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 tablets 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.

3 DOSAGE FORMS AND STRENGTHS Tablets: Each pink, film-coated, oval tablet debossed with “W824” on one side and “TEVA” on the other side contains 210 mg ferric iron equivalent to 1 g ferric citrate. Tablets: 210 mg ferric iron, equivalent to 1 g ferric citrate. ( 3 )

4 CONTRAINDICATIONS Ferric citrate tablets are contraindicated in patients with iron overload syndromes (e.g., hemochromatosis) [see Warnings and Precautions (5.1) ] . Iron overload syndromes (e.g., hemochromatosis). ( 4 )

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 tablets 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 tablets for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated with ferric citrate tablets; 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 tablets 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 tablets 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 tablets (14%). Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Across two trials, 190 patients with CKD-NDD were treated with ferric citrate tablets. This included a study of 117 patients treated with ferric citrate tablets and 116 patients treated with placebo in a 16-week, randomized, double-blind period and a study of 75 patients treated with ferric citrate tablets 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 tablets 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 Tablets Body System Adverse Reaction Ferric Citrate Tablets % (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 tablets 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 tablets (2.6%).

7 DRUG INTERACTIONS Table 2: Oral drugs that can be administered concomitantly with Ferric Citrate Tablets 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 Tablets and meals Dosing Recommendations Doxycycline Take at least 1 hour before ferric citrate tablets Ciprofloxacin Take at least 2 hours before or after ferric citrate tablets Oral medications not listed in Table 2 There are no empirical data on avoiding drug interactions between ferric citrate tablets 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. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on ferric citrate tablet 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 tablets. Skeletal and encephalic malformation was observed in neonatal mice when ferric gluconate was administered intraperitoneally to gravid dams on gestation days 7-9. 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 tablets 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. 8.2 Lactation Risk Summary There are no human data regarding the effect of ferric citrate in human milk, the effects on the breastfed child, or the effects on milk production. Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1). Hence, there is a possibility of infant exposure when ferric citrate tablets are administered to a nursing woman. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ferric citrate tablets and any potential adverse effects on the breastfed child from ferric citrate tablets or from the underlying maternal condition. 8.4 Pediatric Use The safety and efficacy of ferric citrate tablets have 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 tablets are 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. 8.5 Geriatric Use Clinical studies of ferric citrate tablets included 292 subjects aged 65 years and older (104 subjects aged 75 years and older). Overall, the clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of ferric citrate tablets.

12.1 Mechanism of Action Hyperphosphatemia in Chronic Kidney Disease on Dialysis Ferric iron binds dietary phosphate in the GI tract and precipitates as ferric phosphate. This compound is insoluble and is excreted in the stool. By binding phosphate in the GI tract and decreasing absorption, ferric citrate lowers the phosphate concentration in the serum. Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the GI tract. After transport through the enterocytes into the blood, oxidized ferric iron circulates bound to the plasma protein transferrin, and can be incorporated into hemoglobin.

11 DESCRIPTION Ferric citrate, a phosphate binder and iron replacement product, is known chemically as iron (+3), x (1, 2, 3-propanetricarboxylic acid, 2-hydroxy-), y (H2O). Ferric citrate 210 mg ferric iron tablets for oral administration, equivalent to 1 g ferric citrate, are film-coated, peach-colored, and oval-shaped tablets debossed with “KX52.” The inactive ingredients are pregelatinized starch and calcium stearate. In addition, the film-coating contains the following inactive ingredients: hypromellose, titanium dioxide, triacetin, and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake, FD&C Red #40/Allura Red AC Aluminum Lake, and FD&C Blue #2/Indigo Carmine Aluminum Lake. Chemical Formula

10 OVERDOSAGE No data are available regarding overdose of ferric citrate tablets 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 tablets may lead to excessive elevations in iron stores, especially when concomitant intravenous iron is used [see Warnings and Precautions (5.1) ] . 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 tablets.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tablets: Ferric Citrate Tablets 210 mg ferric iron tablets equivalent to 1 g of ferric citrate are supplied as 200 tablets in 400cc high-density polyethylene bottles. The 210 mg ferric iron tablets are film-coated, peach-colored, and oval-shaped tablets debossed with “KX52.” 1 Bottle of 200-count 210 mg ferric iron tablets (NDC 0378-2895-20) 16.2 Storage and Handling Storage: Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F). [See USP controlled room temperature]. Protect from moisture.