INDICATIONS
TRIFERIC IS INDICATED FOR THE REPLACEMENT OF IRON TO MAINTAIN HEMOGLOBIN IN ADULT PATIENTS WITH HEMODIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE (HDD-CKD).
LIMITATION OF USE
TRIFERIC IS NOT INTENDED FOR USE IN PATIENTS RECEIVING PERITONEAL DIALYSIS.
TRIFERIC HAS NOT BEEN STUDIED IN PATIENTS RECEIVING HOME HEMODIALYSIS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
EACH TRIFERIC AMPULE CONTAINS 27.2 MG IRON (III) PER 5 ML (5.44 MG OF IRON (III) PER ML).
STORAGE AND HANDLING
TRIFERIC IS AVAILABLE IN SINGLE USE AMPULES IN THE FOLLOWING PACKAGE SIZES:
NDC CODE AMOUNT/TOTAL VOLUME (PER AMPULE) AMPULES/POUCH
NDC XXXXX-YYY-01 27.2 MG IRON (III)/5ML (5.44 MG OF IRON (III) PER ML) 5 AMPULES/POUCH
STORAGE
STORE PROTECTED FROM LIGHT IN THE ALUMINUM POUCH AT CONTROLLED ROOM TEMPERATURE (20° TO 25°C [68° TO 77°F]; EXCURSIONS PERMITTED TO 15°-30°C (59° TO 86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
MANUFACTURED FOR: ROCKWELL MEDICAL, INC., WIXOM, MI 48393. REVISED: JUNE 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
INSPECT TRIFERIC AMPULES FOR SIGNS OF PRECIPITATION PRIOR TO MIXING WITH THE BICARBONATE CONCENTRATE. TRIFERIC AMPULES APPEAR SLIGHTLY YELLOW-GREEN IN COLOR.
TRIFERIC SHOULD ONLY BE ADDED TO THE BICARBONATE CONCENTRATE AND SHOULD NOT BE ADDED TO ACID CONCENTRATE MIXTURES.
ADD TRIFERIC TO BICARBONATE CONCENTRATE USED FOR GENERATION OF HEMODIALYSATE. THE FINAL CONCENTRATION OF TRIFERIC IRON (III) IN THE FINAL HEMODIALYSATE IS 2 MICROMOLAR (110 MCG/L). ADD ONE TRIFERIC AMPULE TO 2.5 GALLONS (9.46 L) OF BICARBONATE CONCENTRATE FOR PREPARATION OF THE HEMODIALYSATE WITH 2 MICROMOLAR (110 MCG/L) IRON (III) FINAL CONCENTRATION. MULTIPLE AMPULES CAN BE ADDED TO THE MASTER BICARBONATE MIX AT EACH CENTER AT A RATIO OF ONE (1) AMPULE TO EACH 2.5 GALLONS OF BICARBONATE CONCENTRATE.
ADMINISTER TRIFERIC TO PATIENTS AT EACH DIALYSIS PROCEDURE FOR AS LONG AS PATIENTS ARE RECEIVING MAINTENANCE HEMODIALYSIS THERAPY FOR CKD.
THE DOSAGE OF TRIFERIC® IS EXPRESSED AS MG OF IRON (III). EACH ML OF TRIFERIC CONTAINS 5.44 MG OF IRON AS IRON (III).
HEMODIALYSIS SOLUTIONS SHOULD BE USED WITHIN 24 HOURS OF THE PREPARATION OF THE TRIFERIC/BICARBONATE CONCENTRATE MIXTURE.
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" HYPERSENSITIVITY REACTIONS [SEE WARNINGS AND PRECAUTIONS].
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]. 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 REACTION 229 (78.4) 223 (75.3)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
PERIPHERAL EDEMA 20 (6.8) 11 (3.7)
PYREXIA 13 (4.5) 9 (3.0)
ASTHENIA 12 (4.1) 9 (3.0)
FATIGUE 11 (3.8) 6 (2.0)
INFECTIONS AND INFESTATIONS
URINARY TRACT INFECTION 13 (4.5) 4 (1.4)
INJURY, POISONING, AND PROCEDURAL COMPLICATIONS
PROCEDURAL HYPOTENSION 63 (21.6) 57 (19.3)
ARTERIOVENOUS FISTULA THROMBOSIS 10 (3.4) 6 (2.0)
ARTERIOVENOUS FISTULA SITE HEMORRHAGE 10 (3.4) 5 (1.7)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
MUSCLE SPASMS 28 (9.6) 24 (8.1)
PAIN IN EXTREMITY 20 (6.8) 17 (5.7)
BACK PAIN 13 (4.5) 10 (3.4)
NERVOUS SYSTEM DISORDERS
HEADACHE 27 (9.2) 16 (5.4)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
DYSPNEA 17 (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.
READ THE TRIFERIC (FERRIC PYROPHOSPHATE CITRATE SOLUTION, FOR ADDITION TO BICARBONATE CONCENTRATE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
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.
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 CMAX 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.
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 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 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 1 STUDY 2
TRIFERIC
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 PERIOD MEAN ± SD G/DL -0.03
(1.147)† -0.38 (1.240) -0.08
(1.152)† -0.44 (1157)
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 (1191) -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)
† P < 0.05 FOR PRIMARY EFFICACY ENDPOINT