Ferric Citrate Drug Information
Generic name: FERRIC CITRATE
Uses of Ferric Citrate
Hyperphosphatemia in Chronic Kidney Disease on Dialysis Ferric citrate tablets are indicated
for the control of serum phosphorus levels in adult patients with chronic kidney disease on dialysis.
Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Ferric citrate
tablets are indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease not on dialysis.
Dosage & Administration of Ferric Citrate
Dosage for Hyperphosphatemia in Chronic Kidney Disease on Dialysis
The recommended starting dose is 2 tablets, swallowed whole, 3 times per day with meals. Ferric citrate tablets must not be chewed or crushed because it may cause discoloration of mouth and teeth. Monitor serum phosphorus levels and titrate the ferric citrate tablet dose in decrements or increments of 1 to 2 tablets per day as needed to maintain serum phosphorus at target levels, up to a maximum dose of 12 tablets daily.
Dose can be titrated at 1-week or longer intervals. In a clinical trial, patients required an average of 8 to 9 tablets a day to control serum phosphorus levels.
Dosage for Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis
The recommended starting dose is 1 tablet, swallowed whole, 3 times per day with meals. Ferric citrate tablets must not be chewed or crushed because it may cause discoloration of mouth and teeth. Titrate the dose of ferric citrate tablets as needed to achieve and maintain hemoglobin at target levels, up to a maximum dose of 12 tablets daily.
In a clinical trial in patients with chronic kidney disease not on dialysis (CKD-NDD), patients required an average of 5 tablets per day to increase hemoglobin levels.
Side Effects of Ferric Citrate
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to adverse reaction rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hyperphosphatemia in Chronic Kidney Disease on Dialysis A total of 289 patients were treated with ferric citrate and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week, randomized, open-label, active control phase of a trial in patients on dialysis. A total of 322 patients were treated with ferric citrate for up to 28 days in three short-term trials.
Across these trials, 557 unique patients were treated with ferric citrate; dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of ferric citrate. Adverse reactions reported in more than 5% of patients treated with ferric citrate in these trials included diarrhea (21%), discolored feces (19%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). During the 52-week, active-control period, 61 patients (21%) on ferric citrate discontinued study drug because of an adverse reaction, as compared to 21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and sevelamer carbonate) were not eligible to enroll in the study.
Gastrointestinal adverse reactions were the most common reason for discontinuing ferric citrate (14%). Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Across two trials, 190 patients with CKD-NDD were treated with ferric citrate. This included a study of 117 patients treated with ferric citrate and 116 patients treated with placebo in a 16-week, randomized, double-blind period and a study of 75 patients treated with ferric citrate and 73 treated with placebo in a 12-week randomized double-blind period. Dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of ferric citrate.
Adverse reactions reported in at least 5% of patients treated with ferric citrate in these trials are listed in Table 1. Table 1: Adverse Reactions Reported in Two Clinical Trials in at least 5% of patients receiving Ferric Citrate Body System Adverse Reaction Ferric Citrate % (N=190) Placebo % (N=188) Any Adverse Reaction 75 62 Metabolism and Nutrition Disorders Hyperkalemia 5 3 Gastrointestinal Disorders Discolored Feces 22 0 Diarrhea 21 12 Constipation 18 10 Nausea 10 4 Abdominal Pain 5 2 During the 16-week, placebo-control trial, 12 patients (10%) on ferric citrate discontinued study drug because of an adverse reaction, as compared to 10 patients (9%) in the placebo control arm. Diarrhea was the most common adverse reaction leading to discontinuation of ferric citrate (2.6%).
Warnings & Cautions for Ferric Citrate
Iron Overload Iron absorption from ferric citrate may lead to excessive elevations
in iron stores. Increases in serum ferritin and transferrin saturation (TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial evaluating the control of serum phosphate levels in patients with chronic kidney disease on dialysis in which concomitant use of intravenous iron was permitted, 55 (19%) of patients treated with ferric citrate had a ferritin level >1500 ng/mL as compared with 13 (9%) of patients treated with active control.
Assess iron parameters (e.g., serum ferritin and TSAT) prior to initiating ferric citrate and monitor iron parameters while on therapy . Patients receiving intravenous iron may require a reduction in dose or discontinuation of intravenous iron therapy.
