ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. The following clinically significant adverse reactions are described below and elsewhere in the labeling:Hypersensitivity Reactions. see Warnings and Precautions (5.1)] Hypersensitivity Reactions. see Warnings and Precautions (5.1)] Most common adverse reactions (incidence >=3%) are: headache, peripheral edema, asthenia, AV fistula thrombosis, urinary tract infection, AV fistula site hemorrhage, pyrexia, fatigue, procedural hypotension, muscle spasms, pain in extremity, back pain, and dyspnea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Rockwell Medical at 1-855-333-4315 or 1-248-960-9009 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 drug may not reflect the rates observed in practice.The safety of ferric pyrophosphate citrate injection, for intravenous use, has been established based on adequate and well-controlled studies of ferric pyrophosphate citrate solution for hemodialysis see Clinical Studies (14)]. Below is display of the adverse reactions of ferric pyrophosphate citrate solution for hemodialysis in these adequate and well-controlled studies. The safety of ferric pyrophosphate citrate solution for hemodialysis was evaluated in 292 patients in two randomized, placebo-controlled clinical trials (CRUISE (NCT01320202) and CRUISE (NCT01322347)) who were administered ferric pyrophosphate citrate solution for hemodialysis usefor periods of up to year[ see Clinical Studies (14)]. The mean total exposure in the randomized treatment period was months. total of 296 patients received placebo treatment for similar time period. In the two studies, 64% were male and 54% were Caucasian. The median age of patients was 60 years (range, 20 to 89 years). Adverse reactions occurring in 3% or greater of patients treated with ferric pyrophosphate citrate solution for hemodialysis use in the randomized clinical trials are listed in Table 1. Table 1. Table 1: Adverse Reactions Reported in Two Clinical Trials in at Least 3% of Patients Receiving Ferric Pyrophoshate Citrate Solution for Hmodialysis Use and at an Incidence at Least 1% Greater than PlaceboBody System Adverse ReactionFerric Pyrophosphate CitrateSolution for Hemodialysis UseN=292n (%)PlaceboN=296n (%)Numberof patients with at least one adverse reaction 229 (78) 223 (75)General Disorders and Administration Site Reactions Peripheral edema 20 (7) 11 (4) Pyrexia 13 (5) (3) Asthenia 12 (4) (3) Fatigue 11 (4) (2) Infections and Infestations Urinary tract infection 13 (5) (1) Injury, Poisoning and Procedural Complications Procedural hypotension 63 (22) 57 (19) Arteriovenous fistula thrombosis 10 (3) (2) Arteriovenous fistula site hemorrhage 10 (3) (2) Musculoskeletal and Connective Tissue Disorders Muscle spasms 28 (10) 24 (8) Pain in extremity 20 (7) 17 (6) Back pain 13 (5) 10 (3) Nervous System Disorders Headache 27 (9) 16 (5) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 17 (6) 13 (4). Other Adverse Reactions:Less common adverse reactions occurring at frequency of <3%:Hypersensitivity Reactions. [see Warnings and Precautions (5.1)] Adverse Reactions Leading to Treatment Discontinuation:In clinical trials,adverse reactionsleading to treatment discontinuation include headache, asthenia, dizziness, constipation,nausea,hypersensitivity reactions, intradialytic hypotension, pruritis and pyrexia.. Hypersensitivity Reactions. [see Warnings and Precautions (5.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies examining the carcinogenic potential of ferric pyrophosphate citrate have not been conducted.Ferric pyrophosphate citrate was clastogenic in the in vitro chromosomal aberration assay in CHO cells in the presence of metabolic activation. Ferric pyrophosphate citrate was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro chromosomal aberration assay in CHO cells in the absence of metabolic activation or in the in vivo mouse micronucleus assay. In combined male and female fertility study in rats, ferric pyrophosphate citrate was administered intravenously over one hour three times per week at doses of up to 40 mg/kg. No adverse effects on fertility or reproduction were noted.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Triferic AVNU contains iron in the form of ferric pyrophosphate citrate. Iron binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin. 12.2 Pharmacodynamics. Ferric pyrophosphate citrate exposure-response relationships and the time course of pharmacodynamics response are unknown.Drug interaction StudiesIn vitro studies showed that ferric pyrophosphate citrate did not impact the pharmacodynamics of unfractionated heparin or low molecular weight heparin. 12.3 Pharmacokinetics. Following administration of ferric pyrophosphate citrate 6.75 mg via 3-hour intravenous infusion at rate of 1.5 mg/hr (6.5 mg delivered), the total plasma iron and transferrin bound iron exposure values are provided in Table 2. Table 2. Total Plasma Iron and Transferrin Bound Iron Exposure Parameters after Intravenous Administration of Ferric Pyrophosphate Citrate via the Pre-dialyzer and Post-dialyzer Infusion Line during Hemodialysis Plasma Analyte PK Parameter Ferric Pyrophosphate Citrate pre-dialyzer infusion line(N-26)post-dialyzer infusion line(N=25) Total Plasma Iron max (ug/dL) 170 (24%) 164 (23%) AUC 0-last (ugoh/dL) 1260 (35%) 1230 (33%) Transferrin Bound Iron Cmax (ug/dL) 180 (24%) 169 (28%) AUC0-last (ugoh/dL) 1250 (37%) 1190 (46%) N=17 for pre-dialyzer and N= 16 for post-dialyzer.

