ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following 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) ]. The most common adverse reactions in controlled clinical studies include: 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.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.In two randomized, placebo-controlled clinical trials, total of 292 patients were administered Triferic for 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 events occurring in 3% or greater of patients treated with Triferic in the randomized clinical trials are listed in Table 1.Table 1: Adverse Reactions Reported in Two Clinical Trials in at Least 3% of Patients Receiving Triferic and at an Incidence at Least 1% Greater than PlaceboSystem Organ Class Preferred Term Triferic N=292 (%) Placebo N=296 (%) Number of patients with at least one adverse reaction229 (78.4)223 (75.3)General Disorders and Administration Site Conditions Peripheral edema20 (6.8)11 (3.7) Pyrexia13 (4.5)9 (3.0) Asthenia12 (4.1)9 (3.0) Fatigue11 (3.8)6 (2.0)Infections and Infestations Urinary tract infection13 (4.5)4 (1.4)Injury, Poisoning, and Procedural Complications Procedural hypotension63 (21.6)57 (19.3) Arteriovenous fistula thrombosis10 (3.4)6 (2.0) Arteriovenous fistula site hemorrhage10 (3.4)5 (1.7)Musculoskeletal and Connective Tissue Disorders Muscle spasms28 (9.6)24 (8.1) Pain in extremity20 (6.8)17 (5.7) Back pain13 (4.5)10 (3.4)Nervous System Disorders Headache27 (9.2)16 (5.4)Respiratory, Thoracic and Mediastinal Disorders Dyspnea17 (5.8)13 (4.4). Adverse Reactions Leading to Treatment DiscontinuationIn clinical trials, adverse reactions leading to treatment discontinuation included headache, asthenia, dizziness, constipation, nausea, hypersensitivity reactions, intradialytic hypotension, pruritus, and pyrexia.Adverse reactions reported in the treatment extension period were similar to those observed in the randomized clinical studies.

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 contains iron in the form of ferric pyrophosphate citrate and is added to hemodialysate solution to be administered to patients by transfer across the dialyzer membrane. Iron delivered into the circulation binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.. 12.3 Pharmacokinetics. The pharmacokinetics of serum iron was investigated in healthy volunteers administered 2.5, 5, 7.5 and 10 mg Triferic intravenously over hours, or 15 mg and 20 mg Triferic intravenously over 12 hours. After correcting for the basal iron levels, the AUC and max of baseline-corrected serum iron increased in dose-proportional manner. The half-life of serum iron was approximately 1.48 hours, the mean clearance (CL) ranged from 0.406 to 0.556 L/hour, the mean apparent volume of distribution (Vz) ranged from 0.765 to 0.859 after 4-hour intravenous administration of Triferic. Compared to the 4-hour infusion of Triferic, higher mean CL and Vz were observed following the administration of Triferic 15 mg (CL 0.672 L/hour and Vz 1.66 L) and Triferic 20 mg (CL 0.661 L/hour, Vz 2.08L) infused over 12 hours. In study that assessed the impact of different dialysis conditions on iron delivery in patients administered Triferic via hemodialysis, reduction of the blood and dialysate flow rates (Qb/Qd of 200/400 mL/min vs. >= 350/ >= 600 mL/min) resulted in 33% decrease in the median cumulative iron delivered.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Prior to the administration of Triferic:Question patients regarding any prior history of reactions to parenteral iron products.Advise patients of the risks associated with Triferic.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 risks associated with Triferic.. 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) ].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of Triferic in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Triferic and any potential adverse effects on the breastfed infant from Triferic or from the underlying maternal condition.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of Triferic 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. Triferic was added to the 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 Study 1, the mean age of patients was 58 years (range 23 to 89); 32% were female, 55% were Caucasian, 32% were African American, and 13% were other races.In Study 2, the mean age of patients was 58 years (range 20 to 89); 41% were female, 54% were Caucasian, 40% were African American, and 6% were other races.The primary endpoint of the studies was 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 patients completed 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 2: Changes from Baseline to End-of-Treatment in Hemoglobin, Ferritin, Reticulocyte Hgb (CHr), and Transferrin Saturation (TSAT)Study 1Study 2Triferic n=152 Placebo n=153 Triferic n=147 Placebo n=147 Baseline Hemoglobin Mean +- (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) < 0.05 for primary efficacy endpoint -0.38 (1.240) -0.08 (1.152) -0.44 (1.157) Baseline Ferritin Mean (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-Treatment Mean (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 (2.210) 32.57 (1.932) CHr, Change from Baseline to End-of-Treatment Mean (SD), pg -0.22 (1.191) -0.90 (1.407) -0.55 (1.441) -0.85 (1.474) Baseline TSAT Mean (SD), 28.2 (8.23) 27.1 (7.76) 28.0 (8.15) 28.2 (8.52) TSAT, Change from Baseline to End-of-Treatment) Mean (SD), -1.0 (9.07) -2.9 (7.65) -0.9 (7.54) -3.6 (7.29).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None.

DESCRIPTION SECTION.

