Ferric Citrate

Ferric citrate tablets are a phosphate binder indicated for the control of serum phosphorus levels in adult patients with chronic kidney disease on dialysis. Ferric citrate tablets are an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease not on dialysis.

1.1Hyperphosphatemia 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.

1.2Iron 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.

Hyperphosphatemia in Chronic Kidney Disease on Dialysis: Starting dose is 2 tablets orally 3 times per day with meals. Adjust dose by 1 to 2 tablets as needed to maintain serum phosphorus at target levels, up to a maximum of 12 tablets daily. Dose can be titrated at 1-week or longer intervals. Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis: Starting dose is 1 tablet orally 3 times per day with meals. Adjust dose as needed to achieve and maintain hemoglobin goal, up to a maximum of 12 tablets daily.

2.1Dosage 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.

2.2Dosage 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.

Iron overload: Monitor ferritin and TSAT. Patients may require a reduction in dose or discontinuation of intravenous iron. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

5.1Iron 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.

5.2Risk 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.

Ferric citrate is contraindicated in patients with iron overload syndromes (e.g., hemochromatosis) . Iron overload syndromes (e.g., hemochromatosis).

8.1Pregnancy 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.

Most common adverse reactions (incidence ≥5%) are discolored feces, diarrhea, constipation, nausea, vomiting, cough, abdominal pain, and hyperkalemia. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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%).