Zerenex(ferric citrate coordination complex) meets all pri-mary and key secondary endpoints in phase 2 studyof non-dialysis dependent CKD patients with elevatedserum phosphorus and iron deficiency anemia [pressrelease]. Keryx Biopharmaceuticals Web site. http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-newsArticle&ID=1872314&highlight. Published November5, 2013. Accessed November 13, 2014.

13. Ferric citrate. ClinicalTrials.gov Web site. http://clinical-trials.gov/ct2/show/NCT02128074. Published April 2014.Accessed May 29, 2014.

14. Keryx Biopharmaceuticals announces FDA acceptance forfiling of Zerenex new drug application [press release]. Keryx Bio-pharmaceuticals Web site. http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-newsArticle&ID=1862465&highlight.Published October 8, 2013. Accessed May 29, 2014.

15. Iida A, Kemmochi Y, Kakimoto K, et al. Ferric citratehydrate, a new phosphate binder, prevents the complicationsof secondary hyperparathyroidism and vascular calcification.Am J Nephrol. 2013;37(4):346-358.

16. Yokoyama K, Hirakata H, Akiba T, Sawada K, Kum-agai Y. Effect of oral JTT-751 (ferric citrate) on hyperphos-phatemia in hemodialysis patients: Results of a random-

ized, double-blind, placebo-controlled trial. Am J Nephrol.2012;36(5):478-487.

17. Yokoyama K, Akiba T, Fukagawa M, et al. Long-termsafety and efficacy of a novel iron-containing phosphatebinder, JTT-751, in patients receiving hemodialysis. J RenNutr. 2014;24(4):261-267.

18. Hsu CH, Patel SR, Young EW. New phosphatebinding agents: Ferric compounds. J Am Soc Nephrol.1999;10(6):1274-1280.

19. Yang WC, Yang CS, Hou CC, Wu TH, Young EW, HsuCH. An open-label, crossover study of a new phosphate-bind-ing agent in haemodialysis patients: Ferric citrate. NephrolDial Transplant. 2002;17(2):265-270.

20. Keryx Biopharmaceuticals, Inc. announces Zerenex phase3 data presented at the 2013 World Congress of Nephrol-ogy [press release]. Keryx Biopharmacuticals Web site. http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-newsArticle&ID=1826253&highlight. Published June3, 2013. Accessed May 29, 2014.

21. Lewis JB, Koury M, Schulman G, et al. Ferric citrate as aphosphate binder reduces IV iron and erythropoietin stimulat-ing agent (ESA) use [poster]. Presented at: 2013 ASN KidneyWeek Meeting; November 5-10, 2013; Atlanta, GA. AbstractTH-PO521.

22. Sika M, Sinsakul MV, Niecestro RM, Chiang SS. Pro-longed use of ferric citrate (FC) as a phosphate binder reducesIV iron use in pts with ESRD [abstract]. Presented at: 2010ASN Kidney Week Meeting; November 16-21, 2010; Denver,CO. Abstract SA-PO2946.

23. Sinsakul M, Korbet S, Greene T, et al. Iron absorptionwith higher doses of ferric citrate in controlling serum phos-phorus in ESRD patients. Am J Kidney Dis. 2010;55(4):A103.

24. Bond C, Jensen D, Wang S, et al. A meta-analysis of fer-ric citrate for hyperphosphatemia: the effects of an oral iron-containing phosphate binder on serum ferritin and saturatedtransferring in hemodialysis patients [abstract]. Presented at:2012 49th ERA-EDTA Congress; May 24-27, 2012; Paris,France. Abstract SAP534.

25. Lewis JB, Dwyer JP, Koury M, et al. Ferric citrate bindsphosphorus, delivers iron, and reduces IV iron and erythropoi-etic stimulating agent use in end-stage renal disease [abstract].Presented at: 2013 ASN Kidney Week Meeting; November

5-10, 2013; Atlanta, GA. Abstract SA-PO542.

