Ferric Citrate

1 INDICATIONS AND USAGE Ferric citrate tablets are a phosphate binder indicated for the control of serum phosphorus levels in adult patients with chronic kidney disease on dialysis. ( 1 ) 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 ) 1.1 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. 1.2 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.

2 DOSAGE AND ADMINISTRATION Hyperphosphatemia in Chronic Kidney Disease on Dialysis: Starting dose is 2 tablets orally 3 times per day with meals. ( 2.1 ) 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. ( 2.1 ) Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis: Starting dose is 1 tablet orally 3 times per day with meals. ( 2.2 ) Adjust dose as needed to achieve and maintain hemoglobin goal, up to a maximum of 12 tablets daily. ( 2.2 ) 2.1 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. 2.2 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.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5%) are discolored feces, diarrhea, constipation, nausea, vomiting, cough, abdominal pain, and hyperkalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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%).

12.3 Pharmacokinetics Absorption and Distribution Formal pharmacokinetic studies have not been performed with ferric citrate. Examination of serum iron parameters has shown that there is systemic absorption of iron from ferric citrate [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.1)] . Drug Interaction Studies In vitro Of the drugs screened for an interaction with ferric citrate in vitro, only doxycycline showed the potential for interaction with at least 70% decrease in its concentration. This interaction can be avoided by spacing the administration of doxycycline and ferric citrate [see Drug Interactions (7)] . In vivo Six drug interaction studies (N=26 to 60/study) were conducted to establish the effects of ferric citrate (administered as 3 x 2 g/day with meals) on the disposition of concomitantly orally administered clopidogrel, ciprofloxacin, digoxin, diltiazem, glimepiride and losartan in healthy subjects. With the exception of ciprofloxacin, ferric citrate did not alter the systemic exposure of the tested drugs, as measured by the area under the curve (AUC) and C max of the tested drugs when either co-administered with ferric citrate or given 2 hours later. Ferric citrate decreased the relative bioavailability of concomitantly administered ciprofloxacin by approximately 45%. However, there was no interaction when ferric citrate and ciprofloxacin were taken 2 hours apart. Consequently, ciprofloxacin should be taken at least 2 hours before or after ferric citrate is dosed [see Drug Interactions (7)] .