CLINICAL STUDIES SECTION.

14. CLINICAL STUDIES. The efficacy of Triferic AVNU has been established based on adequate and well-controlled adult studies of ferric pyrophosphate citrate in iron replacement in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Below is display of the results of the adequate and well-controlled studies of ferric pyrophosphate citrate in this condition.The efficacy of ferric pyrophosphate citrate in patients with HDD-CKD was assessed in two randomized, single blind, placebo-controlled clinical trials. Patients with hemoglobin of g/dL to 12 g/dL with TSAT 20% and serum ferritin concentrations 200 mcg/L were enrolled. Patients were to remain in randomized treatment until pre-specified hemoglobin or ferritin criteria were met, indicating the need for change in anemia management or if they completed 48 weeks. Ferric pyrophosphate citrate was added to bicarbonate concentrate with final concentration of 110 mcg iron/L in the dialysate and was administered or times per week during hemodialysis. Most patients were receiving stable dose of erythropoiesis stimulating agents (ESAs) at baseline. After randomization, patients ESA doses were not to be changed.In CRUISE (NCT01320202), the mean age of patients was 58 years (range 23 to 89); 68% were male, 55% were Caucasian, 32% were African American, and 13% were other races. In CRUISE (NCT01322347), the mean age of patients was 58 years (range 20 to 89); 59% were male, 54% were Caucasian, 40% were African American, and 6% were other races.Efficacy was assessed by the mean change in hemoglobin from baseline to the end-of-treatment period (average hemoglobin of the last one-sixth (1/6th) of the time in the randomized treatment period). About 18% of patientscompleted the planned 48 week treatment duration. Table shows the mean changes in hemoglobin (Hgb) and iron parameters in each treatment group from baseline to the end-of-treatment period for the ITT population.Table Changes from Baseline to end of Treatment in Hemoglobin, Ferritin, Reticulocyte Hgb (CHr) and Transferrin Saturation (TSAT)CRUISE CRUISE Ferric Pyrophsophate Citrate n=152 Placebo n=153 Ferric Pyrophosphate Citrate n=147Placebo n=147 Baseline HemoglobinMean (SD), g/dL 10.96 (0.592) 10.91 (0.632) 10.96 (0.605) 10.94 (0.622)Hemoglobin, Change from Baseline to End-of-Treatment MEan (SD), g/dL -0.03 (1.147) -0.38 (1.24) -0.08 (1.152) -0.44 (1.157)Baseline FerriitnMean (SD), mcg/L 508.2 (193.55) 509.3 (209.06) 519.0 (201.56) 478.4 (200.59)Ferritin, Change from Baseline to End-of-TreatmentMean (SD), mcg/L -70.8 (132.41) -141.2 (187.74) -65.3 (162.45) -120.9 (268.19)Baseline Reticulocyte Hemoglobin (CHr)Mean (SD), pg 32.37 (1.967) 32.53 (1.965) 32.56 (2.21) 32.57 (1.932)CHR, Change from Baseline to End-of-TreatmentMean (SD), pg -0.22 (1.191) -0.90 (1.407) -0.55 (1.441) -0.85 (1.474)Baseline TSATMean (SD), 28.2 (8.23) 27.1 (7.76) 28.0 (8.15) 28.2 (8.52)TSAT, Change from Baseline to End-of-TreatmentMEan (SD), -1.0 (9.07)-2.9 (7.65) -0.9 (7.54) -3.6 (7.29) p<0.05.