26. Middleton JP, Athreya BP, Ayodeji OB, et al. Ferric citrate,a phosphate binder, increases iron stores but is not associatedwith evidence of the malnutrition-inflammation-cachexia syn-drome [abstract]. Presented at: 2013 ASN Kidney Week Meet-ing; November 5-10, 2013; Atlanta, GA. Abstract SA-OR083.

27. Umanath K, Blumenthal SS, Koury M, et al. Ferric citratebinds phosphorus, delivers iron, and reduces IV iron andESA use in ESRD [poster]. Presented at: 2013 ASN KidneyWeek Meeting; November 5-10, 2013; Atlanta, GA. AbstractSA-PO542.

28. Umanath K, Blumenthal SS, Sika M, et al; the Collab-

orative Study Group. Ferric citrate as a phosphate binderreduces IV iron and erythropoietin stimulating agent (ESA)use [abstract]. Presented at: 2013 ASN Kidney Week Meeting;November 5-10, 2013; Atlanta, GA. Abstract TH-PO521.

29. Sinsakul M, Sika M, Koury M, et al; CollaborativeStudy Group. The safety and tolerability of ferric citrate asa phosphate binder in dialysis patients. Nephron Clin Pract.2012;121(1-2):c25-c29.

30. National Kidney Foundation. K/DOQI clinical practiceguidelines for bone metabolism and disease in chronic kidneydisease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

31. Kidney Disease: Improving Global Outcomes (KDIGO)CKD-MBD Work Group. KDIGO clinical practice guide-line for the diagnosis, evaluation, prevention, and treat-ment of chronic kidney disease-mineral and bone disorder(CKD-MBD). Kidney Int. 2009;(suppl 113):S1-S130.

32. Sika M, Kabani S, Chen M, et al. Oral ferric citrate(FC) eliminates the need for intravenous (IV) iron in dialysispatients [abstract]. Presented at: 2014 National Kidney Foun-dation Spring Clinical Meeting; April 23-26, 2014; Las Vegas,NV. Abstract 79.

33. Sika M, Umanath K, Goral S, et al. Keryx FC phase IIIsafety thumbnail ferric citrate as a phosphate binder hasa safety profile similar to sevelamer carbonate and calcium


13/15



acetate [poster]. Presented at: 2013 ASN Kidney Week Meeting;

November 5-10, 2013; Atlanta, GA. Abstract SA-PO540.

34. Umanath K, Sika M, Koury M, et al. Achieved iron stores

and clinical outcomes in a trial of ferric citrate as a phosphate

binder [abstract]. Presented at: 2013 ASN Kidney Week Meet-

ing; November 5-10, 2013; Atlanta, GA. Abstract SA-PO382.

35. Sika M, Umanath K, Goral S, et al. Ferric citrate as a

phosphate binder has a safety profile similar to sevelamer car-

bonate and calcium acetate [abstract]. Presented at: 2013 ASN

Kidney Week Meeting; November 5-10, 2013; Atlanta, GA.

Abstract SA-PO540.

36. Weiner DE, Sika M, Dwyer JP, et al. Impact of fer-

ric citrate, an oral phosphate binder, on mineral and bone

metabolism markers in dialysis patients [abstract]. Presented

at: 2013 ASN Kidney Week Meeting; November 5-10, 2013;

Atlanta, GA. Abstract SA-PO543.

37. Lewis JB, Sika M, Koury MJ, et al. Ferric citrate controlsphosphorus and delivers iron in patients on dialysis [published

online ahead of print July 24, 2014].J Am Soc Nephrol.

38. Keryx Biopharmaceuticals provides update from ongo-

ing Zerenex (ferric citrate coordination complex) long-term

safety extension study in patients with hyperphosphatemia on

dialysis [press release]. Keryx Biopharmaceuticals Web site.

http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-

newsArticle&ID=1874366&highlight. Published November

8, 2013. Accessed May 29, 2014.

39. Ferric citrate. ClinicalTrials.gov Web site. http://clinical-

trials.gov/ct2/show/NCT01554982. Published March 2012.

Accessed May 29, 2014.

40. Thomas A, Peterson LE. Reduction of costs for anemia-

management drugs associated with the use of ferric citrate. IntJ Nephrol Renovasc Dis. 2014;7:191-201.