Risk of Overdosage in Children Due to Accidental Ingestion Accidental ingestion and
resulting overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age . Advise patients of the risks to children and to keep ferric citrate tablets out of the reach of children.
Drug Interactions with Ferric Citrate
Table 2: Oral drugs that can be administered concomitantly with ferric citrate Amlodipine Aspirin Atorvastatin Calcitriol Clopidogrel Digoxin Diltiazem Doxercalciferol Enalapril Fluvastatin Glimepiride Levofloxacin Losartan Metoprolol Pravastatin Propranolol Sitagliptin Warfarin Oral drugs that have to be separated from ferric citrate and meals Dosing Recommendations Doxycycline Take at least 1 hour before ferric citrate Ciprofloxacin Take at least 2 hours before or after ferric citrate Oral medications not listed in Table 2. There are no empirical data on avoiding drug interactions between ferric citrate 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 of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product.
Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range. When clinically significant drug interactions are expected, consider separation of the timing of administration. Consider monitoring clinical responses or blood levels of the concomitant medication.
Pregnancy Safety for Ferric Citrate
Pregnancy Risk Summary There are no available data on ferric citrate use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted using ferric citrate. Skeletal and encephalic malformation was observed in neonatal mice when ferric gluconate was administered intraperitoneally to gravid dams on gestation days 7 to 9. However, oral administration of other ferric or ferrous compounds to gravid CD1-mice and Wistar-rats caused no fetal malformation.
An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes and fetal malformation. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations The effect of ferric citrate on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy.
Pediatric Use of Ferric Citrate
Pediatric Use The safety and efficacy of ferric citrate has not been established in pediatric patients. Juvenile Animal Toxicity Data In animal studies, greater gastrointestinal toxicity was observed when ferric citrate was administered by gavage as compared to administration with solid food. Because ferric citrate is recommended to be taken with meals and patients under 6 months of age are unlikely to be eating solid food, they may be at greater risk of gastrointestinal toxicity.
Contraindications for Ferric Citrate
Ferric citrate is contraindicated in patients with iron overload syndromes (e.g., hemochromatosis) . Iron overload syndromes (e.g., hemochromatosis).
Overdosage Information for Ferric Citrate
No data are available regarding overdose of ferric citrate in patients. In patients with chronic kidney disease, the maximum dose studied was 2,520 mg ferric iron (12 tablets of ferric citrate) per day. Iron absorption from ferric citrate may lead to excessive elevations in iron stores, especially when concomitant intravenous iron is used . In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient on dialysis administered intravenous iron and ferric citrate.
Clinical Studies of Ferric Citrate
Hyperphosphatemia in Chronic Kidney Disease on Dialysis
The ability of ferric citrate to lower serum phosphorus in patients with CKD on dialysis was demonstrated in randomized clinical trials: one 56-week, safety and efficacy trial, consisting of a 52-week active-controlled phase and a 4-week, placebo-controlled, randomized withdrawal period, and one 4-week open-label trial of different fixed doses of ferric citrate. Both trials excluded subjects who had an absolute requirement for aluminum containing drugs with meals. Study KRX-0502-304 (NCT 01191255) Study KRX-0502-304 was a long-term, randomized, controlled, safety and efficacy trial.
After the 2-week washout period during which phosphate binders were held, patients with a mean serum phosphorus of 7.5 mg/dL during washout were randomized 2:1 to ferric citrate (N=292) or active control (calcium acetate and/or sevelamer carbonate; N=149). The majority (>96%) of subjects were on hemodialysis. The starting dose of ferric citrate was 6 tablets/day, divided with meals. The starting dose of active control was the patient’s dose prior to the washout period.
The dose of phosphate binder was increased or decreased as needed to maintain serum phosphorus levels between 3.5 and 5.5 mg/dL, to a maximum of 12 tablets/day. As shown in the figure below, serum phosphorus levels declined following initiation of therapy. The phosphorus lowering effect was maintained over 52 weeks of treatment.