DESCRIPTION SECTION.

11. DESCRIPTION. Triferic AVNU (ferric pyrophosphate citrate), an iron replacement product, is mixed-ligand iron complex in which iron (III) is bound to pyrophosphate and citrate. It has molecular formula of Fe 4(C 6H 4O 7) 3(H 2P 2O 7) 2(P 2O 7)and relative molecular weight of approximately 1313 daltons. Ferric pyrophosphate citrate has the following structure: Triferic AVNU (ferric pyrophosphate citrate) injection is clear, slightly yellow-green color sterile solution containing 6.75 mg of elemental iron (III) per 4.5 mL (1.5 mg iron (III) per mL) filled in 5 mL low density polyethylene (LDPE) luer-lock ampule. Each Triferic AVNU ampule contains iron (0.14-0.17 w/w), and less than 0.1% w/w citrate, pyrophosphate, phosphate, sodium and sulfate. One Triferic AVNU ampule is administered directly into the pre-dialyzer infusion line, post-dialyzer infusion line, or to separate connection to the venous blood line over to hours.. Triferic AVNU.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. 6.75 mg iron (III)intravenously over to hours at each hemodialysis session via pre-dialyzer infusion line, post-dialyzer infusion line, or separate connection to the venous blood line. (2.2). 2.1 Recommended Dosage. The recommended dosage of Triferic AVNU is 6.75 mg iron (III) undiluted as slow continuous intravenous infusion over to hours via the pre-dialyzer infusion line, post-dialyzer infusion line, or via separate connection to the venous blood line during hemodialysis.Administer Triferic AVNU at each dialysis procedure for as long as patients are receiving maintenance hemodialysis therapy for CKD.The dosage of Triferic AVNU solution is expressed as mg of iron (III). Each mL of Triferic AVNU injection for intravenous administration contains 1.5 mg iron as iron (III). 2.2 Preparation and Administration. Each ampule of Triferic AVNU is intended for single-use only.Use aseptic technique to prepare Triferic AVNU as follows:Visually inspect Triferic AVNU solution for signs of precipitation prior to use. The solution should be clear and slightly yellow-green in color.Holding the top of the ampule, shake with one single downward movement in order to remove the solution remaining in the cap.To open, twist the ampule body and the ampule head in opposite directions until the neck breaks off the top.Attach 10 mL or 20 mL luer-lock syringe to the ampule and withdraw the contents (6.75 mg in 4.5 mL).Connect the syringe to the attached pre-dialyzer infusion line, post-dialyzer infusion line, or to separate connection to the venous blood line. Mount the syringe on an infusion pump and administer as slow continuous infusion of Triferic AVNU (4.5 mL) over to hours.Discard unused portion.. Visually inspect Triferic AVNU solution for signs of precipitation prior to use. The solution should be clear and slightly yellow-green in color.. Holding the top of the ampule, shake with one single downward movement in order to remove the solution remaining in the cap.. To open, twist the ampule body and the ampule head in opposite directions until the neck breaks off the top.. Attach 10 mL or 20 mL luer-lock syringe to the ampule and withdraw the contents (6.75 mg in 4.5 mL).. Connect the syringe to the attached pre-dialyzer infusion line, post-dialyzer infusion line, or to separate connection to the venous blood line. Mount the syringe on an infusion pump and administer as slow continuous infusion of Triferic AVNU (4.5 mL) over to hours.. Discard unused portion.