41. Mutell R, Rubin JL, Bond TC, Mayne T. Reduced use oferythropoiesis-stimulating agents and intravenous iron withferric citrate: A managed care cost-offset model. IntJ NephrolRenovasc Dis. 2013;6:79-87.

42. Ferric citrate in managing serum phosphorus and irondeficiency in anemic chronic kidney disease (CKD) subjectson dialysis. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01736397. Published November 2012.Accessed May 30, 2014.

43. Ghosh AK. Efficacy of ferric citrate as a phosphate-bindingagent in end-stage renal disease. Nephrol Dial Transplant.2002;17(7):1354; author reply 1354.

44. Bleeding in the digestive tract. National Digestive DiseasesInformation Clearinghouse. National Institutes of HealthWeb site. 2010. http://digestive.niddk.nih.gov/ddiseases/pubs/bleeding/bleeding_508.pdf. Published July 2014. AccessedNovember 13, 2014.

45. Phosphate binders; iron-products. Drug Facts and Com-parisons. Facts & Comparisons [database online]. St. Louis,MO: Wolters Kluwer Health Inc; 2014. Accessed June 5, 2014.

46. Levothroid (levothyroxine sodium) [prescribing infor-mation]. Shenandoah, IA: Lloyd Pharmaceutical; September2005.

47. Doryx (doxycycline hyclate) [prescribing information],Rockaway, NJ: Warner Chilcott; July 2013.

48. Keryx receives notification of PDUFA date extension forZerenex [press release]. Keryx Biopharmaceuticals Web site.http://investors.keryx.com/phoenix.zhtml?c=122201&p=irol-newsArticle&ID=1933836&highlight. Published May 22,

2014. Accessed May 29, 2014.

49. Velphoro (sucroferric oxyhydroxide) [prescribing infor-mation]. Waltham, MA: Fresenius Medical Care; December2013.


14/15


Hosp Pharm 2015;50(2):1521532015 Thomas Land Publishers, Inc.

www.hospital-pharmacy.com

doi: 10.1310/hpj5002-152

Continuing Education Case Study Quiz

GoalThe goal of this activity is to educate pharmacists about the use of ferric citrate for the treat-ment of patients with chronic kidney disease.

ObjectivesAt the completion of this activity, the reader will be able to:1. Describe the pharmacology and pharmacokinetics of ferric citrate.2. Discuss the risks associated with the use of ferric citrate.3. Discuss the potential benefit of ferric citrate for an individual patient.4. Apply the information on the use of ferric citrate to a case study.

Key Wordsferric citrate, new drugs, chronic kidney disease, dialysis

This CE activity is co-sponsoredby ProCE, Inc. and Hospital Pharmacy.ProCE, Inc. is accredited by the Accredi-tation Council for Pharmacy Educationas a provider of continuing pharmacyeducation. ACPE Universal ActivityNumber 0221-9999-15-032-H01-P hasbeen assigned to this knowledge-basedhome-study CE activity (initial release

date 02-01-2015). This CE activity is approved for

1.5 contact hours (0.15 CEUs) in states that recog-nize ACPE providers. This CE activity is provided atno cost to participants. Completion of the evaluationand the post-test with a score of 70% or higher arerequired to receive CE credit. No partial credit willbe given.

Faculty: Dennis J. Cada, PharmD, FASHP, FASCP(Editor),Founder and Contributing Editor, The For-mulary;Jasen Cong, PharmD, Drug Information Res-ident, College of Pharmacy, Washington State Univer-sity; and Danial E. Baker, PharmD, FASHP, FASCP,Director, Drug Information Center, and Professor ofPharmacy Practice, College of Pharmacy, WashingtonState University. The authors indicate no relation-ships that could be perceived as a conflict of interest.This activity is self-funded by Hospital Pharmacy.

Release Date:February 1, 2015Expiration Date:February 1, 2017Continuing Education for this activity is pro-

cessed through the ProCE online CE Center. Toreceive CE credit, please go to:

www.ProCE.com/HPJFDR Click to access the activity pageto enroll and complete the Post-Testand Evaluation

For questions related to register-ing for and obtaining CE credit, contact ProCE at630-540-2848 or [email protected].

