TRIFERIC- ferric pyrophosphate solution TRIFERIC- ferric pyrophosphate citrate powder

Triferic by

Drug Labeling and Warnings

Triferic by is a Prescription medication manufactured, distributed, or labeled by Rockwell Medical, Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 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).

    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.

  • 2 DOSAGE AND ADMINISTRATION

    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 2 micromolar (110 mcg/L).

    • Add one 5 mL ampule of Triferic solution to 2.5 gallons (9.46 liters) of bicarbonate concentrate. Multiple 5 mL ampules can be added to the master bicarbonate mix at each center at a ratio of one 5 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 a 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 a ratio of one packet for each 25 gallons (94.6 liters) of bicarbonate concentrate.

    Product comparison table with dilution instructions for the 5 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 Powder
    5 mL Ampule50 mL AmpulePacket
    Iron content per Ampule or Packet27.2 mg272 mg272 mg
    Number of Ampules or Packets to be added to each unit of bicarbonate concentrate111
    Per 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/L

    Administer 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.

  • 3 DOSAGE FORMS AND STRENGTHS

    Each 5 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).

  • 4 CONTRAINDICATIONS

    None

  • 5 WARNINGS AND PRECAUTIONS

    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 1 (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.

  • 6 ADVERSE REACTIONS

    The following adverse reactions are described below and elsewhere in the labeling:

    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 may not reflect the rates observed in practice.

    In two randomized, placebo-controlled clinical trials, a total of 292 patients were administered Triferic for periods of up to 1 year [ see Clinical Studies (14)]. The mean total exposure in the randomized treatment period was 5 months. A total of 296 patients received placebo treatment for a 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 Placebo
    System Organ Class
      Preferred Term     		Triferic
    N=292
    n (%)     		Placebo
    N=296
    n (%)
    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 Discontinuation

    In 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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    There are no data with Triferic use in pregnant women to inform a 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 Data

    In a 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 a 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 Summary

    There 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 mother's 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 2 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)].

  • 10 OVERDOSAGE

    No data are available regarding overdosage of Triferic in humans.

  • 11 DESCRIPTION

    Triferic (ferric pyrophosphate citrate) is a mixed-ligand iron complex in which iron (III) is bound to pyrophosphate and citrate. It has a molecular formula of Fe 4(C 6H 4O 7) 3(H 2P 2O 7) 2(P 2O 7) and a 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 5 mL filled into a 5 mL low density polyethylene ampule or 272 mg of iron (III) per 50 mL filled into a 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
  • 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 4 hours, or 15 mg and 20 mg Triferic intravenously over 12 hours. After correcting for the basal iron levels, the AUC and C max of baseline-corrected serum iron increased in a 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 L after a 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 a study that assessed the impact of different dialysis conditions on iron delivery in patients administered Triferic via hemodialysis, a reduction of the blood and dialysate flow rates (Qb/Qd of 200/400 mL/min vs. ≥ 350/ ≥ 600 mL/min) resulted in a 33% decrease in the median cumulative iron delivered.

  • 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 a 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.

  • 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 9 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 a change in anemia management, or if they completed 48 weeks. Triferic was added to the bicarbonate concentrate with a final concentration of 110 mcg iron/L in the dialysate and was administered 3 or 4 times per week during hemodialysis. Most patients were receiving a 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 2 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 2
    Triferic
    n=152     		Placebo
    n=153     		Triferic
    n=147     		Placebo
    n=147
  • * p < 0.05 for primary efficacy endpoint
    		•
    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) *    		-0.38
    (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)
  • 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 Ampule
    5 mL Ampule27.2 mg iron (III)/ 5mL as Triferic solution (5.44 mg of iron (III) per mL)
    NDC: 57278-314-015 Ampules per Pouch
    NDC: 57278-314-028 Pouches per Carton
    NDC: 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 Pouch
    NDC: 57278-316-036 Pouches per Carton
    NDC CodePackage DescriptionAmount/Packet
    NDC: 57278-315-01Packet272 mg iron (III)/ packet as Triferic powder
    NDC: 57278-315-02100 Packets per Carton

    16.2 Storage

    Store ampules protected from light in the aluminum pouch at controlled room temperature (20° to 25°C [68° to 77°F]); excursions permitted to 15°to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

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

  • 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)].
  • SPL UNCLASSIFIED SECTION

    Manufactured for: Rockwell Medical, Inc., Wixom, MI 48393

  • PRINCIPAL DISPLAY PANEL - 40 Ampule Carton

    NDC: 57278-314-01
    40 Ampules

    Rx Only

    TRIFERIC™
    ferric pyrophosphate citrate

    27.2 mg Fe/5 mL
    (5.44 mg Fe/mL)

    ROCKWELL
    MEDICAL

    Protect from light
    Keep ampules in pouch until time of use
    For dialysis use only
    Must be diluted

    PRINCIPAL DISPLAY PANEL - 40 Ampule Carton
  • PRINCIPAL DISPLAY PANEL - 100 Packet Carton

    NDC: 57278-315-02
    Rx only
    100 Packets

    TRIFERIC™
    ferric pyrophosphate citrate

    Powder
    Packet

    Must be diluted in 25 gallons (94.6 liters) of
    bicarbonate concentrate prior to use.

    Dialysis use only
    Do not freeze

    272 mg Fe
    PER PACKET

    PRINCIPAL DISPLAY PANEL - 100 Packet Carton
  • INGREDIENTS AND APPEARANCE
    TRIFERIC 
    ferric pyrophosphate solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 57278-314
    Route of AdministrationPARENTERAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    FERRIC PYROPHOSPHATE CITRATE (UNII: UBY79OCO9G) (FERRIC CATION - UNII:91O4LML611) FERRIC CATION5.44 mg  in 1 mL
    Product Characteristics
    Colorgreen (Greenish-yellow) Score    
    ShapeSize
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 57278-314-018 in 1 CARTON02/06/2015
    15 in 1 POUCH
    15 mL in 1 AMPULE; Type 0: Not a Combination Product
    2NDC: 57278-314-026 in 1 CARTON02/06/2015
    24 in 1 POUCH
    250 mL in 1 AMPULE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20631702/06/2015
    TRIFERIC 
    ferric pyrophosphate citrate powder
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 57278-315
    Route of AdministrationPARENTERAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    FERRIC PYROPHOSPHATE CITRATE (UNII: UBY79OCO9G) (FERRIC CATION - UNII:91O4LML611) FERRIC CATION272 mg
    Product Characteristics
    Colorgreen (Slightly yellow-green) Score    
    ShapeSize
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 57278-315-02100 in 1 CARTON04/25/2016
    11 in 1 PACKET; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20855104/25/2016
    Labeler - Rockwell Medical, Inc (933721433)

    • Trademark Results [Triferic]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    TRIFERIC
    TRIFERIC
    86036014 4837260 Live/Registered
    ROCKWELL MEDICAL, INC.
    2013-08-13
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