11 DESCRIPTION. Triferic (ferric pyrophosphate citrate) 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. Triferic contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20-35%). Ferric pyrophosphate citrate has the following molecular structure: Triferic solution:A clear, slightly yellow-green color, sterile solution containing 27.2 mg of iron (III) per mL filled into 5 mL low density polyethylene ampule or 272 mg of iron (III) per 50 mL filled into 50 mL low density polyethylene ampule. Triferic powder:A slightly yellow-green powder packaged in paper, polyethylene and aluminum foil packets, each containing 272.0 mg of iron (III). Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Add one mL ampule of Triferic solution to each 2.5 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) Add one 50 mL ampule of Triferic solution to each 25 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) Add one packet of Triferic powder to each 25 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) Add one mL ampule of Triferic solution to each 2.5 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) Add one 50 mL ampule of Triferic solution to each 25 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) Add one packet of Triferic powder to each 25 gallons of bicarbonate concentrate to achieve concentration of iron (III) in the final hemodialysate of micromolar (110 mcg/L). 2.1) 2.1 Recommended Dosage. Inspect Triferic solution in ampules for signs of precipitation prior to mixing with the bicarbonate concentrate. Triferic solution should appear slightly yellow-green in color.Triferic solution or powder should only be added to the bicarbonate concentrate and should NOT be added to acid concentrate mixtures.Add Triferic solution or powder to bicarbonate concentrate used for the generation of hemodialysate. The concentration of iron (III) in the final hemodialysate is micromolar (110 mcg/L).Add one mL ampule of Triferic solution to 2.5 gallons (9.46 liters) of bicarbonate concentrate. Multiple mL ampules can be added to the master bicarbonate mix at each center at ratio of one mL ampule for each 2.5 gallons (9.46 liters) of bicarbonate concentrate.Add one 50 mL ampule of Triferic solution to 25 gallons (94.6 liters) of bicarbonate concentrate. Multiple 50 mL ampules can be added to the master bicarbonate mix at each center at ratio of one 50 mL ampule for each 25 gallons (94.6 liters) of bicarbonate concentrate.Add one packet of Triferic powder to 25 gallons (94.6 liters) of bicarbonate concentrate. Multiple packets can be added to the master bicarbonate mix at each center at ratio of one packet for each 25 gallons (94.6 liters) of bicarbonate concentrate.Product comparison table with dilution instructions for the mL ampule of Triferic solution, the 50 mL ampule of Triferic Solution, and the packet of Triferic Powder are provided in the Table below.Triferic Dosage FormTriferic SolutionTriferic Powder5 mL Ampule50 mL AmpulePacketIron content per Ampule or Packet27.2 mg272 mg272 mgNumber of Ampules or Packets to be added to each unit of bicarbonate concentrate111Per unit of bicarbonate concentrate (volume)2.5 gallons (9.46 Liters) 25 gallons (94.6 Liters) 25 gallons (94.6 Liters) Final iron concentration in dialysate110 mcg/L110 mcg/L110 mcg/LAdminister Triferic to patients at each dialysis procedure for as long as patients are receiving maintenance hemodialysis therapy for CKD.Dosage of Triferic is expressed as mg of iron (III).Hemodialysis solutions should be used within 24 hours of the preparation of the bicarbonate concentrate mixture.. Add one mL ampule of Triferic solution to 2.5 gallons (9.46 liters) of bicarbonate concentrate. Multiple mL ampules can be added to the master bicarbonate mix at each center at ratio of one mL ampule for each 2.5 gallons (9.46 liters) of bicarbonate concentrate.. Add one 50 mL ampule of Triferic solution to 25 gallons (94.6 liters) of bicarbonate concentrate. Multiple 50 mL ampules can be added to the master bicarbonate mix at each center at ratio of one 50 mL ampule for each 25 gallons (94.6 liters) of bicarbonate concentrate.. Add one packet of Triferic powder to 25 gallons (94.6 liters) of bicarbonate concentrate. Multiple packets can be added to the master bicarbonate mix at each center at ratio of one packet for each 25 gallons (94.6 liters) of bicarbonate concentrate.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Each mL ampule contains Triferic solution (5.44 mg of iron (III) per mL) equivalent to 27.2 mg iron (III).Each 50 mL ampule contains Triferic solution (5.44 mg of iron (III) per mL) equivalent to 272 mg iron (III).Each packet contains Triferic powder equivalent to 272 mg iron (III).. 27.2 mg of iron (III) per mL ampule as Triferic solution (5.44 mg of iron (III) per mL). 3) 272 mg of iron (III) per 50 mL ampule as Triferic solution (5.44 mg of iron (III) per mL). 3) 272 mg of iron (III) per packet as Triferic powder. 3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Triferic may cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception measures to prevent pregnancy during treatment with Triferic and for at least weeks following completion of therapy.

GERIATRIC USE SECTION.