HOW SUPPLIED SECTION.

16. HOW SUPPLIED STORAGE AND HANDLING. 16.1 How Supplied. Triferic AVNUinjection is clear to slightly yellow-green solution available in single-dose luer lock ampules in the following package sizes:NDC CodePackage DescriptionAmount/Total Volume (per ampule)NDC 57278-318-0110 Luer-lock ampules per pouch6.75 mg iron (III)/4.5 mL (1.5 mg iron (III) per mL)NDC 57278-318-024 Pouches per Carton. 16.2 Storage. Store ampules protected from light in the aluminum pouch at controlled room temperature (20 to 25C [68 to 77F]); excursions permitted to 15-30C (59 to 86F) [See USP Controlled Room Temperature]. Do not freeze.

INDICATIONS & USAGE SECTION.

1. INDICATIONS AND USAGE. Triferic AVNU is an iron replacement product indicated for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Limitations of UseTriferic AVNU is not intended for use in patients receiving peritoneal dialysis. Triferic AVNU has not been studied in patients receiving home hemodialysis.. Triferic AVNU is not intended for use in patients receiving peritoneal dialysis. Triferic AVNU has not been studied in patients receiving home hemodialysis.. Triferic AVNU is an iron replacement product indicated for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). (1) Limitations of UseTriferic AVNU is not intended for use in patients receiving peritoneal dialysis. (1)Triferic AVNU has not been studied in patients receiving home hemodialysis (1). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis. (1). Triferic AVNU has not been studied in patients receiving home hemodialysis (1).