Figure 1: Serum Phosphorus Control over 52 Weeks Following completion of the 52-week active-controlled phase, ferric citrate-treated patients were eligible to enter a 4-week placebo-controlled randomized withdrawal phase, in which patients were re-randomized in a 1:1 ratio to receive ferric citrate (N=96) or placebo (N=96). During the placebo-controlled period, the serum phosphorus concentration rose by 2.2 mg/dL on placebo relative to patients who remained on ferric citrate. Table 3: Effect of Ferric Citrate on serum phosphorus during randomized withdrawal Primary Endpoint (Week 56) Ferric Citrate Placebo Treatment Difference (95% CI) p-value Serum phosphorus (mg/dL) Mean baseline (Week 52) Mean change from baseline (Week 56) 5.12 −0.24 5.44 1.79 −2.18 (−2.59, −1.77) <0.0001 a a The LS mean treatment difference and p-value for the change in mean were created via an ANCOVA model with treatment as the fixed effect and Week-52 baseline (phosphorus) as the covariate. Between-treatment differences were calculated as the LS mean (ferric citrate) – LS mean (placebo or active control). Note: Analyses using ANCOVA with last observation carried forward.
ANCOVA=analysis of covariance; CI=confidence interval. Study KRX-0502-305 (NCT 01074125) Following a 1- to 2-week washout from all phosphate-binding agents, 154 patients with hyperphosphatemia (mean serum phosphorus of 7.5 mg/dL) and CKD on dialysis were randomized in a 1:1:1 ratio to 1, 6, or 8 tablets/day of ferric citrate for 4 weeks. Ferric citrate was administered with meals; subjects receiving 1 tablet/day were instructed to take it with their largest meal of the day, and subjects on 6 or 8 tablets/day took divided doses in any distribution with meals.
Dose-dependent decreases in serum phosphorus were observed by Day 7 and remained relatively stable for the duration of treatment. The demonstrated reductions from baseline to Week 4 in mean serum phosphorus were significantly greater with 6 and 8 tablets/day than with 1 tablet/day (p<0.0001). Mean reduction in serum phosphorus at Week 4 was 0.1 mg/dL with 1 tablet/day, 1.9 mg/dL with 6 tablets/day, and 2.1 mg/dL with 8 tablets/day. 1
Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Study
KRX-0502-306 (NCT 02268994) The efficacy of ferric citrate for the treatment of iron deficiency anemia in adult patients with CKD not on dialysis was demonstrated in a 24-week study consisting of a 16-week, randomized, double-blind, placebo-controlled, efficacy period followed by an 8-week open-label safety extension period in which all patients remaining in the study, including the placebo group, received ferric citrate. Patients with eGFR <60 mL/min/1.73m 2, who were intolerant of or have had an inadequate therapeutic response to oral iron supplements, with Hgb ≥9.0 g/dL and ≤11.5 g/dL, serum ferritin ≤200 ng/mL and TSAT ≤25% were enrolled. Patients were randomized to treatment with either ferric citrate (n=117) or placebo (n= 117). Dosing with ferric citrate or placebo was initiated at 3 tablets/day with meals.
Dose titration could occur at Weeks 4, 8 and 12 during Randomized Period, and at Weeks 18 and 20 during Safety Extension Period based on Hgb response. Use of oral or intravenous iron, erythropoiesis stimulating agents (ESAs) was not permitted at any time during the study. The mean age of the patients was 65 years (range 26 to 93); 63% were female, 69% Caucasian, 30% were African American and <2% were other races.
The main efficacy outcome measure was the proportion of subjects achieving an increase in Hgb of ≥1.0 g/dL at any time point between baseline and the end of the 16-week Randomized Period. Table 4: Efficacy of Ferric Citrate in Iron Deficiency Anemia in Chronic Kidney Disease (Not on Dialysis) Ferric Citrate (N=117) Placebo (N=115) p-value Proportion of patients achieving an increase in hemoglobin of ≥1.0 g/dL at any time point during the 16 week randomized period 52% 19% <0.001 During the 16-week randomized period 49% of subjects in the ferric citrate arm and 15% of subjects in the placebo arm (p <0.001) had a mean change in hemoglobin from baseline ≥0.75 g/dL over any 4-week time period provided that an increase of at least 1.0 g/dL had occurred during that 4-week period. Increases in mean hemoglobin (0.75 ± 0.09 g/dL), serum ferritin (163 ± 9 ng/mL) and transferrin saturation (18 ± 1%) were observed from baseline during the 16-week randomized period in the ferric citrate arm.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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