8.5 Geriatric Use. In controlled clinical trials, 99 (28.6%) patients >= 65 years of age were treated with Triferic. No overall differences in safety and efficacy were observed between older and younger patients in these trials see Clinical Studies (14) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Triferic is available in ampules or packets in the following package sizes:NDC CodePackage DescriptionAmount/Total Volume in Ampule5 mL Ampule27.2 mg iron (III)/ 5mL as Triferic solution (5.44 mg of iron (III) per mL)NDC 57278-314-015 Ampules per PouchNDC 57278-314-028 Pouches per CartonNDC 57278-316-0150 mL Ampule272 mg iron (III)/ 50 mL as Triferic solution (5.44 mg of iron (III) per mL)NDC 57278-316-024 Ampules per PouchNDC 57278-316-036 Pouches per CartonNDC CodePackage DescriptionAmount/PacketNDC 57278-315-01Packet272 mg iron (III)/ packet as Triferic powderNDC 57278-315-02100 Packets 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 15to 30C (59 to 86F) [See USP Controlled Room Temperature]. Store packets at controlled room temperature (20 to 25C [68 to 77F]); excursions permitted to 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Triferic 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).. TRIFERIC 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) Limitation of UseTriferic is not intended for use in patients receiving peritoneal dialysis. 1.1) Triferic has not been studied in patients receiving home hemodialysis. 1.1) 1.1 Limitation of Use. Triferic is not intended for use in patients receiving peritoneal dialysis.Triferic has not been studied in patients receiving home hemodialysis.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Triferic contains iron in the form of ferric pyrophosphate citrate and is added to hemodialysate solution to be administered to patients by transfer across the dialyzer membrane. Iron delivered into the circulation binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No data are available regarding overdosage of Triferic in humans.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 40 Ampule Carton. NDC 57278-314-01 40 Ampules Rx OnlyTRIFERIC(TM)ferric pyrophosphate citrate 27.2 mg Fe/5 mL (5.44 mg Fe/mL) ROCKWELLMEDICAL Protect from light Keep ampules in pouch until time of use For dialysis use only Must be diluted PRINCIPAL DISPLAY PANEL 40 Ampule Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of serum iron was investigated in healthy volunteers administered 2.5, 5, 7.5 and 10 mg Triferic intravenously over hours, or 15 mg and 20 mg Triferic intravenously over 12 hours. After correcting for the basal iron levels, the AUC and max of baseline-corrected serum iron increased in dose-proportional manner. The half-life of serum iron was approximately 1.48 hours, the mean clearance (CL) ranged from 0.406 to 0.556 L/hour, the mean apparent volume of distribution (Vz) ranged from 0.765 to 0.859 after 4-hour intravenous administration of Triferic. Compared to the 4-hour infusion of Triferic, higher mean CL and Vz were observed following the administration of Triferic 15 mg (CL 0.672 L/hour and Vz 1.66 L) and Triferic 20 mg (CL 0.661 L/hour, Vz 2.08L) infused over 12 hours. In study that assessed the impact of different dialysis conditions on iron delivery in patients administered Triferic via hemodialysis, reduction of the blood and dialysate flow rates (Qb/Qd of 200/400 mL/min vs. >= 350/ >= 600 mL/min) resulted in 33% decrease in the median cumulative iron delivered.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no data with Triferic use in pregnant women to inform drug-associated risk. No teratogenicity was observed in animal reproduction studies with administration of ferric pyrophosphate citrate to pregnant rats and rabbits during organogenesis at doses 96 and 128 times, respectively, the maximum recommended human dose (MRHD) of 27.2 mg per dialysis [see Data]. 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.. Data. Animal 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 (IV) 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 IV 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.A 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.

SPL UNCLASSIFIED SECTION.

1.1 Limitation of Use. Triferic is not intended for use in patients receiving peritoneal dialysis.Triferic has not been studied in patients receiving home hemodialysis.

STORAGE AND HANDLING SECTION.

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 15to 30C (59 to 86F) [See USP Controlled Room Temperature]. Store packets at controlled room temperature (20 to 25C [68 to 77F]); excursions permitted to 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no data with Triferic use in pregnant women to inform drug-associated risk. No teratogenicity was observed in animal reproduction studies with administration of ferric pyrophosphate citrate to pregnant rats and rabbits during organogenesis at doses 96 and 128 times, respectively, the maximum recommended human dose (MRHD) of 27.2 mg per dialysis [see Data]. 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.. Data. Animal 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 (IV) 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 IV 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.A 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 is no information regarding the presence of Triferic in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Triferic and any potential adverse effects on the breastfed infant from Triferic or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. Triferic may cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception measures to prevent pregnancy during treatment with Triferic and for at least weeks following completion of therapy.. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.. 8.5 Geriatric Use. In controlled clinical trials, 99 (28.6%) patients >= 65 years of age were treated with Triferic. 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. 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) ]. Hypersensitivity reactions have been reported in (0.3%) of 292 patients receiving Triferic in two randomized clinical trials.. 5.2 Iron Laboratory Testing. Iron status should be determined on pre-dialysis blood samples. Post dialysis serum iron parameters may overestimate serum iron and transferrin saturation.