1. The US Food and Drug Administration (FDA)

approved indication for ferric citrate is for thetreatment of:a. Adult and pediatric patients with iron defi-

ciency anemia.b. Adult patients with macrocytic anemia.c. Adult patients with elevated serum phospho-

rus associated with chronic kidney disease(CKD) requiring dialysis.

d. Adult and pediatric patients with elevatedserum phosphorus associated with CKD notrequiring dialysis.

2. Ferric citrate produces its serum phosphorouslowering effects by:a. Binding dietary phosphorous to increase

fecal excretion.b. Forming insoluble calcium phosphate complex.c. Exchanging ligands between dietary phos-

phate and hydroxyl groups.d. Forming ionic and hydrogen bonds with

intestinal phosphate.


15/15


Continuing Education Case Study Quiz

3. Ferric citrate contains how many milligrams ofelemental ferric iron per 1 g of ferric citrate?a. 210 mgb. 248 mg

c. 400 mgd. 500 mg

4. Which of the following is a contraindication totherapy with ferric citrate?a. Low serum ferritinb. History of gastrointestinal disordersc. Known iron overload syndromed. Concomitant acid-reducing medications (eg,

H2-blockers, protein pump inhibitors)

5. Ferric citrate is in Pregnancy Category:a. A.b. B.c. C.d. X.

Case HistoryB.B. is a 62-year-old obese female patient with

hypertension, diabetes, chronic kidney disease, andmajor depressive disorder. Her current medicationsinclude lisinopril, diltiazem, sitagliptin, glipizide, andparoxetine. Her physician has just diagnosed herwith end-stage renal disease and has decided to start

her on dialysis. Her current laboratory values of noteinclude phosphorous of 7.5 mg/dL, ferritin 180 mg/dL,and transferrin saturation of 35%. Her physicianthinks she may benefit from the use of ferric citrate.

6. The recommended initial dose of ferric citratefor B.B. would be:a. 1 g three times daily.b. 4 g per day in divided doses.c. 2 g twice daily.d. 2 g three times daily.

7. How many tablets make up the maximum rec-ommended dose of ferric citrate for B.B.?a. 6 tabletsb. 8 tabletsc. 9 tabletsd. 12 tablets

8. B.B. should be instructed to take ferric citrate:a. On an empty stomach.b. With meals.c. Three times daily with or without food.d. Every 3 days, after dialysis.

9. Which of B.B.s medications can be taken con-comitantly with the ferric citrate?a. Lisinoprilb. Sitagliptinc. Diltiazemd. None of the above

10. Which of the following potential options forthe treatment of urinary tract infection may beadministered with ferric citrate?a. Ciprofloxacinb. Levofloxacinc. Doxycyclined. None of the above

11. What baseline and periodic monitoring wouldyou recommend for B.B.s ferric citrate therapy?

a. Serum phosphorous and iron parametersb. Serum phosphorous and corrected calciumc. Serum creatinine and corrected calciumd. Serum creatinine and serum uric acid

12. The most common side effects associated withferric citrate include:a. Nausea, headache, and pruritus.b. Nausea, headache, and diarrhea.c. Diarrhea, nausea, and constipation.d. Vomiting, rash, and abnormal liver function

tests.

13. At what interval should you adjust B.B.s dose offerric citrate?a. Every 3 days as neededb. No more frequently than every weekc. No more frequently than every 2 weeksd. Daily until at the maximum dose.

14. B.B. has been taking ferric citrate for 6 monthsand has recently been experiencing postpran-dial fullness and bloating. Her physician hasdiagnosed her with diabetic gastroparesis. What

action is recommended?a. Reduce the dose of ferric citrate by half.b. Reduce the dose by one fourth.c. Monitor her more closely.d. Increase the dose by one fourth.

15. Ferric citrate should be stored:a. Only in the original container.b. In the refrigerator and protected from moisture.c. In the freezer and protected from light.d. At controlled room temperature and pro-

tected from moisture.

Ferric Citrate

Documents

Transcript of Ferric Citrate