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATION. Prior to the administration of Triferic AVNU:Question patients regarding any prior history of reactions to parenteral iron products.Advise patients of the risk of hypersensitivity reactions associated with Triferic AVNU.Advise patient to report any signs and symptoms of hypersensitivity that may develop during and after the dialysis session, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems see Warnings and Precautions (5)]. Question patients regarding any prior history of reactions to parenteral iron products.. Advise patients of the risk of hypersensitivity reactions associated with Triferic AVNU.. Advise patient to report any signs and symptoms of hypersensitivity that may develop during and after the dialysis session, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems see Warnings and Precautions (5)]. . Manufactured forRockwell Medical, Inc.30142 Wixom RdWixom, MI 48393.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL PHARMACOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies examining the carcinogenic potential of ferric pyrophosphate citrate have not been conducted.Ferric pyrophosphate citrate was clastogenic in the in vitro chromosomal aberration assay in CHO cells in the presence of metabolic activation. Ferric pyrophosphate citrate was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro chromosomal aberration assay in CHO cells in the absence of metabolic activation or in the in vivo mouse micronucleus assay. In combined male and female fertility study in rats, ferric pyrophosphate citrate was administered intravenously over one hour three times per week at doses of up to 40 mg/kg. No adverse effects on fertility or reproduction were noted.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following administration of ferric pyrophosphate citrate 6.75 mg via 3-hour intravenous infusion at rate of 1.5 mg/hr (6.5 mg delivered), the total plasma iron and transferrin bound iron exposure values are provided in Table 2. Table 2. Total Plasma Iron and Transferrin Bound Iron Exposure Parameters after Intravenous Administration of Ferric Pyrophosphate Citrate via the Pre-dialyzer and Post-dialyzer Infusion Line during Hemodialysis Plasma Analyte PK Parameter Ferric Pyrophosphate Citrate pre-dialyzer infusion line(N-26)post-dialyzer infusion line(N=25) Total Plasma Iron max (ug/dL) 170 (24%) 164 (23%) AUC 0-last (ugoh/dL) 1260 (35%) 1230 (33%) Transferrin Bound Iron Cmax (ug/dL) 180 (24%) 169 (28%) AUC0-last (ugoh/dL) 1250 (37%) 1190 (46%) N=17 for pre-dialyzer and N= 16 for post-dialyzer.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on Triferic AVNU usein pregnant women to inform drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of ferric pyrophosphate citrate to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes at maternally toxic dose levels that were higher than the maximum theoretical amount of iron transferred to patients from Triferic AVNU (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn fertility and early embryonic development study in female rats, the maternally toxic ferric pyrophosphate citrate dose of 40 mg/kg administered three times per week by intravenous infusion was not toxic to the developing embryo.In embryo-fetal developmental toxicity studies, ferric pyrophosphate citrate was administered during the period of organogenesis as one-hour intravenous infusion to pregnant rats and rabbits. No maternal or developmental toxicity was observed at doses up to 30 mg/kg/day in rats and 20 mg/kg/day in rabbits. Maternally toxic doses affected embryo-fetal development, resulting in post-implantation loss due to early resorptions, abnormal placentae, decreased fetal body weight and fetal head and vertebral malformations at 90 mg/kg/day in rats and vertebral malformations at 40 mg/kg/day in rabbits. pre-and post-natal development study was conducted in pregnant rats with intravenous doses of ferric pyrophosphate citrate up to 90 mg/kg/day. The maternally toxic dose of 90 mg/kg/day resulted in reductions in the number of live offspring and lower offspring body weights. There were no adverse effects on survival of offspring at doses up to 30 mg/kg/day, or on behavior, sexual maturation or reproductive parameters of offspring at any dose level.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on Triferic AVNU usein pregnant women to inform drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of ferric pyrophosphate citrate to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes at maternally toxic dose levels that were higher than the maximum theoretical amount of iron transferred to patients from Triferic AVNU (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn fertility and early embryonic development study in female rats, the maternally toxic ferric pyrophosphate citrate dose of 40 mg/kg administered three times per week by intravenous infusion was not toxic to the developing embryo.In embryo-fetal developmental toxicity studies, ferric pyrophosphate citrate was administered during the period of organogenesis as one-hour intravenous infusion to pregnant rats and rabbits. No maternal or developmental toxicity was observed at doses up to 30 mg/kg/day in rats and 20 mg/kg/day in rabbits. Maternally toxic doses affected embryo-fetal development, resulting in post-implantation loss due to early resorptions, abnormal placentae, decreased fetal body weight and fetal head and vertebral malformations at 90 mg/kg/day in rats and vertebral malformations at 40 mg/kg/day in rabbits. pre-and post-natal development study was conducted in pregnant rats with intravenous doses of ferric pyrophosphate citrate up to 90 mg/kg/day. The maternally toxic dose of 90 mg/kg/day resulted in reductions in the number of live offspring and lower offspring body weights. There were no adverse effects on survival of offspring at doses up to 30 mg/kg/day, or on behavior, sexual maturation or reproductive parameters of offspring at any dose level. 8.2 Lactation. Risk SummaryThere are no data on the presence of ferric pyrophosphate citrate in human milk, the effects on the breastfed child, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Triferic AVNU and any potential adverse effects on the breastfed child from Triferic AVNU or from the underlying maternal condition. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use. In controlled clinical trials, 99 (29%) patients >= 65 years of age were treated with ferric pyrophosphate citrate. No overall differences in safety and efficacy were observed between older and younger patients in these trials [see Clinical Studies (14)].

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after hemodialysis and until clinically stable. Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after hemodialysis and until clinically stable. (5.1). 5.1 Hypersensitivity Reactions. Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving parenteral iron products. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after hemodialysis until clinically stable. Personnel and therapies should be immediately available for the treatment of serious hypersensitivity reactions. see Adverse Reactions (6.1)] Hypersensitivity reactions have been reported in (0.3%) of 292 patients receiving ferric pyrophosphate citrate in two randomized clinical trials. 5.2 Iron Laboratory Testing. Determine iron status on pre-dialysis blood samples. Post-dialysis serum iron parameters may overestimate serum iron and transferrin saturation.